A cytokine pattern that predicts adverse outcomes in COVID-19

The current pandemic of COVID-19 has caused many millions of people to become sick, and hundreds of thousands have been left dead. However, without a clear understanding of how its fatal effects are brought about, there is a lack of effective management strategies. A new study published on the preprint server medRxiv* in May 2020 reports the discovery of a predictive pattern of cytokines in COVID-19 infection that could guide clinical management if validated.

Novel Coronavirus SARS-CoV-2: This scanning electron microscope image shows SARS-CoV-2 (round gold objects) emerging from the surface of cells cultured in the lab.  Credit: NIAID-RML

SARS-CoV-2 – Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Uncontrolled Inflammation and COVID-19

Many scientists think that the high mortality rate of the COVID-19 outbreak is due to a combination of direct viral injury and uncontrolled release of inflammatory cytokines that worsen tissue damage. This type of cytokine storm is not unique to COVID-19, however. In fact, it is similar to the cytokine release syndrome (CRS) seen with CAR-T cell therapy in cancer patients.

One cytokine believed to be involved in CRS is IL-6, based on the use of tocilizumab has widely used to treat such patients. This has been extended recently to COVID-19 patients as well, but with qualified success only.

Another cytokine that is higher in CRS is TNF-alpha, which amplifies inflammatory response pathways. Drugs that inhibit TNF-alpha are at present being used in more than ten autoimmune conditions.

IL-1 is another active proinflammatory chemical, and its blocker is used for rheumatoid arthritis management and other autoinflammatory conditions with sustained favorable effects. IL-8 also plays a significant role in recruiting and activating neutrophils during inflammation.

In view of these findings, many possible immunomodulatory drugs have started being used in clinical trials and for off-label use in COVID-19. However, they have significant side effects, which mandates careful study to find biomarkers that will tell doctors when to use these drugs to maximum effect.

Identifying Cytokines that Predict COVID-19 Severity: The Study

The current study aimed to find out how and which inflammatory cytokines could help predict the course and outcome of disease in COVID-19. The researchers narrowed down their field to just four cytokines, as mentioned above – IL-6, IL-8, TNF-α, and IL-1β. The researchers tested clinically available drugs to counteract the four pathogenic cytokines, using the ELLA microfluidics platform to measure them within 3 hours.

The study included over 1,480 patients with suspected (167) or confirmed (1,257) COVID-19, in Mount Sinai hospitals, who were followed up from admission to discharge or death. At admission, all patients had their blood checked for the levels of these four cytokines. These were then correlated with disease severity, by clinical and laboratory findings, and the patient outcome.

Overall, COVID-19 patients had higher levels of IL-6, IL-8, and TNF-α than healthy controls or those on CAR-T cell therapy but without CRS. Most of the COVID-19 patients had high cytokine levels consistent with a cytokine storm, but interestingly, the concentration of each of the cytokines was not well correlated with those of the others. IL-6 showed the most significant fluctuation and IL-1β, the lowest, indeed, at the lower limit of detection.

With men, IL-6 levels were higher than for women. With the first three cytokines, levels increased with age, but not with body mass index. However, the prevalence of obesity in this group was higher. IL-1 β and TNF- α levels were significantly higher in Hispanics vs. blacks.

Chronic kidney disease (CKD) was linked to IL-8 and TNF-α. No other disease condition showed a significant association. Only age and CKD were linked to an increased risk of mortality from COVID-19. Singly, the first measurement of each cytokine was capable of predicting overall survival.

After adjusting for demographic factors and other illnesses, all except IL-1 β remained significant. Thus, patients aged over 70 had a 45% lower survival compared to those aged 50-70 years, and 76% lower compared to those below 50 years. A high IL-6 predicted a 227% increase in chances of death, and TNF- α reduced the chances of survival by 150%.

Cytokines to Predict High-Risk Patients

The researchers found strong correlations between the four cytokines and known laboratory markers of inflammation, and with fever as well in the case of IL-6 and IL-1 β. In addition, the clinical severity scale was also closely correlated with IL-6 and IL-8, which remained independent predictors of disease severity. TNF-α rose with end-organ damage.

