SARS-CoV-2 virus. Source: Fusion Medical Animation on Unsplash
In a study published in JAMA Network Open, researchers reported that the blood pressure medication losartan is not effective in reducing lung injury in patients with COVID.
This drug was investigated based on early reports suggesting benefit in preclinical models of the 2003 SARS virus, a close family member to the current SARS-CoV-2 virus.
The research team sought to determine if a common blood pressure medication might decrease lung injury in patients hospitalised with COVID. Their results found that losartan treatment did not reduce lung injury in patients admitted with COVID, and had no effect on mortality.
In addition, critically-ill patients treated with losartan needed additional, temporary blood pressure support. However, this did not result in worse outcomes overall.
“Even though this particular drug was not effective for the treatment of COVID-19, repurposing inexpensive and relatively safe medications remains an important approach to contain healthcare costs,” said study co-author Michael Puskarich, MD, an associate professor in emergency medicine.
“Finding effective treatments for COVID that can be widely used across both the developed and developing world remains an important ongoing area of investigation,” Dr Puskarich added.
The researchers noted that more studies of protein and cellular signalling from ALPS-COVID trial participants are ongoing.
“We hope that future study findings of these proteins may show insights into why the body responds the way it does to COVID,” said co-author Christopher Tignanelli, MD, MS, FACS, FAMIA, an assistant professor in surgery. “Critically, this will help us understand why some people develop severe disease following COVID infection and others are asymptomatic.”
During the extenuating circumstances of an emerging pandemic, grouping patients together in one area or facility, a practice known as cohorting, was successful in providing high-quality care and containing infectious patients, according to a new study published in JAMA Open.
The University of Minnesota Medical School researchers reported that cohorting was implemented by M Health Fairview early in the pandemic when there was little known about how to effectively treat patients with COVID.
“This study highlights the academic and clinical expertise of the M Health Fairview system to deliver outstanding medical care to the people of Minnesota,” said Dr Greg Beilman, a critical care surgeon at the U of M Medical School and was a co-lead of the M Health Fairview COVID response team. “In this study we demonstrated our ability to rapidly bring new developments in science to the patient’s bedside and improve outcomes for patients affected by this frequently dire disease.”
Because every person being treated in the cohorts had COVID, frontline healthcare workers quickly gained experience in COVID care. These experienced specialists worked side by side with academic physicians who were translating the latest medical research into new solutions they could apply in real time to patient care. COVID patients had access to leading-edge clinical trials, internal COVID testing capabilities, and innovative technology.
The study found that dedicated COVID units in Minnesota were associated with a 2% overall improvement in in-hospital survival rates when patients were properly matched for severity of illness. Complications associated with COVID were significantly better in this group as was the swift implementation of new care processes by health care providers.
“The opportunity to care for patients at our COVID cohort hospitals was a shining light in a dark time for many of us,” said Dr Andrew Olson, medical intensivist at the U of M Medical School and medical director of COVID hospital medicine at M Health Fairview. “We watched our colleagues develop expertise, conduct research and care for one another while staying healthy in a challenging time.”
The research team hopes the cohorting method could be implemented during other infectious disease outbreaks, like viral pneumonia. The framework helps provide infectious patients the best care during times of rapid learning in scientific research.
“As the pandemic progressed, we had broad availability of personal protective equipment, vaccinations, and more health care workers developed familiarity with treatment of COVID,” said Dr Beilman. “These developments combined with the fact that the incidence of COVID decreased last year – this care model was no longer necessary.”
Researchers plan to further investigate which patients benefit most from care at such facilities, as well as evaluate the experience for those healthcare professionals who work in them.
Interim analysis of a South African clinical trial has revealed that nitazoxanide, an oral antiparasitic agent with antiviral properties, was ineffective in improving outcomes in ambulatory patients with mild-to-moderate COVID.
