Drugs used to treat initial signs of rheumatoid arthritis also improve the early stages of heart disease, according to new research
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LONDON/BRUSSELS (Reuters) – Fears of a second wave of COVID-19 infections shut six major food markets in Beijing on Friday, while India, which opened up this week, recorded a record daily increase and half a dozen U.S. states said their hospital beds were filling up fast.
FILE PHOTO: People wearing face masks queue to enter a reopened Primark store as Madrid eases lockdown restrictions following the coronavirus disease (COVID-19) outbreak, in Madrid, Spain, June 11, 2020. REUTERS/Susana Vera/
Health officials worldwide have expressed concerns in recent days that some countries grappling with the devastating economic impact of lockdowns may lift restrictions too swiftly, and that the coronavirus could spread during mass anti-racism protests.
“We must be ready to roll back relaxation of measures if needed,” the European Union’s health commissioner Stella Kyriakides said after urging its 27 members to plough ahead with testing the population as they reopen schools and businesses.
In China, where the new coronavirus originated, two new cases of COVID-19, the disease it causes, were recorded in the capital. Authorities closed part or all of six big wholesale food markets which the two men had recently visited but it was not known how they had become infected.
India opened most public transport, offices and malls this week after nearly 70 days even though health officials said it was weeks away from flattening the rising infection curve.
The official death toll, at 8,498, is relatively small, but the health ministry said registered cases rose by 10,956 on Friday, a record, with many in Delhi, Mumbai and Chennai.
Syed Ahmed Bukhari, the head of Delhi’s Jama Masjid, one of India’s biggest mosques, ordered a halt to congregations until the end of the month.
“What is the point of visiting mosques at a time when the virus is spreading so fast?” he said.
In Turkey, the top medical association said the easing of restrictions on June 1 had come too soon, although the daily death toll as fallen in recent weeks to about 20.
“There is talk of when the second wave will hit, but we have not yet been able to overcome the first wave,” Cavit Isik Yavuz, part of the coronavirus research team at the Turkish Medics Association said.
While new infections are slowing in most of Europe, health experts see a moderate to high risk that post-lockdown rises may warrant new restrictions.
The European Centre for Disease Prevention and Control (ECDC) predicted a moderate acceleration across Europe in coming weeks, which could place healthcare systems under stress if not checked rapidly. Government control measures could check and reverse upward trends within two to three weeks, it said.
Andrea Ammon, director of the ECDC, stressed the importance of maintaining physical distancing, hand hygiene and what she called “respiratory etiquette”.
Officials have expressed concern the virus could spread among the tens of thousands who have crowded together in Europe’s big cities to demonstrate against racism after the death in U.S. police custody of George Floyd.
“Mass events could be a major route of transmission,” said Martin Seychell, a health official at the EU Commission.
World Health Organization (WHO) Director General Tedros Adhanom Ghebreyesus said late on Thursday that the threat of a resurgence remained very real.
“We must also remember that, although the situation is improving here in Europe, globally it’s getting worse … We will continue to need global solidarity to defeat this pandemic fully,” he said.
Of 5,347 new deaths recorded worldwide, 3,681 were in the Americas, the WHO said on Thursday.
In about half a dozen U.S. states including Texas and Arizona, the number of coronavirus patients filling hospital beds is rising, fanning concerns that the reopening of the U.S. economy may unleash a second wave of infections. Alabama, Florida, North Carolina, South Carolina, Oregon and Nebraska all had a record number of new cases on Thursday.
“I want the reopening to be successful,” Harris County Judge Lina Hidalgo, the top executive for the county that encompasses Houston, Texas, told reporters. “But I’m growing increasingly concerned that we may be approaching the precipice of a disaster.”
More hospitalisations inevitably mean more deaths ahead, said Spencer Fox, research associate at the University of Texas at Austin.
“We are starting to see very worrying signs about the course the pandemic is taking in cities and states in the U.S. and around the world,” he said. “When you start seeing those signs, you need to act fairly quickly.”
Wall Street’s main indexes opened sharply higher on Friday, a day after the biggest one-day dive in about three months on fears of a resurgence in infections. Global stocks .MIWD00000PUS were up 1.3% after four days of consecutive losses.
