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2.
Nat Med ; 28(5): 1031-1041, 2022 05.
Article in English | MEDLINE | ID: covidwho-1773989

ABSTRACT

Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237 ; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study's primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2-4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs present even in asymptomatic infection. All infected individuals developed serum spike-specific IgG and neutralizing antibodies. Results from lateral flow tests were strongly associated with viable virus, and modeling showed that twice-weekly rapid antigen tests could diagnose infection before 70-80% of viable virus had been generated. Thus, with detailed characterization and safety analysis of this first SARS-CoV-2 human challenge study in young adults, viral kinetics over the course of primary infection with SARS-CoV-2 were established, with implications for public health recommendations and strategies to affect SARS-CoV-2 transmission. Future studies will identify the immune factors associated with protection in those participants who did not develop infection or symptoms and define the effect of prior immunity and viral variation on clinical outcome.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Humans , Kinetics , Treatment Outcome , Viral Load , Young Adult
3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-320215

ABSTRACT

Background: Determine the impact of tobacco smoking status on patients hospitalized with COVID-19 pneumonia in the need for ICU care, mechanical ventilation and mortality. Methods: We performed a retrospective cohort study, that involved chart review. All adults 18 years or older with a diagnosis of COVID-19 pneumonia hospitalized from March 15 th , 2020 to May 06 th , 2020 with a positive reverse transcription polymerase chain reaction (RT-PCR) nasopharyngeal swab for COVID-19. We used chi-squared test for categorical variables and student t-tests or Wilcoxon rank sum tests for continuous variables. We further used adjusted and unadjusted logistic regression to assess risk factors for mortality and intubation. Results: Among 577 patients hospitalized with COVID-19 pneumonia, 268 (46.4%) had a history of smoking including 187 former and 81 active smokers. The former smokers when compared with non-smokers were predominantly older with more comorbidities. Also, when compared with never smokers D Dimer levels were elevated in active (p=0.05) and former smokers (p<0.01). The former smokers versus non-smokers required increased need for advanced non-invasive respiratory support on admission (p<0.05), ICU care (p<0.05) and had higher mortality [1.99 (CI 95% 1.03-3.85, p<0.05)]. Active smokers versus non-smokers received more mechanical ventilation [OR 2.11 (CI 95% 1.06-4.19, p<0.05)]. Conclusions: In our cohort of hospitalized patients with COVID-19 pneumonia, former smokers had higher need for non-invasive respiratory support on admission, ICU care, and mortality compared to non-smokers. Also, active smokers versus non-smokers needed more mechanical ventilation.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-311524

ABSTRACT

Background: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods: /Design: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. Discussion: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tociluzimab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial registrations: EudraCT Number: 2020-001860-27 14th March 2020 ClinicalTrials.gov Identifier: NCT04746183ISRCTN reference: 27106947

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-305538

ABSTRACT

Coronavirus − 19 (COVID-19) has rapidly spread throughout the world resulting in a significant amount of morbidity and mortality. Despite advances in therapy, social distancing, masks, and vaccination many places in the world continue to see an increase in the number of cases and deaths. Viremia is commonly present in severely ill patients with COVID-19 infections and is associated with organ dysfunction and poor outcomes. Exosomes released by activated cells have been implicated in the pathogenesis of COVID-19 infection. We report the experience of two cases of critically ill COVID-19 patients treated with the Hemopurifier;a lectin affinity cartridge designed to remove mannosylated viruses and exosomes. Both patients tolerated the Hemopurifier sessions without adverse effects. In the first patient removal of exosomes and exosomal microRNAs was associated with improved coagulopathy, oxygenation, and clinical recovery, while in a second patient removal of COVID-19 by the Hemopurifier cartridge was observed. The Hemopurifier is currently under further investigation in up to 40-patients in a safety and feasibility study in ICU patients with COVID-19 infection.

6.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328567

ABSTRACT

To establish a novel SARS-CoV-2 human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID 50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Two participants were excluded from per protocol analysis due to seroconversion between screening and inoculation. Eighteen (~53%) became infected, with viral load (VL) rising steeply and peaking at ~5 days post-inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log 10 copies/ml (median, 95% CI [8.41,9.53). Viable virus was recoverable from the nose up to ~10 days post-inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation. Anosmia/dysosmia developed more gradually in 12 (67%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection, followed by the development of serum spike-specific and neutralising antibodies. However, lateral flow results were strongly associated with viable virus and modelling showed that twice-weekly rapid tests could diagnose infection before 70-80% of viable virus had been generated. Thus, in this first SARS-CoV-2 human challenge study, no serious safety signals were detected and the detailed characteristics of early infection and their public health implications were shown. ClinicalTrials.gov identifier: NCT04865237.