Funded by the South African Medical Research Council (SAMRC), the study was performed at four sites in South Africa. The primary goal of the trial was to evaluate the effectiveness of nitazoxanide (1g twice daily for 7 days) in reducing the progression from mild to severe COVID in ambulatory patients. Progression to severe disease was defined as hospitalisation or death. The trial underwent an interim analysis at 67% of the recruitment target (290 participants), and the data was reviewed by an independent data and safety monitoring board (DSMB). Following the interim analysis, the DSMB recommended halting recruitment of the trial on the grounds of futility.
No significant difference was seen in serious adverse events, which included all causes of hospitalisation and death, between the nitazoxanide and the placebo groups [12/144 (8.3%) vs 10/146 (6.8%)]. Hospitalisation and death specifically due to COVID showed the same pattern [7/144 (4.9%) vs 8/146 (5.5%)].
Principal investigator Prof Keertan Dheda from the University of Cape Town (UCT) and the London School of Hygiene and Tropical Medicine, said that the results of the trial, although disappointing, contributes to the growing body of evidence, clarifying what works and what doesn’t for the treatment of COVID. Thus, clarifying what does not work is as important as finding effective therapies so that clinically useful management algorithms can be developed.
Nitazoxanide is a low-cost broad-spectrum antiviral drug with an extensive safety record. Originally developed as antiparasitic, it seemed promising against SARS-CoV-2 in the lab but the real world test did not show any benefit. It is still possible that nitazoxanide may be of benefit at higher doses (greater than the dose used in the trial, which was already twice the normal dose), however this will most likely cause an increase in intolerable gastrointestinal side effects. “The next step will be to focus on formally publishing the data in a peer reviewed journal and to evaluate secondary objectives of the study, including assessing the efficacy of nitazoxanide in reducing the duration of illness, reducing SARS-CoV-2 viral load, and its efficacy, if any, in preventing COVID in close contacts,” said Prof Dheda.
Prof Dheda concluded that nitazoxanide could have a less than 30% benefit which may be detectable in a larger study. However, it is questionable whether such an effect size is clinically relevant given the number needed to treat to prevent disease progression, adverse events, cost and that other therapies have emerged (eg paxlovid) with an efficacy benefit of greater than 80%.
SAMRC President and CEO, Prof Glenda Gray said although the study did not meet its primary endpoint, the results are an important addition into the scientific repository. “COVID and HIV in their very nature are unique and complex viruses which have posed unprecedented challenges for vaccine development, globally – however, the knowledge gained from this trial will help us advance our pursuit of effective therapies and vaccines for both COVID and HIV alike,” said Prof Gray.
Prof Gray, who also has led numerous trials in search of effective HIV and COVID vaccines, said COVID poses substantial challenges for those living with HIV which evades the immune system. “Until an effective vaccine has been found, all people living with HIV should take all recommended preventive measures to minimise their exposure to COVID,” concluded Prof Gray.
Researchers at the Medical University of Vienna have now shown that the anticoagulant heparin not only has a beneficial effect on survival of COVID patients, but also influences the duration of active infection with the SARS-CoV-2 coronavirus. The results were published in the journal Cardiovascular Research.
COVID is now known to be a multifaceted infectious disease, which affects several functional systems in the human body following infection with the pathogen SARS-CoV-2. One of these functional systems is blood clotting. COVID patients are at greater risk of thromboses and embolisms, such as strokes, pulmonary or myocardial infarctions, and even deep vein thromboses. The use of drugs that inhibit blood clotting has been part of the treatment guidelines for COVID since July 2020. “These complications during hospitalisation have a direct impact on the well-being of patients and increased the risk of dying from COVID,” said first author David Pereyra from MedUni Vienna’s Department of General Surgery. The underlying coagulopathy is still not fully understood.
“The coagulopathy observed in COVID patients is novel and differs in many respects from previously known coagulation problems,” said senior author Alice Assinger, group leader at the Institute of Vascular Biology and Thrombosis Research at the Medical University of Vienna. “COVID-associated coagulopathy displays characteristics that, although partially comparable with other coagulation diseases, cannot be fully explained by them.” Alice Assinger’s group therefore started to look for an explanation for this sub-condition of COVID in the spring of 2020, in an early phase of the pandemic.