The United States has now recorded more than 113,000 coronavirus deaths, by far the most in the world. That figure could be over 200,000 by September, Ashish Jha, the head of Harvard’s Global Health Institute, told CNN.
additional reporting by Reuters bureax around the world, writing by Philippa Fletcher; Editing by Kevin Liffey and Toby Chopra
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(Reuters) – The following is a brief roundup of some of the latest scientific studies on the novel coronavirus and efforts to find treatments and vaccines for COVID-19, the illness caused by the virus.
FILE PHOTO: A worker checks the temperature of a client at a local store opened for pick up, as phase one of reopening after lockdown begins, during the outbreak of the coronavirus disease (COVID-19), at 5th Avenue in New York City, New York, U.S., June 12, 2020. REUTERS/Eduardo Munoz/File Photo
Coronavirus has more than one gateway into cells
Two teams of European researchers, working independently, have identified a new entryway through which the coronavirus gets into cells and infects them, suggesting another approach to stopping it. One key route – via a protein on cell surfaces called ACE2 – is well known. The newly identified gateway is a cell-surface protein called neuropilin-1, or NRP1. A “spike” on the surface of the coronavirus binds to NRP1, allowing the virus to break into the cell, similar to how a virus spike attaches itself to ACE2. Other viruses also employ NRP1 as an entry into cells, including the one that causes mononucleosis. In laboratory experiments with human cells, one of the teams found that an antibody that binds to NRP1 can block the coronavirus spike from attaching and prevent infection. Neither of the studies has been through the peer-review process. One was posted on the preprint server bioRxiv on Wednesday and the other late last week. The research groups say their findings suggest that NRP1 could be another target for drugs and vaccines against the new virus. (bit.ly/2C1nKk4; bit.ly/2UE2pDJ)
Mouse study suggests Moderna vaccine will be safe in humans
A study of Moderna Inc’s COVID-19 vaccine in mice lends some assurance that it will not increase the risk of more severe disease in humans, and that one dose may provide protection against the novel coronavirus, according to preliminary data released on Friday. Prior studies testing vaccines in similar viruses have suggested that rather than being protective, they might accidentally cause more severe disease, especially in individuals who do not produce an adequately strong immune response. Scientists see this risk as a key hurdle that must be cleared before vaccines can be safely tested in thousands of healthy people. While the data released by the U.S. National Institutes of Allergy and Infectious Disease and Moderna were encouraging, mouse data is no guarantee of what will happen in humans. Further testing also suggested that the vaccine induces potent neutralizing antibody responses – the type of response needed to block the virus from infecting cells – and that it appeared to protect against infection in the lungs and nose without evidence of toxic effects. The study, which has not yet been peer reviewed, was posted on the bioRxiv website. Moderna said on Thursday it plans to begin final-stage trials enrolling 30,000 people in July. (; reut.rs/37pvckt;bit.ly/30Br3sr)
Hydroxychloroquine affect on immune system not helpful against virus
Researchers studying how hydroxychloroquine modifies the body’s immune response have found it is unlikely to be helpful in fighting the coronavirus, in the latest evidence against use of the decades-old malaria drug promoted by U.S. President Donald Trump. The medicine, which is also used treat inflammatory conditions like lupus and rheumatoid arthritis, was shown to prevent the new coronavirus from replicating in test tube experiments. While it does reduce severe inflammation, the researchers say, it simultaneously suppresses the immune responses needed to fight off the virus and does not allow the body to develop so-called trained immunity, which facilities the defense against infections. “The fact that hydroxychloroquine averts trained immunity argues against the usefulness of this drug in clearing SARS-CoV-2 infection,” the researchers wrote in a not-yet-peer-reviewed paper posted on Tuesday on the preprint server medRxiv. (bit.ly/30CRQoe)
COVID-19 is a neurological disease too
Add problems with the brain and nervous system to the list of complications in patients with COVID-19, say doctors, providing further evidence that it is far more than a respiratory illness. For a report on Thursday in the Journal of Neurology, researchers pooled data from 41 previously published studies of the neurological effects of the coronavirus. The most common nonspecific neurological symptoms were fatigue (seen in 33.2% of patients), loss of appetite (30.0%), shortness of breath (26.9%), and general malaise (26.7%). The most common specific neurological symptoms – which occurred less often – included disorders of smell and taste, Guillain-Barré syndrome and inflammation of the brain, spinal cord, and meninges. These tallies did not include strokes that result from blood clotting disorders caused by the coronavirus. In a report published on Sunday in Annals of Neurology, a separate team of doctors called COVID-19 “a global threat to the nervous system” and said, “the number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating.” (bit.ly/2YnRuz6; bit.ly/3hgFCYp)
