Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Authors: Bryant, Andrew MSc1,*; Lawrie, Theresa A. MBBCh, PhD2; Dowswell, Therese PhD2; Fordham, Edmund J. PhD2; Mitchell, Scott MBChB, MRCS3; Hill, Sarah R. PhD1; Tham, Tony C. MD, FRCP4 American Journal of Therapeutics: July/August 2021 – Volume 28 – Issue 4 – p e434-e460doi: 10.1097/MJT.0000000000001402

Abstract

Background: 

Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials.

Areas of uncertainty: 

We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection.

Data sources: 

We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.

Therapeutic Advances: 

Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian–Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.

Conclusions: 

Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.

For More Information:https://journals.lww.com/americantherapeutics/Fulltext/2021/08000/Ivermectin_for_Prevention_and_Treatment_of.7.aspx

Further evidence supports controversial claim that SARS-CoV-2 genes can integrate with human DNA

Authors: By Jon CohenMay. 6, 2021 , 2:45 PM

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

A team of prominent scientists has doubled down on its controversial hypothesis that genetic bits of the pandemic coronavirus can integrate into our chromosomes and stick around long after the infection is over. If they are right—skeptics have argued that their results are likely lab artifacts—the insertions could explain the rare finding that people can recover from COVID-19 but then test positive for SARS-CoV-2 again months later.

Stem cell biologist Rudolf Jaenisch and gene regulation specialist Richard Young of the Massachusetts Institute of Technology, who led the work, triggered a Twitter storm in December 2020, when their team first presented the idea in a preprint on bioRxiv. The researchers emphasized that viral integration did not mean people who recovered from COVID-19 remain infectious. But critics charged them with stoking unfounded fears that COVID-19 vaccines based on messenger RNA (mRNA) might somehow alter human DNA. (Janesich and Young stress that their results, both original and new, in no way imply that those vaccines integrate their sequences into our DNA.)

Researchers also presented a brace of scientific criticisms, some of which the team addresses in a paper released online today by the Proceedings of the National Academy of Sciences (PNAS). “We now have unambiguous evidence that coronavirus sequences can integrate into the genome,” Jaenisch says.

SARS-CoV-2, the virus that causes COVID-19, has genes composed of RNA, and Jaenisch, Young, and co-authors contend that on rare occasions an enzyme in human cells may copy the viral sequences into DNA and slip them into our chromosomes. The enzyme, reverse transcriptase, is encoded by LINE-1 elements, sequences that litter 17% of the human genome and represent artifacts of ancient infections by retroviruses. In their original preprint, the researchers presented test tube evidence that when human cells spiked with extra LINE-1 elements were infected with the coronavirus, DNA versions of SARS-CoV-2’s sequences nestled into the cells’ chromosomes.

Many researchers who specialize in LINE-1 elements and other “retrotransposons” thought the data were too thin to support the claim. “If I would have had this data, I would have not submitted to any publication at that point,” says Cornell University’s Cedric Feschotte, who studies endogenous retrovirus chunks in the human genome. He and others also said they expected higher quality work coming from scientists of the caliber of Jaenisch and Young. In two subsequent studies, both posted on bioRxiv, critics presented evidence that the supposed chimeras of human and viral DNA traces are routinely created by the very technique the group used to scan for them in chromosomes. As one report concluded, the human-virus sequences “are more likely to be a methodological product, [sic] than the result of genuine reverse transcription, integration and expression.”

In their new paper, Jaenisch, Young, and colleagues acknowledge that the technique they used accidentally creates human-viral chimeras. “I think it’s a valid point,” Jaenisch says. He adds that when they first submitted the paper to a journal, they knew it needed stronger data, which they hoped to add during the review process. But the journal, like many, requires authors to immediately post all COVID-19 results to a preprint server. “I probably should have said screw you, I won’t put it on bioRxiv. It was a misjudgment,” Jaenisch says.