In a multi-centre analysis of COVID patients, the group saw that COVID-associated coagulopathy occurs almost exclusively in patients requiring intensive care or in patients who die as a result of COVID. While anticoagulant drugs improve the survival of COVID patients, they show no effect on immunological processes related to blood coagulation (immunothrombosis).
However, an analysis of the results showed that the length of active SARS-CoV-2 infection is shortened in patients treated with low-molecular-weight heparin, the most commonly used anticoagulant. “In patients who receive this drug, infection time is an average of four days shorter than in patients who are not treated with low-molecular-weight heparin. We were surprised to see that low-molecular-weight heparin may have a direct effect on coronavirus and its infectivity,” said David Pereyra. Experimental data show that heparin can inhibit the ability of SARS-CoV-2 to bind to cells, thereby preventing them from being infected.
These observations were made in the context of a close collaboration between the three hospitals involved – the Favoriten Hospital in Vienna, the Innsbruck Regional Hospital Innsbruck and the Johannes Kepler University Hospital in Linz – as well as through the active exchange between basic researchers and clinicians,” says Alice Assinger, underscoring the relevance of good cooperation during the COVID pandemic for a better understanding of the disease and its treatment.
Pharmaceutical giant Pfizer announced today that Paxlovid, its investigational novel COVID oral antiviral candidate, significantly reduced hospitalisation and death, based on an interim analysis of its phase II/III clinical trials showing an 89% reduction of risk of hospitalisation or death due to COVID.
The phase II/III EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomised, double-blind study of non-hospitalised adult patients with COVID, who are at high risk of progressing to severe illness. The scheduled interim analysis showed an 89% reduction in risk of COVID-related hospitalisation or all-cause mortality compared to placebo in patients treated within three days of symptom onset (primary endpoint). Only 0.8% of patients who received Paxlovid were hospitalised through Day 28 with zero deaths, compared to 7.0% of patients who received placebo and were hospitalised or died. Similar reductions in COVID-related hospitalisation or mortality were seen in patients treated within five days of symptom onset; 1.0% of patients in the intervention arm were hospitalised through Day 28 with zero deaths, compared to 6.7% of placebo arm patients. In the overall study population through Day 28, no deaths were reported in intervention arm patients as compared to 10 (1.6%) deaths in placebo arm patients.
The results show such an overwhelming effectiveness that Pfizer, in consultation with the US Food and Drug Administration (FDA), will cease further enrollment into the study and will apply for Emergency Use Authorization (EUA) as soon as possible.
If it gets the green light, Pfizer’s Paxlovid, would be the first oral antiviral of its kind, a specifically designed SARS-CoV-2-3CL protease inhibitor. PF-07321332 inhibits viral replication at the proteolysis stage, before viral RNA replication. Co-administration with a low dose of ritonavir helps slow the metabolism of PF-07321332 in order for it to remain active in the body for longer at higher concentrations. It has shown effectiveness against multiple variants, and could have broad general effectiveness against coronaviruses.
“All of us at Pfizer are incredibly proud of our scientists, who designed and developed this molecule, working with the utmost urgency to help lessen the impact of this devastating disease on patients and their communities,” said Mikael Dolsten, MD, PhD, Chief Scientific Officer and President, Worldwide Research, Development and Medical of Pfizer. “We’re thankful to all of the patients, investigators, and sites around the world who participated in this clinical trial, all with the common goal of bringing forth a breakthrough oral therapy to help combat COVID.”
The review of safety data included a larger cohort of 1881 patients in EPIC-HR, whose data were available at the time of the analysis. Adverse events were comparable between paxlovid (19%) and placebo (21%), which were mostly mild.
