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1.
Int. j. artif. organs ; 45(1): 3-4, Jan. 2022.
Artigo em Inglês | Sec. Est. Saúde SP, CONASS, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1147026

RESUMO

It is established that coronaviruses are transmitted most through aerosols produced when an infected individual coughs or sneezes.1 Although there is no clear evidence of person-to-person airborne transmission, it is possible that part of this component could be due to microscopic respiratory droplets at short to medium distances (up to several meters, or room scale) and deposits from respiratory droplets on surfaces.2,3 However, recent studies revealed that infected patients can potentially be a source of the virus not only through respiratory but also fecal­oral or body fluid routes, raising also the theoretical possibility of bloodborne transmission.4 Based on these arguments, the possibility has also been raised of some equipment that could be a new source of transmission, like the membranes used for extracorporeal oxygenation, which act the same as lungs and also have a direct contact with the blood. Most centers worldwide report a reduction in the cardiac procedures due to the pandemic, however emergency surgeries with conventional cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) procedures have been performed every day. Despite guidelines and modifications for operating theatre preparation for the management of suspected or confirmed SARS-CoV-2 patients submitted to cardiac surgery, many aspects still need to be clarified.5 Potential risk of transmission with these membranes exists, so much that Dres et al.6 reported a study evaluating the risks of SARS-CoV-2 dissemination through membranes used for extra corporeal organ support in critically ill patients, within 48 h after ECMO and continuous renal replacement therapy (CRRT) initiation. They investigated whether SARS-CoV-2 RNA was detected in the dialysis effluent fluid or in the condensate collected from the ECMO membrane gas outlet, when the virus was present in the lower respiratory tract and the plasma. Results showed that in 25 patients on veno-venous ECMO, SARSCoV-2 RNA was not detected in the membrane oxygenator gas outlet condensate in any of 25 patients of whom 13 were plasma RNA positive. Also, they were not able to measure any SARS-CoV-2 RNA in the dialysate of those patients who additionally were treated by CRRT.


Assuntos
Oxigenadores de Membrana , Coronavirus , Aerossóis , Membranas
2.
Bridgetown; PAHO; 2022-01-07.
em Inglês | PAHO-IRIS | ID: phr2-55591

RESUMO

SITUATION IN NUMBERS: Region of the Americas 108,806,129 cases; 2,422,138 deaths in 56 countries, areas, or territories; 1,482,883,046 total vaccine doses administered. | Global 296,496,809 cases; 5,462,631 deaths in 236 countries, areas, or territories; 9,118,223,397 total vaccine doses administered.


Assuntos
COVID-19 , Coronavirus , Infecções por Coronavirus , Betacoronavirus , Análise de Situação , Imunização , Vacinas , Emergências , América , Região do Caribe
3.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-474713

RESUMO

Thailand was the first country outside China to officially report COVID-19 cases. Despite the strict regulations for international arrivals, up until February 2021, Thailand had been hit by two major outbreaks. With a large number of SARS-CoV-2 sequences collected from patients, the effects of many genetic variations, especially those unique to Thai strains, are yet to be elucidated. In this study, we analysed 439,197 sequences of the SARS-CoV-2 spike protein collected from NCBI and GISAID databases. 595 sequences were from Thailand and contained 52 variants, of which 6 had not been observed outside Thailand (p.T51N, p.P57T, p.I68R, p.S205T, p.K278T, p.G832C). These variants were not predicted to be of concern. We demonstrate that the p.D614G, although already present during the first Thai outbreak, became the prevalent strain during the second outbreak, similarly to what was described in other countries. Moreover, we show that the most common variants detected in Thailand (p.A829T, p.S459F and p.S939F) do not appear to cause any major structural change to the spike trimer or the spike-ACE2 interaction. Among the variants identified in Thailand was p.N501T. This variant, which involves an asparagine critical for spike-ACE2 binding, was not predicted to increase SARS-CoV-2 binding, thus in contrast to the variant of global concern p.N501Y. In conclusion, novel variants identified in Thailand are unlikely to increase the fitness of SARS-CoV-2. The insights obtained from this study could aid SARS-CoV-2 variants prioritisations and help molecular biologists and virologists working on strain surveillance.