Mask-wearing significantly reduces infection risk
Of all the lifestyle changes imposed to prevent the spread of the new coronavirus, mask-wearing may be the most important, a new study suggests. Researchers say infection trends shifted dramatically when mask-wearing rules were implemented on April 6 in northern Italy and April 17 in New York City – two epicenters of the pandemic. “This protective measure alone significantly reduced the number of infections, that is, by over 78,000 in Italy from April 6 to May 9 and over 66,000 in New York City from April 17 to May 9,” they calculated in a study published on Thursday in PNAS: The Proceedings of the National Academy of Sciences of the USA. When mask-wearing went into effect in New York, the daily new infection rate fell by about 3% per day, researchers said. In the rest of the country, daily new infections continued to increase. Direct contact precautions – social distancing, quarantine and isolation, and hand sanitizing – were all in place before mask-wearing rules went into effect in Italy and New York City. But they only help minimize virus transmission by direct contact, while face covering helps prevent airborne transmission, the researchers say. “The unique function of face covering to block atomization and inhalation of virus-bearing aerosols accounts for the significantly reduced infections,” they said. That would indicate “that airborne transmission of COVID-19 represents the dominant route for infection,” they conclude. (bit.ly/3fvbabp)
(GRAPHIC: The lifeline pipeline, COVID-19 treatments, vaccines in development – here)
Reporting by Nancy Lapid and Julie Steenhuysen; Editing by Bill Berkrot
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Around the country, nursing homes trying to protect their residents from the coronavirus eagerly await boxes of masks, eyewear and gowns promised by the federal government. But all too often the packages deliver disappointment — if they arrive at all.
Some contain flimsy surgical masks or cloth face coverings that are explicitly not intended for medical use. Others are missing items or have far less than the full week’s worth of protective equipment the government promised to send. Instead of proper medical gowns, many packages hold large blue plastic ponchos.
“It’s like putting a trash bag on,” said Pamela Black, the administrator of Enterprise Estates Nursing Center in Enterprise, Kansas. “There’s no real place for your hands to come out.”
As nursing homes remain the pandemic’s epicenter, the federal government is failing to ensure they have all the personal protective equipment, or PPE, needed to prevent the spread of the virus, according to interviews with administrators and federal data.
Despite President Donald Trump’s pledge April 30 to “deploy every resource and power that we have” to protect older Americans, a fifth of the nation’s nursing homes — 3,213 out of more than 15,000 — reported during the last two weeks of May that they had less than a week’s supply of masks, gowns, gloves, eye protectors or hand sanitizer, according to federal records. Of those, 946 reported they had at least one confirmed COVID infection since the pandemic began.
“The federal government’s failure to nationalize the supply chain and take control of it contributed to the deaths in nursing homes,” said Scott LaRue, president and CEO of ArchCare, the health care system of the Roman Catholic Archdiocese of New York, which operates five nursing homes.
Widespread equipment shortages continue in some places as the virus rages lethally through nursing homes and other long-term care facilities. More than 217,000 short-term patients and long-term residents in nursing homes have contracted COVID-19, and 43,000 have died.
Some homes still have not received the first of two batches of supplies the Federal Emergency Management Agency said it would ship in May. Instead, some got only cloth masks that the Department of Health and Human Services commissioned through a contract with HanesBrands, the apparel company known for its underwear. An HHS webpage says the masks are not intended for caring for contagious patients but can be given to workers for their commutes or to residents when they leave their rooms.
As homes keep scrounging for supplies in a chaotic market with jacked-up prices and continued scarcity, 653 skilled nursing facilities informed the government they had completely run out of one or more types of protective supplies at some point in the last two weeks of May, according to records released last week by the Centers for Medicare & Medicaid Services, or CMS.
“The federal government has got to step up,” said Lori Smetanka, executive director of the National Consumer Voice for Quality Long-Term Care, an advocacy group based in Washington, D.C. “We’re now — what? — three months into this pandemic, and these facilities still don’t have enough PPE to protect themselves and their residents?”
A ‘Relentless Commitment’
In April, Trump pledged his administration “will never waver in its relentless commitment to America’s seniors.” But FEMA’s shipments of masks, gloves, gowns and eye protection have had a more modest goal: “to serve as a bridge between other PPE shipments.”