In the new PNAS paper, the team provides evidence that artifacts alone can’t explain the detected levels of virus-human chimeric DNA. The scientists also show that portions of LINE-1 elements flank the integrated viral genetic sequence, further supporting their hypothesis. And they have collaborated with one of the original skeptics, Stephen Hughes of the National Cancer Institute, who suggested an experiment to clarify whether the integration was real or noise, based on the orientation of the integrated viral sequences relative to the human ones. The results support the original hypothesis, says Hughes, a co-author of the new paper. “That analysis has turned out to be important,” he says.

“The integration data in cell culture is much more convincing than what was presented in the preprint, but it’s still not totally clean,” says Feschotte, who now calls Jaenisch’s and Young’s hypothesis “plausible.” (SARS-CoV-2, he notes, can also persist in a person for months without integrating its genes.)

The real question is whether the cell culture data have any relevance to human health or diagnostics. “In the absence of evidence of integration in patients, the most I can take away from these data is that it is possible to detect SARS-CoV-2 RNA retroposition events in infected cell lines where L1 is overexpressed,” Feschotte says. “The clinical or biological significance of these observations, if any, is a matter of pure speculation at this point.”

Jaenisch’s and Young’s team do report hints of SARS-CoV-2 integration in tissue from living and autopsied COVID-19 patients. Specifically, the researchers found high levels of a type of RNA that is only produced by integrated viral DNA as the cell reads its sequence to make proteins. But, Young acknowledges, “We do not have direct evidence for that yet.”

Harmit Malik, a specialist in ancient viruses in the human genome at the Fred Hutchinson Cancer Research Center, says it’s a “legitimate question” to ask why people who should have cleared the virus sometimes have positive polymerase chain Reaction tests for its sequences. But he also remains unconvinced that the explanation is integrated virus. “Under normal circumstances, there is so little reverse transcription machinery available” in human cells, Malik says.

The controversy has grown decidedly more civil since December. Both Young and Jaenisch say they received more intense criticism for their preprint than any studies in their careers, in part because some researchers worried it played into the hands of vaccine skeptics spreading false claims about the newly authorized mRNA vaccines. “If there ever was a preprint that should be deleted, it is this one! It was irresponsible to even put it up as a preprint, considering the complete lack of relevant evidence. This is now being used by some to spread doubts about the new vaccines,” Marie-Louise Hammarskjöld, a microbiologist at the University of Virginia, posted in a comment on bioRxiv at the time.

And what of the original journal submission? “They rejected it,” Jaenisch says.

Prophylaxis against covid-19: living systematic review and network meta-analysis

Authors: Jessica J Bartoszko, methodologist,1 ,*Reed A C Siemieniuk, methodologist, internist,1 ,*Elena Kum, methodologist,1 ,*Anila Qasim, methodologist,1 ,*Dena Zeraatkar, methodologist,1 ,*Long Ge, methodologist,2 ,*Mi Ah Han, methodologist,3Behnam Sadeghirad, assistant professor,1,4Arnav Agarwal, methodologist, internist,1,5Thomas Agoritsas, methodologist, internist,1,6Derek K Chu, methodologist, immunologist,1,7Rachel Couban, librarian,4Andrea J Darzi, methodologist,1Tahira Devji, methodologist,1Maryam Ghadimi, methodologist,1Kimia Honarmand, methodologist, critical care physician,8Ariel Izcovich, methodologist, internist,9Assem Khamis, data analyst,10Francois Lamontagne, methodologist, critical care physician,11Mark Loeb, methodologist, infectious disease physician,1,7Maura Marcucci, methodologist, internist,1,7Shelley L McLeod, methodologist, assistant professor,12,13Sharhzad Motaghi, methodologist,1Srinivas Murthy, clinical associate professor, paediatric critical care, infectious diseases physician,14Reem A Mustafa, methodologist, nephrologist,15John D Neary, methodologist, internist,7Hector Pardo-Hernandez, methodologist,16,17Gabriel Rada, methodologist,18,19Bram Rochwerg, methodologist, critical care physician,1,7Charlotte Switzer, methodologist,1Britta Tendal, methodologist,20Lehana Thabane, professor,1Per O Vandvik, methodologist, internist,21Robin W M Vernooij, methodologist,22,23Andrés Viteri-García, methodologist,18,24Ying Wang, methodologist, pharmacist,1Liang Yao, methodologist,1Zhikang Ye, methodologist, pharmacist,1Gordon H Guyatt, methodologist, internist,1,7 and Romina Brignardello-Petersen, methodologist1

BMJ. 2021; 373: n949.Published online 2021 Apr 26. doi: 10.1136/bmj.n949

Abstract

Objective

To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19.