4.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-473343

RESUMO

The emergence and evolution of SARS-CoV-2 is characterized by the occurrence of diverse sets of mutations that affect virus characteristics, including transmissibility and antigenicity. Recent studies have focused mostly on Spike protein mutations; however, SARS-CoV-2 variants of interest (VoI) or concern (VoC) contain significant mutations in the nucleocapsid protein as well. To study the relevance of the mutations at the virion level, recombinant baculovirus expression system based VLPs were generated for the prototype Wuhan sequence along with Spike mutants like D614G, G1124V and the significant RG203KR mutation in Nucleocapsid. All the four structural proteins assembled in a particle wherein the morphology and size of the particle confirmed by TEM closely resembles the native virion. The VLP harbouring RG203KR mutations in nucleocapsid exhibited augmentation of humoral immune responses and enhanced neutralization by the immunized mice sera. Results demonstrate a non-infectious platform to quickly assess the implication of mutations in structural proteins of the emerging variant.

5.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-474639

RESUMO

The emergence and rapid spread of the Omicron variant of SARS-CoV-2, which has more than 30 substitutions in the spike glycoprotein, compromises the efficacy of currently available vaccines and therapeutic antibodies. Using a clinical strain of the Omicron variant, we analyzed the neutralizing power of eight currently used monoclonal antibodies compared to the ancestral B.1 BavPat1 D614G strain. We observed that six of these antibodies have lost their ability to neutralize the Omicron variant. Of the antibodies still having neutralizing activity, Sotrovimab/Vir-7831 shows the smallest reduction in activity, with a factor change of 3.1. Cilgavimab/AZD1061 alone shows a reduction in efficacy of 15.8, resulting in a significant loss of activity for the Evusheld cocktail (42.6 fold reduction) in which the other antibody, Tixagevimab, does not retain significant activity against Omicron. Our results suggest that the clinical efficacy of the initially proposed doses should be rapidly evaluated and the possible need to modify doses or propose combination therapies should be considered.

6.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-474593

RESUMO

Novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose an imminent global threat since its initial outbreak in December 2019. A simple in vitro model system using cell lines highly susceptible to SARS-CoV-2 infection are critical to facilitate the study of the virus cycle and to discover effective antivirals against the virus. Human lung alveolar A549 cells are regarded as a useful and valuable model for respiratory virus infection. However, SARS-CoV-2 uses the ACE2 as receptor for viral entry and the TMPRSS2 to prime the Spike protein, both of which are negligibly expressed in A549 cells. Here, we report the generation of a robust human lung epithelial cell-based model by transducing ACE2 and TMPRSS2 into A549 cells and show that the ACE2 enriched A549ACE2/TMPRSS2 cells (ACE2plus) and its single-cell-derived subclone (ACE2plusC3) are highly susceptible to SARS-CoV-2 infection. These engineered ACE2plus showed higher ACE2 and TMPRSS2 mRNA expression levels than currently used Calu3 and commercial A549ACE2/TMPRSS2 cells. ACE2 and TMPRSS2 proteins were also highly and ubiquitously expressed in ACE2plusC3 cells. Additionally, antiviral drugs like Camostat mesylate, EIDD-1931, and Remdesivir strongly inhibited SARS-CoV-2 replication. Notably, multinucleated syncytia, a clinical feature commonly observed in severe COVID-19 patients was induced in ACE2plusC3 cells either by virus infection or by overexpressing the Spike proteins of different variants of SARS-CoV-2. Syncytial process was effectively blocked by the furin protease inhibitor, Decanoyl-RVKR-CMK. Taken together, we have developed a robust human A549 lung epithelial cell-based model that can be applied to probe SARS-CoV-2 replication and to facilitate the discovery of SARS-CoV-2 inhibitors.