In written comments, FEMA defended the quality of the poncho gowns but said that because of complaints, the contractor was creating a “short instructional video about proper use of the gowns” to share with homes. FEMA officials said that, as of June 4, the agency had shipped packages to 11,287 nursing homes, starting at “the soonest possible date in the COVID-19 global supply chain climate.”
Yet 67 of the Good Samaritan Society’s 147 nursing homes have not received a FEMA shipment, including homes that are fighting the biggest outbreaks in Sioux Falls, South Dakota; Greeley, Colorado; and Omaha, Nebraska, according to Nate Schema, the Evangelical Lutheran society’s vice president of operations. “We have not received a shipment in our six or seven hot spots,” he said.
The supplies that did arrive tended to be in one size only, he said, and “the quality wasn’t quite up to the same level we’ve been receiving” through the society’s affiliation with Sanford Health, a large hospital and physician system.
The society has enough equipment, but small nursing home groups and independent homes are still struggling, particularly with obtaining N95 masks, which filter out tiny particles of the virus and are considered the best way to protect both nursing home employees and residents from transmitting it.
The CMS records show 711 nursing homes reported having run out of N95 masks, and 1,963 said they had less than a week’s worth. But FEMA is not shipping any N95 masks, and nursing homes are having trouble obtaining them from other sources. Instead, it is sending surgical masks, but more than 1,000 homes have less than a week’s supply of those.
Messiah Lifeways at Messiah Village in Mechanicsburg, Pennsylvania, received a FEMA shipment this week that had face shields and gloves, but only three days’ worth of surgical masks and “very low low-grade quality” gowns that lacked sleeves, said Katie Andreano, a Messiah communications specialist.
Only two of ArchCare’s five nursing homes have received any FEMA shipments even though it is based in New York City, the site of the nation’s biggest outbreak. The equipment for those two homes lasted less than a week. LaRue tried to procure equipment from abroad, but all of the potential suppliers turned out to be fraudulent. He said ArchCare has had to rely on sporadic supplies from the state and city emergency management offices.
“As we sit here today, I’m still not able to get more than a few days’ supply of N95 masks, and I still struggle to a certain extent with gowns,” LaRue said. “That doesn’t make you sleep at night, because you’re not sure when the next delivery comes.”
‘It’s Not Going To Work’
In addition to the supplies, the administration has dedicated $5 billion to nursing homes out of $175 billion in provider relief funds appropriated by Congress. Hospitals are getting much more. Administrators said money doesn’t solve the broken private supply chains, where the availability of PPE is spotty and the equipment is vastly overpriced.
“Too often, the only signs of FEMA’s much-hyped promise of PPE are scattershot delivery with varying amounts of ragtag supplies,” said Katie Smith Sloan, president and CEO of LeadingAge, an association of nonprofit nursing homes and other service agencies for older people.
The cloth masks from HHS have been particularly perplexing to nursing home administrators, given the caveats that accompanied them. The instructions for the masks said they could be washed up to 15 times, according to Sondra Norder, president and CEO of St. Paul Elder Services in Kaukauna, Wisconsin.
“I don’t know how we would possibly track how many times each mask has been washed,” she said. The instructions also said the masks should not be washed with disinfectants, bleach or chemicals, which is how Norder said nursing homes clean their laundry.
Norder said she laundered about 100 masks and they shrank. “The ones that have been washed are tiny, and I certainly wouldn’t want to put something on someone’s face that hasn’t been laundered,” she said. “All my colleagues [at other nursing homes] received the same thing and were also baffled by it, wondering, ‘How are we going to use these?’”
KHN senior correspondent Christina Jewett contributed to this report.
Aging Health Industry Public Health
COVID-19 HHS Nursing Homes
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BRUSSELS (Reuters) – German victims of defective breast implants made by French company Poly Implant Prothese (PIP) cannot claim damages from its insurer as its policy covered only French victims, Europe’s top court said on Thursday, dealing a blow to thousands of women worldwide.
The PIP scandal, in which the company filled its implants with unauthorized industrial silicone instead of medical silicone, occurred in 2010 and affected about 300,000 women in some 65 countries. The company shut down in 2010.
A German victim had sought compensation from PIP’s insurer Allianz IARD in a German court for her faulty breast implants, saying that a clause in the company’s policy which restricted coverage to French victims was against EU laws.
The Luxembourg-based Court of Justice of the European Union disagreed.
“The general prohibition of discrimination on grounds of nationality cannot be the basis for challenging a clause, contained in a contract concluded between a manufacturer of medical devices and an insurance company, that places a territorial limit on civil liability insurance coverage,” judges said.
