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ACE inhibitors + angiotensin receptor blockers: meta-analysis of effect on severity and survival in COVID-19 (preprint)

Abstract

Methods

We did a meta-analysis to assess the effect of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) in patients with COVID-19 on severity of disease, risk for hospitalisation, and death compared to those not on ACEi/ARB. We searched the Cochrane library, PubMed, Embase, ClinicalTrial.gov and medRxiv for studies published until 21.04.2020. Inclusion criteria included all studies with patients with confirmed COVID-19 either taking, or not taking, ACEi/ARB. Depending on degree of heterogeneity, fixed or random effect model was selected to calculate effect size (odds ratio).

Findings

Five studies were eligible for meta-analysis. These included 308 patients on ACEi/ARB, and 1172 not on ACEi/ARB. Compared to patients with COVID-19 not on ACEi/ARB, there was a statistically significant 44% reduction in odds of developing severe disease (OR: 0.56; 95% CI: 0.34-1.89, I2=68.15), and 62% reduction in odds of death (OR: 0.38; 95% CI: 0.19-0.74, I2=0.000) in those on ACEi/ARB. There was a non-significant 19% (OR 0.81; 95% CI: 0.42-1.55, I2: 0.000) reduction in odds of hospitalisation among those on ACEi/ARB.

Interpretation

It is safe to use ACEi/ARB in patients with COVID-19 requiring these medications for associated comorbidities. Although limited by confounding factors typical of a meta-analysis of retrospective observational studies, our data suggests that use of these medications may reduce risk of developing severe disease and death.

SOURCE: medRxiv

Editor’s note: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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Heparin-induced thrombocytopenia is associated with mortality in critical COVID-19 (preprint)

Abstract

Methods

Sixty-one critical COVID-19 patients admitted to the intensive care unit (ICU) and 93 severe non-ICU patients at Huoshenshan Hospital (Wuhan, China) were included in this study. Medical records, including demographic, platelet counts, heparin-involved treatments, heparin-induced thrombocytopenia-(HIT) related laboratory tests, and fatal outcomes of COVID-19 patients were analyzed and compared between survivors and nonsurvivors.

Findings

Sixty-one critical COVID-19 patients treated in ICU included 15 survivors and 46 nonsurvivors. Forty-one percent of them (25/61) had severe thrombocytopenia, with a platelet count (PLT) less than 50×109/L, of whom 76% (19/25) had a platelet decrease of >50% compared to baseline; 96% of these patients (24/25) had a fatal outcome. Among the 46 nonsurvivors, 52.2% (24/46) had severe thrombocytopenia, compared to 6.7% (1/15) among survivors.

Discussion

Continuous renal replacement therapy (CRRT) [induced] a significant decrease in platelet count in 81.3% of critical CRRT patients (13/16), resulting in a fatal outcome.

Editor’s note: if this preprint is accepted for publication, the publisher will likely suggest that the conclusion above should be softened to ‘associated with’ rather than ‘resulting in’.

In addition, a high level of anti-heparin-PF4 antibodies, a marker of HIT, was observed in most ICU patients. Surprisingly, HIT occurred not only in patients with heparin exposure, such as in CRRT, but also in heparin-naive patients, suggesting that spontaneous HIT may occur in COVID-19.

Interpretation

Anti-heparin-PF4 antibodies are induced in critical COVID-19 patients, resulting in a progressive platelet decrease. Exposure to a high dose of heparin may trigger further severe thrombocytopenia with a fatal outcome. An alternative anticoagulant other than heparin should be used to treat COVID-19 patients in critical condition.

SOURCE: bioRxiv

Editor’s note: Sodium citrate is a circuit anticoagulant often used in CRRT; its use might reduce the incidence of HIT. ‘Preprints’ are released prior to publication, and in many cases, prior to peer review.

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Early detection of superspreaders by mass group pool testing can mitigate pandemic (preprint)

Abstract

Background

Most epidemiological models applied to COVID-19 do not consider heterogeneity in infectiousness and impact of superspreaders, despite the broad viral loading distributions amongst COVID-19 positive people (1-1 000 000 per mL). Also, mass group testing is not used [due] to existing shortage of tests. I propose new strategy for early detection of superspreaders with reasonable number of RT-PCR tests, which can dramatically mitigate development COVID-19 pandemic and even turn it endemic.