7.
Front Med (Lausanne) ; 8: 744141, 2021.
Article in English | MEDLINE | ID: covidwho-1485068

ABSTRACT

Coronavirus-19 (COVID-19) has rapidly spread throughout the world resulting in a significant amount of morbidity and mortality. Despite advances in therapy, social distancing, masks, and vaccination many places in the world continue to see an increase in the number of cases and deaths. Viremia is commonly present in severely ill patients with COVID-19 infections and is associated with organ dysfunction and poor outcomes. Exosomes released by activated cells have been implicated in the pathogenesis of COVID-19 infection. We report the experience of two cases of critically ill COVID-19 patients treated with the Hemopurifier; a lectin affinity cartridge designed to remove mannosylated viruses and exosomes. Both patients tolerated the Hemopurifier sessions without adverse effects. In the first patient removal of exosomes and exosomal microRNAs was associated with improved coagulopathy, oxygenation, and clinical recovery, while in a second patient removal of COVID-19 by the Hemopurifier cartridge was observed. The Hemopurifier is currently under further investigation in up to 40-patients in a safety and feasibility study in ICU patients with COVID-19 infection.

8.
Clin Pharmacol Ther ; 111(3): 585-594, 2022 03.
Article in English | MEDLINE | ID: covidwho-1482119

ABSTRACT

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , Nitro Compounds/administration & dosage , Nitro Compounds/adverse effects , Nitro Compounds/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Drug Repositioning , Female , Healthy Volunteers , Humans , Male , Middle Aged , Young Adult
9.
J Antimicrob Chemother ; 76(12): 3286-3295, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1376308

ABSTRACT

OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Bayes Theorem , Humans , Research Design , Treatment Outcome
10.
Trials ; 22(1): 487, 2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1327946

ABSTRACT

BACKGROUND: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. METHODS/DESIGN: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. DISCUSSION: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. TRIAL REGISTRATION: EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183  19 February 2021 ISRCTN reference: 27106947.


Subject(s)
COVID-19 , Pandemics , Cohort Studies , Humans , SARS-CoV-2 , Treatment Outcome
11.
Eur Heart J ; 42(19): 1866-1878, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1087735

ABSTRACT

BACKGROUND: Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients. METHODS AND RESULTS: One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms). CONCLUSIONS: During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.


Subject(s)
COVID-19 , Myocarditis , Contrast Media , Female , Gadolinium , Humans , Magnetic Resonance Imaging, Cine , Magnetic Resonance Spectroscopy , Male , Myocarditis/diagnostic imaging , Myocardium , Predictive Value of Tests , SARS-CoV-2 , Troponin , Ventricular Function, Left
12.
Rev Cardiovasc Med ; 21(4): 517-530, 2020 12 30.
Article in English | MEDLINE | ID: covidwho-1005377

ABSTRACT

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.


Subject(s)
COVID-19/drug therapy , Leprostatic Agents/therapeutic use , Pandemics , SARS-CoV-2 , Telemedicine/methods , COVID-19/epidemiology , Drug Therapy, Combination , Humans
13.
J Card Surg ; 36(5): 1683-1692, 2021 May.
Article in English | MEDLINE | ID: covidwho-838066

ABSTRACT

BACKGROUND: To share the results of a web-based expert panel discussion focusing on the management of acute and chronic aortic disease during the coronavirus (COVID-19) pandemic. METHODS: A web-based expert panel discussion on April 18, 2020, where eight experts were invited to share their experience with COVID-19 disease touching several aspects of aortic medicine. After each talk, specific questions were asked by the online audience, and results were immediately evaluated and shared with faculty and participants. RESULTS: As of April 18, 73.3% answered that more than 200 patients have been treated at their respective settings. Sixty-four percent were reported that their hospital was well prepared for the pandemic. In 57.7%, the percentage of infected healthcare professionals was below 5% whereas 19.2% reported the percentage to be between 10% and 20%. Sixty-seven percent reported the application of extracorporeal membrane oxygenation in less than 2% of COVID-19 patients whereas 11.8% reported application in 5%-10% of COVID-19 patients. Thirty percent of participants reported the occurrence of pulmonary embolism in COVID-19 patients. Three percent reported to have seen aortic ruptures in primarily elective patients having been postponed because of the anticipated need to provide sufficient ICU capacity because of the pandemic. Nearly 70% reported a decrease in acute aortic syndrome referrals since the start of the pandemic. CONCLUSION: The current COVID-19 pandemic has-besides the stoppage of elective referrals-also led to a decrease of referrals of acute aortic syndromes in many settings. The reluctance of patients seeking medical help seems to be a major driver. The number of patients, who have been postponed due to the provisioning of ICU resources but having experienced aortic rupture in the waiting period, is still low. Further, studies are needed to learn more about the influence that the COVID-19 pandemic has on the treatment of patients with acute and chronic aortic disease.


Subject(s)
Aortic Diseases , COVID-19 , Aortic Diseases/epidemiology , Humans , Internet , Pandemics , SARS-CoV-2
14.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-1387

ABSTRACT

Background: Hospitalised COVID-19 patients frequently have acute myocardial injury with elevated troponin levels. Underlying aetiologies are ill-defined. We use

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