The PIP Implant World Victims Association called for changes to EU rules for medical devices and more protection for cross-border consumers.
“The regulation favours international exchanges of products, which is a good thing, but consumer protection stops at the border,” said Olivier Aumaitre, a lawyer for the association.
“More than 10 years after the revelation of the scandal, the European authorities have still not deemed it necessary to remedy this major deficiency.”
PIP founder Jean-Claude Mas was jailed for four years and fined 75,000 euros ($85,365) in 2013 after a police investigation revealed a sophisticated fraud.
The case is C-581/18 TÜV Rheinland LGA Products et Allianz IARD (DE).
($1 = 0.88 euros)
Reporting by Foo Yun Chee, additional reporting by Myriam Rivet in Paris; Editing by Angus MacSwan
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(This story corrects UnitedHealth executive’s title)
FILE PHOTO: The ultrastructural morphology exhibited by the 2019 Novel Coronavirus (2019-nCoV), which was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China, is seen in an illustration released by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, U.S. January 29, 2020. Alissa Eckert, MS; Dan Higgins, MAM/CDC/Handout via REUTERS/File Photo
By Caroline Humer and Marisa Taylor
NEW YORK (Reuters) – The scramble to research the novel coronavirus has exposed weaknesses in the vetting of healthcare data being supplied by a growing number of U.S. firms, a flaw that forced two of the most respected medical journals to pull studies last week.
The Lancet and the New England Journal of Medicine (NEJM) retracted COVID-19 studies over questionable patient health data supplied by a small company called Surgisphere.
U.S. researchers say they are routinely peppered with pitches from similar firms, with no widespread standard of how to verify their datasets.
“Whenever you don’t know where data comes from, and precisely how it was managed, then the number of incorrect conclusions you can draw is large,” said Kenneth Mandl, director of the Computational Health Informatics Program at Boston Children’s Hospital. “The field is young enough that those best practices may not be well established across the scientific community.”
The Lancet study, which concluded treating COVID-19 with hydroxychloroquine increased the risk of death, drew scrutiny from scientists worldwide. They suggested that patient outcomes data from several countries did not add up.
Mandeep Mehra, a Harvard Medical School professor and researcher with Brigham and Women’s Hospital in Boston, and his co-authors retracted the Lancet study and a second study in NEJM, saying they could not vouch for the veracity of the data and that Surgisphere would not provide its underlying data to independent auditors.
The retractions “are great examples of why science needs more of a ‘In God We Trust, everyone else needs to show their data’ approach,” said Ivan Oransky, vice president of editorial at Medscape and co-founder of the Retraction Watch blog.
Over the years, more than 1,500 studies have made it into Retraction Watch’s database because of data concerns such as data falsification by the authors, Oransky said. There have been about 15 medical paper retractions related to COVID-19, according to the website.
For years, U.S. healthcare data was concentrated in medical claims compiled by large insurers such as UnitedHealth Group Inc and the government. As hospitals have moved to electronic health records, independent analytics firms are buying hospital data sold without patient names.
The U.S. Food and Drug Administration now allows data gathered outside of clinical trials to be considered in its reviews of new drugs, providing another boost to the healthcare analytics industry.
It is not clear how Surgisphere accessed the data used in the two studies. Surgisphere did not return requests for comment.
At a time when researchers are scrambling to find a cure for COVID-19, data sets like those used in the now retracted studies can appear to be a “goldmine,” Mandl said.
A spokesman for Lancet publisher Elsevier said it will re-assess about 20 additional published articles that contain Surgisphere data.
A spokesman for Brigham and Women’s Hospital said its data oversight mechanisms “were not applicable” to the Lancet and NEJM studies, adding it only provides “support, guidance and oversight on all agreements that involve the use of our institutional resources, including our patient data.”
Harvard Medical School would not comment on its role in vetting the data. Harvard and the Brigham declined to say whether further steps would be taken regarding the researchers’ handling of the matter.
While the NEJM and Lancet articles had external peer review, they relied on the authors to vouch for the data.
“We are reviewing our procedures, including how we assess research analyzing large datasets based on electronic medical record data,” said NEJM spokeswoman Jennifer Zeis.
After the retraction, the Lancet said it was conducting a review, and that serious scientific questions had been raised.
Dr. Deneen Vojta, executive vice president of UnitedHealth’s global research and development division, said it is important to ask questions about how a group obtained their data, and that it must be made available for scrutiny.