Methods

I used stochastic social-epidemiological SEIAR model, where S-suspected, E-exposed, I-infectious, A-admitted (confirmed COVID-19 positive, who are admitted to hospital or completely isolated), R-recovered. The model was applied to real COVID-19 dynamics in London, Moscow and New York City.

Findings

Viral loading data measured by RT-PCR were fitted by broad log-normal distribution, which governed high importance of superspreaders. The proposed full scale model of a metropolis shows that top 10% spreaders (100+ higher viral loading than median infector) transmit 45% of new cases. Rapid isolation of superspreaders leads to 4-8 fold mitigation of pandemic depending on applied quarantine strength and amount of currently infected people. High viral loading allows efficient group matrix pool testing of population focused on detection of the superspreaders requiring remarkably small amount of tests.

Interpretation

The model and new testing strategy may prevent thousand or millions COVID-19 deaths requiring just about 5000 daily RT-PCR test for big 12 million city such as Moscow. Though applied to COVID-19 pandemic the results are universal and can be used for other infectious heterogenous epidemics. 

SOURCE: medRxiv

Editor’s note: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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The approved dose of ivermectin alone is not the ideal dose for COVID-19 (preprint)

Abstract

Caly reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5 uM. The concentration resulting in 50% inhibition (IC50, 2 uM) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted.

Methods

Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 ug/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose.

Results

Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50, even for a dose level 10x higher than the approved dose. Even with higher exposure in lungs than plasma, ivermectin is unlikely to reach the IC50 in lungs after single oral administration of the approved dose (predicted lung: 0.0857 uM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.817 uM).

Conclusions

The likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.

SOURCE: medRxiv

Editor’s note: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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A rapid, inexpensive protocol for a sensitive RT-LAMP assay for SARS-CoV-2 detection (preprint)

Abstract

We have developed a highly sensitive RT-LAMP assay compatible with current reagents, that utilizes a colorimetric readout in as little as 30 minutes. In addition to this, we have developed an inexpensive pipeline to further increase sensitivity without requiring highly specialized equipment. A rapid inactivation protocol capable of inactivating virions, as well as endogenous nucleases, was also developed to increase sensitivity and sample stability.

This protocol, combined with our RT-LAMP assay, has a sensitivity of at least 50 viral RNA copies per microliter in a sample. To further increase the sensitivity, a purification protocol compatible with this inactivation method was developed. The inactivation and purification protocol, combined with our RT-LAMP assay, brings the sensitivity to at least 1 viral RNA copy per microliter in a sample.

We hope that this inactivation and purification pipeline, which costs approximately $0.07 per sample and which uses readily available reagents, will increase the availability of SARS-CoV-2 testing, as well as expand the settings in which this testing can be performed.

SOURCE: medRxiv

Editor’s note: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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A “dry swab, extraction free” protocol for SARS-CoV-2 testing via RT-qPCR (preprint)

Abstract

The urgent need for massively scaled clinical or surveillance testing for SARS-CoV-2 has necessitated a reconsideration of the methods by which respiratory samples are collected, transported, processed and tested.

Conventional testing for SARS-CoV-2 involves collection of a clinical specimen with a nasopharyngeal swab, storage of the swab during transport in universal transport medium (UTM), extraction of RNA, and quantitative reverse transcription PCR (RT-qPCR). As testing has scaled across the world, supply chain challenges have emerged across this entire workflow.

Here we sought to evaluate how eliminating the UTM storage and RNA extraction steps would impact the results of molecular testing. Using paired mid-turbinate swabs self-collected by 11 individuals with previously established SARS-CoV-2 positivity, we performed a comparison of conventional (swab → UTM → RNA extraction → RT-qPCR) vs. simplified (direct elution from dry swab → RT-qPCR) protocols.

Our results suggest that dry swabs eluted directly into a simple buffered solution (TE) can support molecular detection of SARS-CoV-2 via endpoint RT-qPCR without substantially compromising sensitivity. Although further confirmation with a larger sample size and variation of other parameters is necessary, these results are encouraging for the possibility of a simplified workflow that could support massively scaled testing for COVID-19 control.