Cytokines and Treatment Protocols

From a smaller subset of 244 patients who had repeated cytokine measurements, the researchers tested the effect of various treatments on cytokine levels. They found that treatment with the IL-6 receptor blocker tocilizumab, used in some patients with progressive respiratory failure and systemic inflammation, with high IL-6 levels, led to a transient rise in this cytokine alone, while TNF-α slowly fell.

Steroids and remdesivir caused IL-6 but not TNF-α to fall rapidly and slowly over time, respectively. No clear trend was observed with other drugs.

Unsupervised clustering of laboratory measurements in a subset of 1069 patients with sufficient available information. On the y axis are vitals and laboratory values after z-scoring, and on the x axis are individual patients, using metrics measured from the time point corresponding to the first ELLA cytokine test. Grey bars on the side of the plot indicate clusters of patients or analytes, where cytokines co-cluster with known severity metrics, such as LDH, CRP, ferritin, D-dimer, but also high neutrophil, platelet and white blood counts. Annotations show patients who died in orange, and maximum severity score achieved in gray shades. B. Similarity matrix of patients based on analytes and measurements, showing two major clusters, with enrichment in patients who died and had more severe COVID-19 on the upper left. C. Similarity matrix of cytokines, lab measurements and vitals, showing IL-6, IL-8, and IL-1b co-clustering with known inflammatory markers such as LDH, CRP, ferritin, and D-dimer, while TNF-a coclusters with organ damage markers.

Unsupervised clustering of laboratory measurements in a subset of 1069 patients with sufficient available information. On the y axis are vitals and laboratory values after z-scoring, and on the x-axis are individual patients, using metrics measured from the time point corresponding to the first ELLA cytokine test. Grey bars on the side of the plot indicate clusters of patients or analytes, where cytokines co-cluster with known severity metrics, such as LDH, CRP, ferritin, D-dimer, but also high neutrophil, platelet and white blood counts. Annotations show patients who died in orange, and maximum severity score achieved in gray shades. B. Similarity matrix of patients based on analytes and measurements, showing two major clusters, with enrichment in patients who died and had more severe COVID-19 on the upper left. C. Similarity matrix of cytokines, lab measurements, and vitals, showing IL-6, IL-8, and IL-1b co-clustering with known inflammatory markers such as LDH, CRP, ferritin, and D-dimer, while TNF-a coclusters with organ damage markers.

Implications

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The study shows that COVID-19 survival causes high levels of all four cytokines at presentation. IL-6 is among the strongest indicators of survival, more than currently used inflammatory markers like CRP or D-dimer. It can be used with markers of end-organ damage and the ventilation status to predict survival and severe disease.

TNF-α also predicts very severe disease or death even when adjusted for a host of other risk factors and for IL-6 levels.

The study also shows that the cytokine response in COVID-19 is different from that seen in sepsis and CAR-T cell therapy, with an uncoordinated and sustained cytokine response. This could point to the possibility of using specific anti-cytokine treatments to alleviate disease severity. More research must be conducted to find out which and when such therapies are useful.

In summary, the researchers found that when IL-6 and TNF- α are high at the time of admission, the patient is likely to have severe disease and reduced survival, irrespective of the use of other clinical and laboratory findings. The researchers say boldly, “These results suggest that multiplex cytokine profiling should be used to stratify patients and guide resource allocation and prospective interventional studies.”

*Important Notice

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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Lancet issues correction on paper than prompted WHO to suspend Hydroxychloroquine trial

The World Health Organization (WHO) suspended the hydroxychloroquine trial amid the coronavirus pandemic. The decision comes after the study findings published in The Lancet reported issues on the drug’s efficacy and safety. Now, the journal has issued a correction on the figures reported in the study.

The coronavirus disease (COVID-19) has ravaged across the globe, infecting more than 6.26 million people across the globe and killing more than 375,000 people. Hydroxychloroquine is one of the drugs seen as a potential treatment for the novel coronavirus.