Dr. Peter Bach, from Memorial Sloan Kettering in New York, said his research team regularly assesses data offered by these new firms to make sure it jibes with its own knowledge, such as ages of people having a certain surgery or the number of prescriptions the firm says were dispensed.
“We do lots of tire kicking,” Bach said.
Reporting by Caroline Humer in New York and Marisa Taylor in Washington D.C.; Additional reporting by Julie Steenhuysen in Chicago and Nancy Lapid in New York; Editing by Bill Berkrot
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A new study published on the preprint server medRxiv* in June 2020 shows that the drug hydroxychloroquine (HCQ) suppresses a form of immunity called ‘trained immunity,’ with repercussions for its potential use to treat COVID-19.
HCQ is an anti-malarial and a disease-modifying anti-rheumatic drug (DMARD), which was observed to inhibit the replication of SARS-CoV-2 in vitro. However, its antiviral effect in humans in vitro has not been confirmed. It may have an immunomodulatory effect as well. However, the lack of evidence of its efficacy and how they act has roused controversy surrounding its use.
Image Credit: Video_Creative / Shutterstock
The current study aimed to understand how HCQ acts on the immune response in COVID-19. Using techniques that unravel the function of immune cells, as well as transcriptomic analyses, the researchers found marked changes in the expression of molecular markers and functionalities of monocytes in COVID-19 patients. They also found that interferon-stimulated genes (ISG) play a role in disease severity.
With metabolomic and epigenetic studies, the researchers found that HCQ suppresses trained immunity. Trained immunity refers to a change in the way that monocytes function in response to epigenetic changes that reprogram their antiviral responses. These findings suggest that HCQ may not be suitable for the therapy or prevention of COVID-19.
The study included 13 patients hospitalized with SARS-CoV-2, all above 18 years of age. The median age was 68 years. They had various coexisting maladies such as pulmonary disease, cardiovascular disease, and malignancy.
Most patients were admitted to hospital with fever, cough, or breathlessness. Seven of the patients required oxygen at admission. All showed signs of pneumonitis on chest imaging, but none were critically ill. All patients were started on chloroquine (CQ) at admission, for five days.
On blood analysis, the T cell count was slightly lower than normal, and monocyte counts were markedly higher, mostly because of a rise in classical monocytes. Nonclassical monocytes were almost undetectable, and their markers, such as CX3CR1, were reduced.
HLA-DR expression on monocytes was reduced, which has been associated in recent studies with the hyperactivation of monocytes and the excessive release of the pro-inflammatory cytokine IL-6 in COVID-19. CD11b, a monocyte activation marker, is also upregulated. These markers remained constant over five days in those who were still hospitalized at the end of the study.
The researchers then examined the functional status of peripheral blood mononuclear cells (PBMCs) by stimulating them and then measuring the release of cytokines IL-1β, IL-6, and TNFα. They found that excessive cytokine release occurred in COVID-19 patients when lipopolysaccharides and other antigens were used to activate Toll-like receptor (TLR) 4 and other similar receptors.
Next, they looked at whether adaptive immunity was also altered, by stimulating PBMCs for 7 days with Staphylococcal aureus antigens, and measuring Th1 and Th17 cell activation via IFNγ and IL-17 levels respectively. Healthy controls showed increases in the former alone, but in COVID-19 patients, the latter was raised. This indicates a shift towards Th17 cell activation rather than the normal Th1 dominance.
When they compared the 9 patients who recovered without intensive care unit (ICU) admission with the 4 who required ICU care or died (3 and 1, respectively), they found no clear markers at presentation to predict favorable or poor outcomes. However, immune markers showed differences such as a reduced monocyte HLA-DR expression in those who went on to poor outcomes, indicating a more severe inflammatory phenotype in monocytes for these patients.
Transcriptome analysis of monocytes from COVID-19 patients showed a higher level of transcription of ISG, which plays a significant role in antiviral responses. Excessively high ISG expression was linked to poor outcomes.
Six and seven patients were discharged within five days and remained hospitalized, respectively. PBMCs from this group at 5 days from admission showed a clear demarcation between findings indicating a good vs. poor outcome.
Specifically, the inflammatory response is characterized by marked innate immune changes, in agreement with previous reports, in the form of increased monocyte activation, increased ISG expression, and elevated monocyte-derived cytokine release.