Pfizer kicked off the EPIC-HR study in July 2021 after positive results from Phase I clinical trials, followed in August by the Phase II/III EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients), to evaluate efficacy and safety in patients with a confirmed diagnosis of SARS-CoV-2 infection who are at standard (low) risk. This trial includes a cohort of vaccinated at-risk patients who have an acute breakthrough COVID infection. A further trial is investigating prophylaxis among household members of patients with a COVID infection.
Molnupiravir is being developed for the treatment of COVID, which has been submitted for review by the US Food and Drug Administration, but large-scale production to treat COVID is still a challenge. Now, researchers have engineered enzymes to help manufacture the pill, resulting in a much shorter synthesis with a higher yield than current methods. The details of their work are reported in ACS Central Science.
The oral antiviral molnupiravir was originally developed to treat influenza, and works by causing viruses to make errors when copying their own RNA, introducing mutations that inhibit replication. Recently, interim phase 3 clinical trial findings indicated that molnupiravir reduced the risk of hospitalisation and death from COVID for newly diagnosed, at-risk patients, and that it had equal effectiveness against different SARS-CoV-2 variants. Researchers set out to develop a shorter, higher-yielding and sustainable way to synthesise the molecule.
The team came up with a three-step synthesis of molnupiravir from ribose, a sugar molecule. They identified enzymes or chemical treatments to sequentially add the appropriate chemical groups to ribose to generate the molecule. For the second step of the synthesis, the team identified bacterial enzymes that weakly catalysed the desired reactions. Using in vitro evolution, they greatly enhanced these enzymes’ activities. The new synthetic route, which also included a phosphate recycling strategy, was 70% shorter and had a seven-fold higher overall yield than the original route.
Despite high hopes, the first placebo controlled trial of inhaled steroids for COVID suggests that ciclesonide, an inhaled and nasal steroid drug commonly used for asthma and rhinitis, does not help young healthy people with COVID and respiratory symptoms improve earlier.
The study, published in the BMJ, was motivated by research showing that ciclesonide, which is safe, inexpensive and widely available, could decrease viral replication of SARS-Cov2 in mouse models of COVID. A randomised, double-blind, placebo-controlled trial of inhaled ciclesonide was designed to evaluate the resolution of symptoms in adults with COVID presenting with respiratory symptoms.
“Based on my experience treating asthma, I thought it made sense to see if it would decrease the lung inflammation in patients with COVID early in the disease, as lung disease has an important impact for patients and is a major effect of the virus,” explained Dr Nicole Ezer, the first and lead author of the study, who is a lung specialist and a researcher in the Translational Research in Respiratory Diseases Program at the RI-MUHC. “In addition, we felt it was important to study a drug for COVID that has a very good safety profile and could be used in high, middle and low-income countries safely to reduce respiratory symptoms. Access to affordable medications is very important to decrease disparities in health outcomes across the world.”
The importance of placebo control From Sept. 15, 2020 to June 8, 2021, the study recruited 215 symptomatic adults and randomly assigned them to either inhaled and intranasal ciclesonide or inhaled and intranasal placebo for 14 days. Participants were asked to complete a survey online on the day of enrollment and on six other occasions until day 14, with a follow-up survey at day 29.
Based on the assumption that treatment would be most effective if given early in the disease process, participants were recruited within five days of a positive PCR test result for SARS-CoV-2 and symptom onset and received the treatment at home by commercial courier. No vaccinated participants were included in the trial.
No significant difference was seen between the intervention and control group. After seven days of treatment, 40% taking ciclesonide had no more fever and respiratory symptoms, vs 35% taking placebo. At day 14, these figures amounted to 66% in the ciclesonide group compared with 58% in the placebo group.
Those results are disappointing, especially since two recent open label studies had raised hopes in the scientific community that inhaled steroids could alleviate respiratory symptoms associated with COVID, and one study demonstrated efficacy of dexamethasone in admitted patients with COVID.
“The previously published studies had a major limitation: they were open label with no placebo. Other studies have shown that inhalers have a strong placebo effect,” explained the study’s senior author, Dr Emily McDonald, associate professor of medicine at McGill University. “Here’s a strong reminder that any study of a medication, in particular of inhalers, needs to be controlled with a placebo before we rush to recommend them.”