7.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-475918

RESUMO

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoM{phi}). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

8.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21268582

RESUMO

Large-scale vaccination campaigns have prevented countless SARS-CoV-2 infections, hospitalizations and deaths. However, the emergence of variants that escape from immunity challenges the effectiveness of current vaccines. Given this continuing evolution, an important question is when and how to update SARS-CoV-2 vaccines to antigenically match circulating variants, similar to seasonal influenza viruses where antigenic drift necessitates periodic vaccine updates. Here, we studied SARS-CoV-2 antigenic drift by assessing neutralizing activity against variants-of-concern (VOCs) of a unique set of sera from patients infected with a range of VOCs. Infections with ancestral or Alpha strains induced the broadest immunity, while individuals infected with other VOCs had more strain-specific responses. Omicron was substantially resistant to neutralization by sera elicited by all other variants. Antigenic cartography revealed that all VOCs preceding Omicron belong to one antigenic cluster, while Omicron forms a new antigenic cluster associated with immune escape and likely requiring vaccine updates to ensure vaccine effectiveness.

9.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22268675

RESUMO

BackgroundOne of the proposed interventions for mitigating COVID-19 epidemics, particularly in low-income and crisis-affected settings, is to physically isolate individuals known to be at high risk of severe disease and death due to age or co-morbidities. This intervention, known as shielding, could be implemented in various ways. If shielded people are grouped together in residences and isolation is imperfect, any introduction of infections within the shielding group could cause substantial mortality and thus negate the interventions benefits. We explored the effectiveness of shielding under various modalities of implementation and considered mitigation measures to reduce its possible harms. MethodsWe used an individual-based mathematical model to simulate the evolution of a COVID-19 epidemic in a population of which a fraction above a given age cut-off are relocated to shielding residences, in which they have variable levels of contacts with their original household, the outside world and fellow shielding residents. We set our simulation with the context of an internally displaced persons camp in Somaliland, for which we had recently collected data on household demographics and social mixing patterns. We compared an unmitigated epidemic with a shielding intervention accompanied by various measures to reduce the risk of virus introduction and spread within the shielding residences. We did sensitivity analyses to explore parameters such as residence size, reduction in contacts, basic reproduction number, and prior immunity in the population. ResultsShielded residences are likely to be breached with infection during the outbreak. Nonetheless, shielding can be effective in preventing COVID-19 infections in the shielded population. The effectiveness of shielding is mostly affected by the size of the shielded residence, and by the degree by which contacts between shielded and unshielded individuals are reduced. Reductions in contacts between shielded individuals could further increase the effectiveness of shielding, but is only effective in larger shielded residences. Large shielded residences increase the risk of infection, unless very large reductions in contacts can be achieved. In epidemics with a lower reproduction number, the effectiveness of shielding could be negative effectiveness. DiscussionShielding could be an effective method to protect the most at-risk individuals. It should be considered where other measures cannot easily be implemented, but with attention to the epidemiological situation. Shielding should only be implemented through small to medium-sized shielding residences, with appropriate mitigation measures such as reduced contact intensity between shielded individuals and self-isolation of cases to prevent subsequent spread.

10.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21267090

RESUMO

The English SARS-CoV-2 epidemic has been affected by the emergence of new viral variants such as B.1.177, Alpha and Delta, and changing restrictions. We used statistical models and calibration of an stochastic agent-based model Covasim to estimate B.1.177 to be 20% more transmissible than the wild type, Alpha to be 50-80% more transmissible than B.1.177 and Delta to be 65-90% more transmissible than Alpha. We used these estimates in Covasim (calibrated between September 01, 2020 and June 20, 2021), in June 2021, to explore whether planned relaxation of restrictions should proceed or be delayed. We found that due to the high transmissibility of Delta, resurgence in infections driven by the Delta variant would not be prevented, but would be strongly reduced by delaying the relaxation of restrictions by one month and with continued vaccination.