The researchers comment, “This enhanced responsiveness is reminiscent of the inflammatory phenotype previously reported in sepsis and influenza. While inflammation early in the infection contributes to improved antiviral mechanisms and elimination of infection, if exacerbated late during the course of the disease it may play a role in the development of the severe complications of COVID-19.”
This led to an investigation into whether HCQ affects trained immunity. This molecule moves passively into the lysosomes and disrupts its function. Since the lysosomes are central to the regulation of immune metabolism with innate immunity via the mTOR receptor on its membrane, trained macrophages are characterized by the activation of key regulators of lysosome genes.
To understand how HCQ affects trained immunity, they repeatedly stimulated human PBMCs with bacterial antigens. They found that the cells produced much more cytokines with repeated stimulation, but this effect disappeared when the cells were treated with HCQ simultaneously.
On restimulation of monocytes with IFNγ, there was a rise in IL-6 and TNFα production, which also vanished with HCQ treatment. The researchers analyzed the change in terms of lysosomal function and found that the inhibition of vacuolar ATPase (V-ATPase) led to blocking the development of trained immunity, which is similar to the effect of HCQ treatment.
Next, the effects of hydroxychloroquine on the transcription of trained monocytes were analyzed. They found that this led to a substantial reduction in the expression of genes related to inflammatory responses, including ISG. This was accompanied by the increased expression of metabolic pathways involved in inflammation. Altogether, this implies the role of HCQ in suppressing the development of trained immunity and the expression of ISG.
HCQ also affects cellular lipid metabolism, as part of its suppressive effect on trained immunity. The stimulation of the monocytes by bacterial antigens, with and without HCQ exposure followed by lipidomic analysis, showed that the normal wide-ranging and deep changes in the monocyte lipids that accompanies trained immunity was suppressed by HCQ. This may affect the structure and function of the cellular membranes, disrupting the activity of membrane-bound genes, including the all-important mTOR on the lysosomal membrane, as well as inhibiting lipid-dependent activation enzymes required for the normal immune response.
HCQ also prevents the normal epigenetic modifications that are required for trained immunity, shutting down normal changes in epigenetic markers associated with immune and inflammatory responses.
The authors say this data provides crucial new information about how HCQ acts in COVID-19. Though HCQ has been used for decades as an immunomodulator to benefit rheumatoid arthritis and systemic lupus erythematosus because it inhibits pro-inflammatory cytokines like IL-6 and TNFα. It is known that this effect is partly mediated by its inhibition of lysosomal processes like autophagy, antigen processing, and TLR7 processing.
However, the current study adds to this knowledge via the findings that HCQ prevents the development of trained immunity via epigenetic regulation. This may be via its effect on mTOR signaling since this is a lysosome-associated enzyme transmitting information from the lysosome to the cell, and thus mediates inflammation. The data on the changes in lipids that play a key role in mTOR activation supports this reading.
Since trained immunity is required to upregulate the innate immune response and so prevent infection, HCQ is less likely to be of use in preventing or clearing SARS-CoV-2 infection. This agrees with the findings of a recent randomized controlled trial that HCQ given post-exposure does not help prevent symptomatic COVID-19.
The question remains whether the immunomodulatory effects of HCQ could mediate its effectiveness in severe COVID-19 by muting the cytokine storm. The researchers say this is likely to be less useful than IL-6 receptor antibodies or IL-1 receptor antagonists, and an observational study lends some support to this prediction. More research is required to test this hypothesis. They sum up: “Our findings suggest that hydroxychloroquine may not have a beneficial effect on the antiviral immune response in SARS-CoV-2 infection.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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A new study by scientists at Metro Infectious Disease Consultants and published on the preprint server medRxiv* in June 2020 reports that the cytokine blocker tocilizumab is a useful adjunct to supportive medical care in severe COVID-19, with increased survival and a lower requirement for mechanical ventilation.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged in China towards the end of the year 2019 but rapidly spread worldwide to become a pandemic. As many as 20% of patients progress to severe disease, and up to 10% may die of terminal respiratory failure secondary to acute respiratory distress syndrome (ARDS). This percentage varies with the population segment affected, with the highest risk being seen among older adults and those with other medical conditions such as type 2 diabetes, obesity, and hypertension.
The spectrum of illness with COVID-19 varies from asymptomatic or mild symptomatic infection in the majority of cases to progressive pulmonary impairment with a pneumonia-like picture, and finally to rapid multi-organ dysfunction with ARDS and cardiovascular collapse. During this stage, the levels of multiple inflammatory cytokines and markers are raised, including IL-2, IL-6, C-reactive protein (CRP), ferritin, D-dimer, and lactate dehydrogenase (LDH).