In spite of the study’s outcome, researchers still believe there is potential for the treatment of COVID with inhaled steroids.
“It’s still possible that inhaled steroids might be beneficial for older at-risk populations,” said Dr Ezer, who is also an assistant professor of medicine at McGill University. “We need more research focused on older adults and people who are high-risk, but those studies must have a placebo arm to make sure they aren’t coming to a false conclusion of benefit.”
Though small studies have suggested that statins, which lower low-density lipoprotein (LDL), may also reduce COVID severity or mortality, findings from a large study suggest that it has no effect and may even worsen the disease.
In the effort to fight COVID, researchers have attempted to find existing medications that might have an effect on the outcome of the disease, and statins were one readily available candidate that appeared to have some effect. However, a new study published in the journal PLOS ONE suggests they may not be suitable.
“Despite the apparent beneficial effect of statins on the outcomes of various infectious diseases, our study revealed that their specific use to treat COVID is probably not merited,” said senior study author Petros Karakousis, MD, professor of medicine at the Johns Hopkins University School of Medicine. “Compared with earlier research, we looked at a larger and more widely varied inpatient population, and had better criteria for defining disease severity, thereby enabling our results to be more relevant for predicting the impact of statins on COVID outcomes in hospitalised patients.”
In the study, researchers reviewed the records of 4447 hospitalised patients, ages 18 years or older, who had been diagnosed with SARS-CoV-2 infection between March 1 and June 30, 2020. Of these, 594 (13%) were receiving statins at admission, with most statin users being men (57%) and older (ages 52–78 compared with ages 29–62) than the non-statin users. The highest percentage of statin users were black (47%), had hypertension (74%) or diabetes (53%), and were more likely to take medications for lowering blood pressure – along with statins to reduce their LDL cholesterol.
After accounting for confounding factors, statin use was found to have no significant effect on COVID mortality. However, they did find that patients hospitalised with COVID and taking statins had an 18% increased risk for having a more severe form of the disease.
“One plausible explanation for this finding is that statins increase cellular production of angiotensin-converting enzyme 2 [ACE2], the receptor on a cell’s surface through which SARS-CoV-2 gains entry,” said Prof Karakousis. “Therefore, statins may lower a cell’s resistance to infection and in turn, increase the odds that the patient will have a more severe case of COVID.”
Prof Karakousis said future studies should attempt to better define the relationship between statin use and COVID, noting that all previous ones were retrospective and had factors that could not be eliminated, such as many statin users being overweight.
The only way to definitively determine if statins have any benefit for patients with COVID is to conduct a randomised, placebo-controlled clinical trial.
SARS-CoV-2 viruses (yellow) infecting a human cell. Credit: NIH
A high dose of heparin, an inexpensive and globally available medication, reduces mortality risk in hospitalised, moderately-ill COVID patients, suggests a new study led by St. Michael’s Hospital.
Appearing in the BMJ, the RAPID Trial compared a high, therapeutic dose of heparin to a prophylactic low dose for patients with moderate COVID and elevated d-dimer levels admitted to hospitals. D-dimers are protein fragments produced when a blood clot gets dissolved; higher levels indicate increased clotting risks.
The researchers studied 465 patients in hospitals around the world and found that while the therapeutic dose of heparin was not associated with a significant reduction in the study’s primary outcome, a composite of death, the need for mechanical ventilation or admission to intensive care, the dosing of heparin did reduce all-cause death in moderately-ill COVID patients admitted to hospital by 78%.
“Our study confirms therapeutic heparin is beneficial in patients who are on the ward with COVID, but other studies suggest it could be harmful for patients who are in critical care,” said Dr. Peter Jüni, Director of the Applied Health Research Centre at St. Michael’s and co-lead of the study.