11.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22268641

RESUMO

As COVID-19 continues to pose major risk for vulnerable populations including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced inhibition of pseudovirus infection by GLPG-0187. Because integrins activate TGF-{beta} signaling, we compared plasma levels of active and total TGF-{beta} in COVID-19+ patients. Plasma TGF-{beta}1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-{beta}1 levels correlated with activated TGF-{beta}1 levels. In our preclinical studies, Omicron infects lower airway lung cells less efficiently than other COVID-19 variants. Moreover, inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and may mitigate COVID-19 severity through decreased TGF-{beta}1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.

12.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22268609

RESUMO

BackgroundAndrographis paniculata (AP) crude extract has been widely used in Thailand to treat mild COVID-19 infection since early 2020; however, supporting evidence was lacking. PurposeTo evaluate the efficacy of AP compared with standard treatment among hospitalised mild COVID-19 patients. Study designSingle-centre retrospective cohort study MethodsWe collected data between March 2020 and August 2021 from COVID-19 patients admitted to one hospital in Thailand. Patients whose infection was confirmed by Real-Time Polymerase Chain Reaction (RT-PCR) and had normal chest radiography were included, whereas those receiving favipiravir or had unclear chest X-rays at admission were excluded. Participants were categorised as either AP or standard of care and followed for pneumonia confirmed by chest radiography. Multiple logistic regression was used to analyse the main results controlling for age, sex, history of having diabetes, hypertension, receiving statins, and antihypertensive drugs. Results605 out of 1,054 patients were included in the analysis. Of these, 59 patients (9.8%) developed pneumonia during the median follow-up of 7 days. The incidence rates of pneumonia were 13.93 (95%CI 10.09, 19.23) and 12.47 (95%CI 8.21, 18.94) per 1,000 person-days in AP and standard of care group, respectively. Compared to the standard of care group, the odds ratios of having pneumonia in the AP group were 1.24 (95%CI 0.71, 2.16; unadjusted model) and 1.42 (95%CI 0.79, 2.55; fully adjusted model). All sensitivity analyses produced consistent findings with the main results. ConclusionWe do not have sufficient evidence to show the efficacy of AP in mild COVID-19 infection. Interestingly, we observed the potentially harmful signal of using AP. While waiting for insights from ongoing trials, APs use in this condition should be done with caution. Key pointsO_ST_ABSWhat is already known about this subject?C_ST_ABS- Andrographis paniculata (AP) has been used to treat COVID-19 in Thailand since early 2020. - Clinical evidence supporting the use of AP in COVID-19 infections is still lacking. What does this study add?- We had insufficient evidence to show the efficacy of using AP in mild COVID-19 cases. - AP might be potentially associated with an increased risk of pneumonia. How might this impact clinical practice?- While waiting for the ongoing trials, using AP in COVID-19 should be suspended.