Design

Living systematic review and network meta-analysis.

Data sources

World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021.

Study selection

Randomized trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.

Methods

Random effects Bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach.

Results

The first iteration of this living network meta-analysis includes nine randomised trials—six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain.

Conclusions

Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073806/

Asthmatics at no higher risk getting or dying from COVID-19, assessment of studies consisting of 587,000 people shows

Authors: February 19, 2021Source:Taylor & Francis Group

Summary:

A review of 57 studies shows people with asthma had a 14 percent lower risk of getting COVID-19 and were significantly less likely to be hospitalized with the virus.

A new study looking at how COVID-19 affects people with asthma provides reassurance that having the condition doesn’t increase the risk of severe illness or death from the virus.

George Institute for Global Health researchers in Australia analysed data from 57 studies with an overall sample size of 587,280. Almost 350,000 people in the pool had been infected with COVID-19 from Asia, Europe, and North and South America and found they had similar proportions of asthma to the general population.

The results, published in the peer-reviewed Journal of Asthma, show that just over seven in every 100 people who tested positive for COVID-19 also had asthma, compared to just over eight in 100 in the general population having the condition. They also showed that people with asthma had a 14 percent lower risk of acquiring COVID-19 and were significantly less likely to be hospitalized with the virus.

There was no apparent difference in the risk of death from COVID-19 in people with asthma compared to those without.

Head of The Institute’s Respiratory Program, co-author Professor Christine Jenkins said that while the reasons for these findings weren’t clear, there were some possible explanations — such as some inhalers perhaps limiting the virus’ ability to attach to the lungs.

“Chemical receptors in the lungs that the virus binds to are less active in people with a particular type of asthma and some studies suggest that inhaled corticosteroids — commonly used to treat asthma — can reduce their activity even further,” she said.

“Also, initial uncertainty about the impact of asthma on COVID-19 may have caused anxiety among patients and caregivers leading them to be more vigilant about preventing infection.”

Lead author Dr Anthony Sunjaya added that while this study provides some reassurance about the risks of exposure to COVID-19 in people with asthma, doctors and researchers were still learning about the effects of the virus.

“While we showed that people with asthma do not seem to have a higher risk of infection with COVID-19 compared to those without asthma and have similar outcomes, we need further research to better understand how the virus affects those with asthma,” he said.

For More Information: https://www.sciencedaily.com/releases/2021/02/210219091850.htm

More than 50 Long-Term Effects of COVID-19: A Systematic Review and Meta-Analysis

Authors: López-León SWegman-Ostrosky TPerelman CSepulveda RRebolledo PACuapio AVillapol S Preprint from SSRN, 20 Jan 2021

Abstract 


Background: COVID-19, caused by SARS-CoV-2, can involve sequelae that last weeks to months after initial recovery. The objective of this systematic review and meta-analysis is to identify studies assessing the long-term effects of COVID-19 and estimate the prevalence of each symptom, sign, or laboratory parameters of patients at a post-COVID-19 stage.

Methods: In this systematic review and meta-analysis, LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. Studies published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using the I2 statistics. PRISMA guidelines were followed.

Findings: A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 15 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). In order to have a better understanding, there is a need for studies to stratify by sex, age, previous comorbidities, severity of COVID-19 (including asymptomatic), and duration of each symptom.

Interpretation: From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address after-COVID-19 care.

Funding: National Institute for Neurological Disorders and Stroke (NINDS), and Houston Methodist Research Institute, Houston, TX.

Declaration of Interests: SLL is an employee of Novartis Pharmaceutical Company; the statements presented in the paper do not necessarily represent the position of the company. The remaining authors have no competing interests to declare.

For More Information: https://europepmc.org/article/PPR/PPR280403

Prevalence of anosmia and ageusia symptoms among long-term effects of COVID-19.