Therapeutic doses of heparin are used for deep vein thrombosis or pulmonary emboli, whereas prophylactic, or lower, doses are used for patients admitted to Internal Medicine wards to prevent blood clotting while they are in hospital.
Several trials have investigated using blood thinners in COVID patients due to heightened inflammation and clotting in blood vessels caused by the virus. Dr. Michelle Sholzberg, Head of the Division of Hematology-Oncology and Director of the Coagulation Lab at St. Michael’s, and co-lead on the study, hopes this research contributes to a change in treatment guidelines for COVID patients.
“This is a once-in-a-million opportunity – heparin is inexpensive, globally available, and exists in every single hospital pharmacy cabinet right now,” she said. “It’s an opportunity to rapidly repurpose a drug available around the world.”
In particular, she said, the treatment could make a difference in areas where vaccine availability or coverage continues to be limited. Heparin is included in the WHO’s list of essential medicines.
The researchers hope to learn more from the data collected by analysing it further to address new questions, and are also considering revisiting patient outcomes to understand whether these therapies reduce the odds of long COVID.
SARS-CoV-2 virus. Source: Fusion Medical Animation on Unsplash
The global race to develop new stem cell-based COVID treatments during the pandemic was filled with violations of government regulations, inflated medical claims and distorted public communication, according to an article appearing in Stem Cell Reports.
While stem cell therapy has treatment applications for a limited range of diseases and conditions, at present no clinically tested or government-approved cell therapies are available for the treatment or prevention of COVID or long COVID.
Despite this, some clinics have started offering unproven and unsafe “stem cell” therapies that promise to prevent COVID by strengthening the immune system or improving overall health, according to lead author Laertis Ikonomou, PhD, associate professor of oral biology in the University at Buffalo School of Dental Medicine.
The article explores the negative effects that misinformation about cell therapies has on public health, as well as the roles that researchers, science communicators and regulatory agencies should play in curbing the spread of inaccurate information and in promoting responsible, accurate communication of research findings.
“Efforts to rapidly develop therapeutic interventions should never occur at the expense of the ethical and scientific standards that are at the heart of responsible clinical research and innovation,” said Prof Ikonomou.
Other investigators include Megan Munsie, PhD, professor of ethics, education and policy in stem cell science at the University of Melbourne; and
Many of the studies on possible stem cell-based COVID treatments are at an early stage of investigation and further evaluation on larger sample sizes is required, says Munsie. However, the findings from preliminary studies are frequently exaggerated through press releases, social media and uncritical news media reports.
“Given the urgency of the ongoing pandemic, even the smallest morsel of COVID science is often deemed newsworthy and rapidly enters a social media landscape where—regardless of its accuracy – it can be widely shared with a global audience,” said Aaron Levine, PhD, associate professor of public policy at Georgia Institute of Technology..
Clinics selling such treatments sometimes use these findings and news reports to exploit the fears of vulnerable patients by unethically advertising unproven stem cell treatments benefits of boosting the immune system, regenerating lung tissue and preventing transmission of COVID, said co-author Leigh Turner, PhD, professor of health, society and behaviour at the University of California, Irvine.
Reportedly some harm to patients resulted from unproven stem cell therapies, including blindness and death. Patients suffer financially as well, said Prof Ikonomou, as the products range in price from a few thousand to tens of thousands of dollars, and people are often encouraged to receive the expensive treatments every few months.
Patients who COVID may decline vaccines, stop wearing masks and stop other COVID safety measures, Prof Turner warned. They may also be less likely to participate in ethically conducted clinical trials.
“The premature commercialisation of cell-based therapeutics will inevitably harm the field of regenerative medicine, increase risks to patients and erode the public’s trust,” said Prof Ikonomou.
Despite warnings, many offending companies continue to make false claims. The authors recommend that regulatory agencies consider implementing stronger measures.
They also suggest that scientific and professional societies lobby regulatory agencies to increase enforcement of laws and regulations. The authors recommended that science communicators and journalists can combat misinformation by not engaging in hyperbolic coverage of research results and conveying study limitations.