13.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21268495

RESUMO

BackgroundThe Omicron SARS-CoV-2 variant is rapidly spreading in the US since December 2021 and is more contagious than earlier variants. Currently, data on the severity of the disease caused by the Omicron variant compared with the Delta variant is limited. Here we compared 3-day risks of emergency department (ED) visit, hospitalization, intensive care unit (ICU) admission, and mechanical ventilation in patients who were first infected during a time period when the Omicron variant was emerging to those in patients who were first infected when the Delta variant was predominant. MethodThis is a retrospective cohort study of electronic health record (EHR) data of 577,938 first-time SARS-CoV-2 infected patients from a multicenter, nationwide database in the US during 9/1/2021-12/24/2021, including 14,054 who had their first infection during the 12/15/2021-12/24/2021 period when the Omicron variant emerged ("Emergent Omicron cohort") and 563,884 who had their first infection during the 9/1/2021-12/15/2021 period when the Delta variant was predominant ("Delta cohort"). After propensity-score matching the cohorts, the 3-day risks of four outcomes (ED visit, hospitalization, ICU admission, and mechanical ventilation) were compared. Risk ratios, and 95% confidence intervals (CI) were calculated. ResultsOf 14,054 patients in the Emergent Omicron cohort (average age, 36.4 {+/-} 24.3 years), 27.7% were pediatric patients (<18 years old), 55.4% female, 1.8% Asian, 17.1% Black, 4.8% Hispanic, and 57.3% White. The Emergent Omicron cohort differed significantly from the Delta cohort in demographics, comorbidities, and socio-economic determinants of health. After propensity-score matching for demographics, socio-economic determinants of health, comorbidities, medications and vaccination status, the 3-day risks in the Emergent Omicron cohort outcomes were consistently less than half those in the Delta cohort: ED visit: 4.55% vs. 15.22% (risk ratio or RR: 0.30, 95% CI: 0.28-0.33); hospitalization: 1.75% vs. 3.95% (RR: 0.44, 95% CI: 0.38-0.52]); ICU admission: 0.26% vs. 0.78% (RR: 0.33, 95% CI:0.23-0.48); mechanical ventilation: 0.07% vs. 0.43% (RR: 0.16, 95% CI: 0.08-0.32). In children under 5 years old, the overall risks of ED visits and hospitalization in the Emergent Omicron cohort were 3.89% and 0.96% respectively, significantly lower than 21.01% and 2.65% in the matched Delta cohort (RR for ED visit: 0.19, 95% CI: 0.14-0.25; RR for hospitalization: 0.36, 95% CI: 0.19-0.68). Similar trends were observed for other pediatric age groups (5-11, 12-17 years), adults (18-64 years) and older adults ([≥] 65 years). ConclusionsFirst time SARS-CoV-2 infections occurring at a time when the Omicron variant was rapidly spreading were associated with significantly less severe outcomes than first-time infections when the Delta variant predominated.

14.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22268621

RESUMO

Rapid Antigen Diagnostic Tests (RADTs) for the detection of SARS-CoV-2 offer advantages in that they are cheaper and faster than currently used PCR tests but have reduced sensitivity and specificity. One potential application of RADTs is to facilitate gatherings of individuals, through testing of attendees at the point of, or immediately prior to entry at a venue. Understanding the baseline risk in the tested population is of particular importance when evaluating the utility of applying diagnostic tests for screening purposes. We used incidence data to estimate the prevalence of infectious individuals in the community at a particular time point and simulated mass gatherings by sampling from a series of age cohorts. Nine different illustrative scenarios were simulated, small (n=100), medium (n=1000) and large (n=10,000) gatherings each with 3 possible age constructs: mostly younger, mostly older or a gathering with equal numbers from each age cohort. For each scenario, we estimated the prevalence of infectious attendees, then simulated the likely number of positive and negative test results, the proportion of cases detected and the corresponding positive and negative predictive values, and the cost per case identified. Our findings suggest that for each detected individual on a given day, there are likely to be 13.8 additional infectious individuals also present in the community. Prevalence of infectious individuals at events was highest with mostly younger attendees (1.00%), followed by homogenous age gatherings (0.55%) and lowest with mostly older events (0.26%). For small events (100 attendees) the expected number of infectious attendees was less than 1 across all age constructs of attendees. For large events (10,000 attendees) the expected number of infectious attendees ranged from 26 (95% confidence intervals 12 to 45) for mostly older events, to almost 100 (95% confidence intervals 46 to 174) infectious attendees for mostly younger attendees. Given rapid changes in SARS-CoV-2 incidence over time, we developed an RShiny app to allow users to run updated simulations for specific events.