Authors: Moraschini V1Reis D1Sacco R2Calasans-Maia MD3

COVID‐19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that currently presents the greatest, most challenging health concern worldwide. Since the first reports of the disease in December 2019, clinicians and scientists have endeavored to understand the main symptoms, risk factors, and prognosis of the disease (Wynants et al., 2020). Although a significant portion of the infected population remains asymptomatic, many COVID‐19‐infected individuals develop symptoms that vary from mild to severe (Stasi et al., 2020).

Some patients may experience long‐term effects of COVID‐19, which persist for two or more weeks after the onset of the disease (Tenforde et al., 2020). Loss of taste (ageusia) and smell (anosmia) are symptoms that have drawn substantial attention from researchers because of their high prevalence in the early stages of the disease (Eliezer et al., 2020; Gane et al., 2020). However, recent studies have observed persistent dysgeusia and anosmia following recovery from COVID‐19 infection (Andrews et al., 2020; Garrigues et al., 2020; Panda et al., 2020).

The aim of this study was to estimate the prevalence of dysgeusia and anosmia in studies that assessed the long‐term effects of COVID‐19. Four databases (PubMed/MEDLINE, EMBASE, Scopus, and Lilacs) were searched for articles without any restrictions regarding language, and the inclusion criteria were based on the PECO strategy (Morgan et al., 2018). This review included studies that analyzed the prevalence of persistent symptoms (>30 days) of anosmia and dysgeusia in patients who had COVID‐19. There were no language restrictions. Two independent review authors (V.M. and M.D.C.M.) conducted the search‐and‐screening process, commencing with the analysis of titles and abstracts. Next, full papers were selected for careful reading and matched with the eligibility criteria for subsequent data extraction. The search strategy is described in Table S1.

Regarding the quality of the analyzed studies and risk of bias, one study was classified as low quality (Andrews et al., 2020), two as satisfactory (Garrigues et al., 2020; Horvath et al., 2020), and five as of high quality (Carfì et al., 2020; Carvalho‐Schneider et al., 2020; Chopra et al., 2020; Galván‐Tejada et al., 2020; Panda et al., 2020). The analyses can be viewed in Table S2.

The two review authors (V.M. and M.D.C.M.) independently performed risk‐of‐bias and study quality analyses. The Newcastle–Ottawa Scale (Lo et al., 2014) was used in the analysis of non‐randomized studies. For data analysis, the effects reported in one simple arm were estimated by dividing the number of patients with each symptom by the total number of patients with COVID‐19 in the sample and then by multiplying by 100 to estimate the percentage. The prevalence with 95% confidence intervals (CIs) was presented using the software Comprehensive Meta‐Analysis (BioStat).

A total of eight observational studies were selected for this study. Six cohort studies (Andrews et al., 2020; Carfì et al., 2020; Carvalho‐Schneider et al., 2020; Chopra et al., 2020; Horvath et al., 2020; Panda et al., 2020), one cross‐sectional study (Garrigues et al., 2020), and one case–control study (Galván‐Tejada et al., 2020) were included in this study (Figure S1). The studies analyzed 1,483 patients (773 male and 710 female) with a mean age of 48.3 ± 11.2. All patients were diagnosed with COVID‐19 through reverse transcription polymerase chain reaction (RT‐PCR) and exhibited mild, moderate, or severe symptoms. The mean overall follow‐up time was 60.7 days. The main data for each study are shown in Table ​Table11.

For More Information: https://europepmc.org/article/PMC/PMC8242542

Informed consent disclosure to vaccine trial subjects of risk of COVID‐19 vaccines worsening clinical disease

Authors: Timothy Cardozo 1 and Ronald Veazey 2

Abstract

Aims of the study

Patient comprehension is a critical part of meeting medical ethics standards of informed consent in study designs. The aim of the study was to determine if sufficient literature exists to require clinicians to disclose the specific risk that COVID‐19 vaccines could worsen disease upon exposure to challenge or circulating virus.

Methods used to conduct the study

Published literature was reviewed to identify preclinical and clinical evidence that COVID‐19 vaccines could worsen disease upon exposure to challenge or circulating virus. Clinical trial protocols for COVID‐19 vaccines were reviewed to determine if risks were properly disclosed.