SOURCE: bioRxiv

Editor’s note: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine induces antibody titers and viral neutralization (preprint)

Abstract

We present a self-amplifying RNA encoding the SARS-CoV-2 spike protein, encapsulated within a lipid nanoparticle, as a vaccine. [We] demonstrate [the] induction of robust neutralization of a pseudo-virus, proportional to quantity of specific IgG, and of higher quantities than [in] recovered COVID-19 patients.

These data provide insight into the vaccine design and evaluation of immunogenicity to enable rapid translation to the clinic.

SOURCE: bioRxiv

EDITOR’S NOTE: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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COVID-19: weather, demographics and infection (preprint)

Abstract

We study the effects of three types of variables on the early pace of spread of COVID-19: weather variables, temperature and absolute humidity; population density; [and] the timeline of COVID-19 infection, as outbreak of disease occurs in different dates for different regions. The regions considered were all 50 U.S. states and 110 countries (those which had enough data available by April 10th). We looked for associations between the above variables and an estimate of the growth rate of cases, the exponential coefficient, computed using data for 10 days starting when state/country reached 100 confirmed cases.

The results for U.S. states indicate that one cannot expect that higher temperatures and higher levels of absolute humidity would translate into slower pace of COVID-19 infection rate, at least in the ranges of those variables during the months of February and March of 2020 (-2.4 to 24C and 2.3 to 15g/m3). In fact, the opposite is true: the higher the temperature and the absolute humidity, the faster the COVID-19 has expanded in the U.S. states, in the early stages of the outbreak.

Secondly, using the highest county population density for each state, there is strong positive association between population density and (early) faster spread of Covid-19.

Finally, there is strong negative association between the date when a state reached 100 accumulated cases and the speed of COVID-19 outbreak (the later, the lower the estimate of growth rate).

When these variables are considered together, only population density and the timeline variable show statistical significance. We also develop the basic models for the collection of countries, without the demographic variable. Despite the evidence, in that case, that warmer and more humid countries have shown lower rates of COVID-19 expansion, the weather variables lose statistical significance when the timeline variable is added.

SOURCE: medRxiv

Editor’s note: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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High prevalence of invasive pulmonary aspergillosis in critically ill COVID-19 (preprint)

Abstract

Aiming at screening for fungal secondary pneumonia, we collected the data of our first 27 [COVID-19] ICU patients, who underwent bronchoalveolar lavage or bronchial aspirates. We classified the patients based on a recently published study on invasive aspergillosis in influenza (Schauwvlinghe 2018) and found 33% of our COVID-19 patients with putative invasive pulmonary aspergillosis

Observing such a high prevalence in COVID-infected patients was somehow unexpected since the 30% prevalence of invasive aspergillosis in influenza patients has been attributed to the action of oseltamivir on anti-Aspergillus immunity. Almost all critically ill COVID-19 patients develop ARDS and are likely to receive high-dose steroids or immunomodulatory therapies to prevent worsening as suggested by reports from China.

In the COVID-19 patients with putative invasive aspergillosis, antifungal prophylactic therapy may be questioned to avoid increased lung inflammation that may compromise the outcome. This issue remains to be addressed in future clinical trials. We are strongly convinced that testing deep lung specimens for Aspergillus in severe COVID-19 patients should be recommended.

SOURCE: medRxiv

Editor’s note: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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Rapid development of an inactivated vaccine for SARS-CoV-2 (preprint)

Abstract

We developed a pilot-scale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and non-human primates. These antibodies potently neutralized ten representative SARS-CoV-2 strains, indicative of a possible broader neutralizing ability against SARS-CoV-2 strains circulating worldwide.

Immunization with two different doses (3μg or 6 μg per dose) provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without any antibody-dependent enhancement of infection.

Systematic evaluation of PiCoVacc via monitoring clinical signs, hematological and biochemical index, and histopathological analysis in macaques suggests that it is safe. These data support the rapid clinical development of SARS-CoV-2 vaccines for humans.

SOURCE: bioRxiv

Editor’s note: ‘preprints’ are released prior to publication, and in many cases, prior to peer review.

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