15.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21268558

RESUMO

ObjectiveThe clinical utility of point-of-care lung ultrasound (LUS) for disease severity triage of hospitalized patients with COVID-19 is unclear. DesignProspective cohort study SettingA large tertiary care center in Maryland, USA between April 2020 to September 2021. PatientsHospitalized adults ([≥]18 years of age) with positive SARS-CoV-2 RT-PCR results. InterventionsNone. Measurements and Main ResultsAll patients were scanned using a standardized protocol including 12 lung zones and followed to determine clinical outcomes until hospital discharge and vital status at 28-days. Ultrasounds were independently reviewed for lung and pleural line artifacts and abnormalities, and the mean Lung Ultrasound Score (ranging from 0 to 3) across lung zones (mLUSS) was determined. The primary outcome was time to ICU-level care, defined as high flow oxygen, noninvasive, or mechanical ventilation, within 28-days of the initial ultrasound. Cox proportional hazards regression models adjusted for age and sex were fit for mLUSS and each ultrasound covariate. A total of 264 participants were enrolled in the study; the median age was 59 years and 114 (43.2) % of participants were female. The median mLUSS was 1 (interquartile range: 0.5 to 1.3). Following enrollment, 29 (11.0%) participants went on to require ICU-level care and 14 (5.3%) subsequently died by 28 days. Each increase in mLUSS at enrollment was associated with disease progression to ICU-level care (aHR = 3.63; 95% CI: 1.23 to 10.65) and 28-day mortality (aHR = 4.50; 95% CI: 1.52 to 13.31). Pleural line abnormalities were independently associated with disease progression to ICU-level care (aHR = 18.86; CI: 1.57 to 226.09). ConclusionsParticipants with a mLUSS [≥]1 or pleural line changes on LUS had an increased likelihood of subsequent requirement of high flow oxygen or greater. LUS is a promising tool for assessing risk of COVID-19 progression at the bedside.

16.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21267140

RESUMO

ObjectiveThe LIVE-AIR trial demonstrated that the anti-GM-CSF monoclonal antibody, lenzilumab improved the likelihood of survival without invasive mechanical ventilation (SWOV) in COVID-19 patients; with greatest effect in those with baseline CRP below the median baseline value of 79 mg/L. Similar to GM-CSF, C-reactive protein (CRP) levels are correlated with COVID-19 severity. This current analysis assessed the utility of baseline CRP levels to guide treatment with lenzilumab. DesignLIVE-AIR was a phase 3, double-blind, placebo-controlled trial. Participants were randomized 1:1 and stratified according to age and disease severity, to receive lenzilumab or placebo on Day 0, were followed through Day 28. SettingSecondary and tertiary care hospitals in the US and Brazil. Participants520 hospitalized COVID-19 participants with SpO2[≤] 94% on room air or required supplemental oxygen but not invasive mechanical ventilation were included. InterventionsLenzilumab (1800mg; divided as 3 doses, q8h) or placebo infusion alongside standard treatments including corticosteroids and remdesivir. Main outcome measuresA multi-variate logistic regression analysis assessed key baseline risk factors for progression to IMV or death. The primary endpoint, SWOV, and key secondary endpoints were analyzed according to baseline CRP levels in all participants with CRP values. ResultsThe multi-variate analysis demonstrated that elevated baseline plasma CRP was the most predictive feature for progression to IMV or death. SWOV was achieved in 152 (90%; 95%CI: 85to 94) lenzilumab and 183 (79%; 72 to 84) placebo participants with baseline CRP<150 mg/L and its likelihood was greater with lenzilumab than placebo (HR: 2.54; 95%CI, 1.46 to 4.41; p=0.0009) but not in participants with CRP[≥]150 mg/L at baseline. CRP as a covariate in the overall analysis demonstrated a statistically significant interaction with lenzilumab treatment (p=0.044). Grade [≥] 3 adverse events in participants with baseline CRP<150 mg/L were reported in 18% and 28% in lenzilumab or placebo, respectively. No treatment-emergent serious adverse events were attributable to lenzilumab. ConclusionThese finding suggest that COVID-19 participants with low baseline CRP levels achieve the greatest clinical benefit from lenzilumab and that baseline CRP levels may be a useful biomarker to guide therapeutic intervention. Trial RegistrationClinicalTrials.gov NCT04351152 WHAT IS ALREADY KNOWN ON THIS TOPICGM-CSF is one of the early upstream mediators and orchestrators of the hyperinflammatory immune response following SARS-CoV-2 infection. Baseline levels of GM-CSF and CRP have each been shown to correlate with COVID-19 disease progression. Increases in CRP are driven by elevations of IL-6 during the hyperinflammatory response following SARS-CoV-2 infection. In the phase 3, randomized, double-blind, placebo-controlled LIVE-AIR study, GM-CSF neutralization with lenzilumab significantly improved the likelihood of survival without invasive mechanical ventilation (SWOV, primary endpoint, also referred to as ventilator-free survival) vs. placebo (HR:1.54; 95% CI, 1.02 to 2.32; p=0.0403), which included standard supportive care including corticosteroids and remdesivir. No treatment-emergent serious adverse events attributable to lenzilumab have been reported to date. WHAT THIS STUDY ADDSA comprehensive analysis of LIVE -AIR CRP data provides evidence for the utility of baseline CRP to predict progression to IMV and death. Baseline CRP was identified to be the strongest predictor of SWOV in this study. Patients with baseline CRP<150 mg/L represented 78% of the study population and demonstrated the greatest clinical benefit with lenzilumab, including SWOV through day 28 (HR: 2.54; 95%CI; 1.46-4.41; nominal p=0.0009). A biomarker-driven approach using baseline CRP levels to guide therapeutic intervention may improve outcomes in those hospitalized with COVID-19. Participants with baseline CRP levels above 150 mg/L were described as experiencing COVID-19-associated hyperinflammation and were at risk of imminent escalation of respiratory support or death. Elevated baseline plasma CRP was the most predictive feature for progression to IMV or death (OR, 0.15; 95%CI, 0.07-0.29; nominal p<0.001). These findings suggest that baseline CRP may be a useful biomarker in determining which participants may be most successfully treated with lenzilumab.