Results of the study

COVID‐19 vaccines designed to elicit neutralizing antibodies may sensitize vaccine recipients to more severe disease than if they were not vaccinated. Vaccines for SARS, MERS and RSV have never been approved, and the data generated in the development and testing of these vaccines suggest a serious mechanistic concern: that vaccines designed empirically using the traditional approach (consisting of the unmodified or minimally modified coronavirus viral spike to elicit neutralizing antibodies), be they composed of protein, viral vector, DNA or RNA and irrespective of delivery method, may worsen COVID‐19 disease via antibody‐dependent enhancement (ADE). This risk is sufficiently obscured in clinical trial protocols and consent forms for ongoing COVID‐19 vaccine trials that adequate patient comprehension of this risk is unlikely to occur, obviating truly informed consent by subjects in these trials.

Conclusions drawn from the study and clinical implications

The specific and significant COVID‐19 risk of ADE should have been and should be prominently and independently disclosed to research subjects currently in vaccine trials, as well as those being recruited for the trials and future patients after vaccine approval, in order to meet the medical ethics standard of patient comprehension for informed consent.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645850/

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial

Abstract

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has changed our lives. The scientific community has been investigating re-purposed treatments to prevent disease progression in coronavirus disease (COVID-19) patients.

Objective

To determine whether ivermectin treatment can prevent hospitalization in individuals with early COVID-19.

Design, setting and participants: A randomized, double-blind, placebo-controlled study was conducted in non-hospitalized individuals with COVID-19 in Corrientes, Argentina. Patients with SARS-CoV-2 positive nasal swabs were contacted within 48 h by telephone to invite them to participate. The trial randomized 501 patients between August 19th 2020 and February 22nd 2021.

Intervention

Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient’s weight, for 2 days.

Main outcomes and measures

The efficacy of ivermectin to prevent hospitalizations was evaluated as primary outcome. We evaluated secondary outcomes in relationship to safety and other efficacy end points.

Results

The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3–6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32–1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes.

Limitations

Low percentage of hospitalization events, dose of ivermectin and not including only high-risk population.

Conclusion

Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes.

Trial registration

ClinicalTrials.gov NCT04529525.

For More Information: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06348-5

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19

Authors: JACC State-of-the-Art ReviewAzita H. Talasaz, PharmD,a,bParham Sadeghipour, MD,cHessam Kakavand, PharmD,a,bMaryam Aghakouchakzadeh, PharmD,aElaheh Kordzadeh-Kermani, PharmD,aBenjamin W. Van Tassell, PharmD,d,eAzin Gheymati, PharmD,aHamid Ariannejad, MD,bSeyed Hossein Hosseini, PharmD,aSepehr Jamalkhani,cMichelle Sholzberg, MDCM, MSc,f,gManuel Monreal, MD, PhD,hDavid Jimenez, MD, PhD,iGregory Piazza, MD, MS,jSahil A. Parikh, MD,k,lAjay J. Kirtane, MD, SM,k,lJohn W. Eikelboom, MBBS,mJean M. Connors, MD,nBeverley J. Hunt, MD,oStavros V. Konstantinides, MD, PhD,p,qMary Cushman, MD, MSc,r,sJeffrey I. Weitz, MD,t,uGregg W. Stone, MD,k,vHarlan M. Krumholz, MD, SM,w,x,yGregory Y.H. Lip, MD,z,aaSamuel Z. Goldhaber, MD,j and Behnood Bikdeli, MD, MSj,k,w,∗

Abstract

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Thromboembolism in Patients With Coronavirus Disease-2019

Microvascular and macrovascular thrombotic complications, including arterial and especially venous thromboembolism (VTE), seem to be common clinical manifestations of coronavirus disease-2019 (COVID-19), particularly among hospitalized and critically ill patients (1234). Pooled analyses have helped in providing aggregate estimates of thrombotic events (4,5). In a recent systematic review and meta-analysis, the overall incidence of VTE among inpatients with COVID-19 was estimated at 17% (95% confidence interval [CI]: 13.4 to 20.9), with variation based on study design and method of ascertainment; there was a four-fold higher incidence rate in patients in the intensive care units (ICUs) compared with non-ICU settings (28% vs. 7%) (6). In addition, postmortem studies show frequent evidence of microvascular thrombosis in patients with COVID-19 (7,8). The influence of these events on mortality rates remains unknown (9).Go to:

Pathophysiology of Thromboembolism in COVID-19: Virchow’s Triad in Action

COVID-19 can potentiate all 3 components of Virchow’s triad and increases the risk of thrombosis (Figure 1 ). First, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection may trigger endothelial dysfunction. Using the angiotensin-converting enzyme 2, which is expressed on the surface of many cells, SARS-CoV-2 enters endothelial cells and may impair their intrinsic antithrombotic properties. It is proposed that viremia, hypoxia, the inflammatory response, increased expression of tissue factor, and elevated levels of neutrophil extracellular traps (NETs) can together disrupt the hemostasis equilibrium and promote endothelial activation (101112). This induction of a procoagulant state along with the reduction in plasminogen activators further results in increased platelet reactivity (131415). Inflammatory cytokines and endothelial activation can lead to downregulation of antithrombin and protein C expression. They can also lead to an increase in the levels of plasminogen activator inhibitor; fibrinogen; factors V, VII, VIII, and X; and von Willebrand factor (16). Increased platelet reactivity, NETosis, and alterations in the aforementioned hemostatic factors result in a hypercoagulable state (171819202122).

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963001/

More than 50 long-term effects of COVID-19: a systematic review and meta-analysis

Authors: Sandra Lopez-LeonTalia Wegman-OstroskyCarol PerelmanRosalinda SepulvedaPaulina A. ebolledo,

Angelica Cuapio & Sonia Villapol

Abstract

COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. This systematic review and meta-analysis aims to identify studies assessing the long-term effects of COVID-19. LitCOVID and Embase were searched to identify articles with original data published before the 1st of January 2021, with a minimum of 100 patients. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. PRISMA guidelines were followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included (age 17–87 years). The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in China in December 2019. Since then, more than 175 million people worldwide have been infected after a year, and over 3.8 million people have died from the coronavirus disease 2019 (COVID-19)1. Although unprecedented efforts from the scientific and medical community have been directed to sequence, diagnose, treat, and prevent COVID-19, individuals’ lasting effects after the acute phase of the disease are yet to be revealed.

The terminology has been confusing and not standardized. Different authors have used several terms to describe prolonged symptoms following COVID-19 illness, such as “Long COVID-19”, “post-acute COVID-19”, “persistent COVID-19 symptoms”, “chronic COVID-19”, “post-COVID-19 manifestations”, “long-term COVID-19 effects”, “post COVID-19 syndrome”, “ongoing COVID-19”, “long-term sequelae”, or “long-haulers” as synonyms. Most recently, the term “post-acute sequelae of SARS-CoV-2 infection” (PASC), “long-COVID-19”, and “post-acute COVID-19”, has been utilized2.

Symptoms, signs, or abnormal clinical parameters persisting two or more weeks after COVID-19 onset that do not return to a healthy baseline can potentially be considered long-term effects of the disease3. Although such alteration is mainly reported in severe and critical disease survivors, the lasting effects also occur in individuals with a mild infection who did not require hospitalization4. However, it has not yet been established how sex, gender, age, ethnicity, underlying health conditions, viral dose, or progression of COVID-19 significantly affect the risk of developing long-term effects of COVID-195.

Since first reported, there has been a vast amount of social media patient groups, polls, comments, and scientific articles aiming to describe the chronicity of COVID-19. In parallel, hundreds of scientific publications, including cohorts studying specific effects of the disease and lists of case reports, have been described6. However, a broad overview of all the possible longstanding effects of COVID-19 is still needed. Therefore, our study aimed to perform a systematic review and meta-analysis of peer-reviewed studies to estimate the prevalence of all the symptoms, signs, or abnormal laboratory parameters extending beyond the acute phase of COVID-19 reported to date.

For More Information: https://www.nature.com/articles/s41598-021-95565-8