There is no specific treatment or vaccine strategy as of now that is effective against SARS-CoV-2. However, the IL-6 blocker tocilizumab has been explored as a possible therapy for immunomodulation, to mute the so-called cytokine storm, the excessive and damaging rise in pro-inflammatory cytokines, in the final stage of severe COVID-19.
This drug is already approved for the treatment of rheumatoid arthritis and the cytokine release syndrome associated with the CAR-T cell treatment of cancer patients. This last condition is very similar to the pathogenesis of the cytokine storm in severe COVID-19 and justifies the experimental use of tocilizumab in the latter stage.
At present, tocilizumab is used at 4-8 mg/kg (max: 800mg per dose) intravenous infusion, repeated once if necessary. The current study was designed to find the actual benefit and the optimal regimen for this drug in COVID-19 patients with the most severe illness.
The study was made up of 157 patients who were admitted to hospital between March 13, 2020, and April 16, 2020. A retrospective study was done using medical records from multiple practices to retrieve the age, sex, duration of hospital stay, need for mechanical ventilation, the use of steroids and other drugs, and remdesivir. The presence and type of comorbidity were also analyzed, including risk factors like age above 60 years, diabetes, chronic obstructive pulmonary disease, bronchospasm, chronic cardiac or renal disease, immunodeficiency, and cancer.
The dose of tocilizumab was registered as early or late, depending on whether it was given before or within a day after intubation, or later than this, respectively. If the patient was not intubated, the dose was related to the date of admission. The patient outcomes included discharge from hospital, death, or continued hospitalization.
The average patient age was 58 years, and 65% were male. About 40% and 30% were White and Black, respectively, with 22% being Hispanic and a small percentage of Asians. 69% had other illnesses. All patients had raised inflammatory markers on admission.
Steroids were given to 60%, and 99% received hydroxychloroquine and azithromycin. About 85% of patients were given one dose of tocilizumab, and 15% had two doses 12 hours apart. The majority received 4 mg/kg, up to 400 mg in total, while nine patients received 600 or 800 mg.
56% of patients required mechanical ventilation, with 37 receiving tocilizumab early and 44 late.
Among discharged patients (48%), the hospital stay lasted about 15 days. In those who died (28%), it was 16 days and 29 days for those still in hospital at the end of the study period (24%). The highest mortality was among Blacks, at about 44%.
Analysis of the use of ventilators in relation to the timing of tocilizumab from the date of admission, the use of steroids, and demographic factors, showed that with each day of delay from the day of admission, the chances of requiring mechanical ventilation went up by a fifth.
In patients who required mechanical ventilation, the timing of tocilizumab was related to the mortality, with a lower mortality rate among those who received the tocilizumab earlier, compared to later dosing (14% v 868%) after accounting for demographic differences. The rate of discharge was also significantly higher in the early-tocilizumab group, at 60%, compared to 18% in the late tocilizumab group of patients.
Among the 81 patients who were put on mechanical ventilation and then discharged, tocilizumab was given early, about 4.2 days from admission, and within a day of intubation. Those who died received the drug about 4 days from intubation and about 5.5 days from admission.
The time from intubation to dosing was the only predictor for discharge following intubation. Again, later tocilizumab administration increased the odds of death in mechanically ventilated patients by 18-fold compared to earlier administration. Among early-tocilizumab patients, non-whites were 6 times more likely to die than whites.
Among those on steroids, 44% were discharged, and 35% expired. There were 25 patients on steroids and mechanical ventilation who died, compared to 15 who were discharged.
Among those who had two doses of tocilizumab, half were intubated. Half were discharged, 23% died, and 32% were still in hospital at the time of analysis. When those who chose not to be put on ventilation via living wills, about 14% of whites and 32% of non-whites died, focusing attention on the continuing but little understood tendency for non-whites to have higher mortality.
Despite the observational nature of the study, some conclusions were arrived at. Severe drug reactions were rare. However, the use of multiple drugs made it almost impossible to disentangle the effects of any individual drug. This mandates further research with randomized studies.
The study sums up: “While the optimal time to dose tocilizumab has not been previously established, our data strongly support a mortality benefit of dosing tocilizumab early and within 1 day of intubation. Accordingly, we strongly encourage the use of this agent earlier in the COVID-19 treatment spectrum.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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