17.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21266217

RESUMO

AimTo determine association between diabetes in confirmed cases of COVID-19 and intensive care admission and in-hospital mortality, evaluate several laboratory parameters as mortality predictor, and develop predictors of in-hospital mortality among diabetics with COVID-19. MethodsThis retrospective cohort recruited all cases of COVID-19 hospitalized in Fatmawati General Hospital during March to October 2020. Inclusion criteria was RT-PCR confirmed cases of COVID-19 who aged 18 years and older while exclusion criteria were incomplete medical record or cannot be found and pregnant women. ResultsWe enrolled 506 participants to this study with median age of 51 years (IQR:22), female (56.32%), and diabetes (28.46%). Diabetes increased intensive care admission (adjusted OR:6.07;95%CI:3.52-10,43) and in-hospital mortality (adjusted OR:50;95%CI:1.61-3.89). In predicting in-hospital mortality, ferritin and lactate dehydrogenase offered an acceptable discrimination, AUC:0.71 (95%CI: 0.62-0.79) and AUC:0.70 (95%CI: 0.61-0.78), respectively. The optimal cut-off of predicting mortality for ferritin was 786 g/mL and for LDH was 514.94 u/L. Factors include age above 70 years old, RBGs level on admission above 250 mg/dL or below 140 mg/dL, ferritin level above 786 ng/mL, and presence of ARDS increased the odds of mortality among individuals with diabetes. ConclusionsDiabetes increases risk of intensive care admission and in hospital mortality in COVID-19. Multivariate analysis showed that older age, RBG on admission, high ferritin level, presence of ARDS increased the odds of mortality among individuals with diabetes.

18.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21268453

RESUMO

As demonstrated during the SARS-CoV-2 pandemic, detecting and tracking the emergence and spread of pathogen variants is an important component of monitoring infectious disease outbreaks. Pathogen genome sequencing has emerged as the primary tool for variant characterization, so it is important to consider the number of sequences needed when designing surveillance programs or studies, both to ensure accurate conclusions and to optimize use of limited resources. However, current approaches to calculating sample size for variant monitoring often do not account for the biological and logistical processes that can bias which infections are detected and which samples are ultimately selected for sequencing. In this manuscript, we introduce a framework that models the full process from infection detection to variant characterization and demonstrate how to use this framework to calculate appropriate sample sizes for sequencing-based surveillance studies. We consider both cross-sectional and continuous sampling, and we have implemented our method in a publicly available tool that allows users to estimate necessary sample sizes given a specific aim (e.g., variant detection or measuring variant prevalence) and sampling method. Our framework is designed to be easy to use, while also flexible enough to be adapted to other pathogens and surveillance scenarios.

19.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21268516

RESUMO

The ongoing COVID-19 pandemic has produced substantial impacts on our society. Wastewater surveillance has increasingly been introduced to support the monitoring, and thus mitigation, of COVID-19 outbreaks and transmission. Monitoring of buildings and sub-sewershed areas via a wastewater surveillance approach has been a cost-effective strategy for mass testing of residents in congregate living situations such as universities. A series of spatial and spatiotemporal data are involved with wastewater surveillance, and these data must be interpreted and integrated with other information to better serve as guidance on response to a positive wastewater signal. The management and analysis of these data poses a significant challenge, in particular, for the need of supporting timely decision making. In this study, we present a web-based spatial decision support system framework to address this challenge. Our study area is the main campus of the University of North Carolina at Charlotte. We develop a spatiotemporal data model that facilitates the management of space-time data related to wastewater surveillance. We use spatiotemporal analysis and modeling to discover spatio-temporal patterns of COVID-19 virus abundance at wastewater collection sites that may not be readily apparent in wastewater data as they are routinely collected. Web-based GIS dashboards are implemented to support the automatic update and sharing of wastewater testing results. Our web-based SDSS framework enables the efficient and automated management, analytics, and sharing of spatiotemporal data of wastewater testing results for our study area. This framework provides substantial support for informing critical decisions or guidelines for the prevention of COVID-19 outbreak and the mitigation of virus transmission on campus.

20.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-21268526

RESUMO

BackgroundAfter COVID-19 vaccines received approval, vaccination campaigns were launched worldwide. Initially, these were characterized by a shortage of vaccine supply, and specific risk groups were prioritized. Once supply was guaranteed and vaccination coverage saturated, the focus shifted from risk groups to anti-vaxxers, the underaged population, and regions of low coverage. At the same time, hopes to reach herd immunity by vaccination campaigns were put into perspective by the emergence and spread of more contagious and aggressive viral variants. Particularly, concerns were raised that not all vaccines protect against the new-emerging variants. Methods and findingsA model designed to predict the effect of vaccination campaigns on the spread of viral variants is introduced. The model is a comprehensive extension of the model underlying the pandemic preparedness tool CovidSim 2.0 (http://covidsim.eu/). The model is age and spatially stratified, incorporates a finite (but arbitrary) number of different viral variants, and incorporates different vaccine products. The vaccines are allowed to differ in their vaccination schedule, vaccination rates, the onset of vaccination campaigns, and their effectiveness. These factors are also age and/or location dependent. Moreover, the effectiveness and the immunizing effect of vaccines are assumed to depend on the interaction of a given vaccine and viral variant. Importantly, vaccines are not assumed to immunize perfectly. Individuals can be immunized completely, only partially, or fail to be immunized against one or many viral variants. Not all individuals in the population are vaccinable. The model is formulated as a high-dimensional system of differential equations, which is implemented efficiently in the programming language Julia. As an example, the model was parameterized to reflect the epidemic situation in Germany until November 2021 and predicted the future dynamics of the epidemic under different interventions. In particular, without tightening contact reductions, a strong epidemic wave is predicted. At the current state, mandatory vaccination would be too late to have a strong effect on reducing the number of infections. However, it would reduce mortality. An emergency brake, i.e., an incidence-based stepwise lockdown would be efficient to reduce the number of infections and mortality. Furthermore, to specifically account for mobility between regions, the model was applied to two German provinces of particular interest: Saxony, which currently has the lowest vaccine rollout in Germany and high incidence, and Schleswig-Holstein, which has high vaccine rollout and low incidence. ConclusionsA highly sophisticated and flexible but easy-to-parameterize model for the ongoing COVID-19 pandemic is introduced. The model is capable of providing useful predictions for the COVID-19 pandemic, and hence provides a relevant tool for epidemic decision-making. The model can be adjusted to any country, to derive the demand for hospital and ICU capacities as well as economic collateral damages.

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