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What is hydroxychloroquine?

Hydroxychloroquine, sold under the name Plaquenil, and its sister drug chloroquine, sold under Aralen, are under investigation for the treatment of COVID-19, caused by the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The drug is classified as an anti-malarial and used in treating several forms of malaria. Today, it is used to treat rheumatoid arthritis, some symptoms of lupus, childhood arthritis (or juvenile idiopathic arthritis), and other autoimmune diseases.

The drug works by altering the human immune system, since it is an immunomodulator, but has a range of severe side effects, including altered heart rhythm and eye damage.

The trial

The Solidarity Trial aimed to evaluate the efficacy and safety of four drugs and drug combinations to combat COVID-19. In the trial, there are more than 400 hospitals in 35 countries that are actively recruiting patients. At least 3,500 patients have been enrolled in 17 countries.

On May 25, the WHO had announced it suspended the trial of hydroxychloroquine in treating COVID-19 patients due to the drug’s potential danger to patients. Many countries have halted the trials as a precaution.

WHO made the decision after the study suggested that the drug could heighten the risk of patients dying from COVID-19. Further, patients were seen to experience heart problems.

Study corrections

The Lancet issued the study corrections four days after the WHO suspended human trials of the drugs.

On May 29, the journal issued a clarification that the study reported the wrong number of participants in Australia and Asia. However, the study results remain unchanged.

One hospital self-designated to belong to the Australasia continental designation should have been assigned to the Asian continental designation.

“In this Article, in the first paragraph of the Results section, the numbers of participants from Asia and Australia should have been 8101 (8·4%) and 63 (0·1%), respectively. One hospital self-designated as belonging to the Australasia continental designation should have been assigned to the Asian continental designation,” The Lancet corrected.

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“The appendix has also been corrected. An incorrect appendix table S3 was included, originally derived from a propensity score-matched and weighted table developed during preliminary analysis. The unadjusted raw summary data are now included. There have been no changes to the findings of the paper. These corrections have been made to the online version as of May 29, 2020, and will be made to the printed version,” it added.

Scientists challenging study data and findings

In an open letter to the authors of the study and the editor of The Lancet, more than 200 scientists report that the data from Australia are not compatible with government reports.

They are challenging the validity of the influential study that found a link between hydroxychloroquine and chloroquine for COVID-19 patients and an increased in-hospital death. The study also found that the drugs have increased the risk of abnormal heart rhythm.

The scientists highlighted concerns about the quality of the data and its analysis. One of the issues pointed out was the lack of information about the countries and hospitals that contributed data, which was provided by Chicago-based healthcare data analytics firm, Surgisphere.

Further, other issues underscored included discrepancies in the data Australia, where there were more deaths recorded in the hospitals covered by the study than the official figures from the government.

“There are now 201 signatories from all over the world. My email inbox has been flooded, so I apologize if I’ve missed some people,” James Watson posted.

There are now 201 signatories from all over the world. My email inbox has been flooded so I apologize if I’ve missed some people.

Still no reply from @TheLancet @richardhorton1

Everyone is wondering #whats_with_hcq_lancet_paper ? https://t.co/nsTA8606Gk

— James Watson (@jwato_watson) June 1, 2020

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‘Why Do We Always Get Hit First?’ Proposed Budget Cuts Target Vulnerable Californians

Shirley Madden, 83, relies on a caregiver and her two grown daughters to remain living at home — and not in a nursing home.

Her daughters, 55-year-old Carrie and 60-year-old Kristy Madden, both use wheelchairs and need a second caregiver to help them navigate their own daily lives.

But that critical caregiving support, along with other health care benefits for millions of Californians, could be scaled back to help plug a massive budget deficit triggered by the coronavirus.

California Gov. Gavin Newsom has proposed sweeping budget cuts to safety-net health care programs ― including Medi-Cal, California’s Medicaid program for low-income people ― just as enrollment is projected to spike because of record job losses related to the pandemic.

Health care experts also fear the cuts could jeopardize billions of dollars in emergency federal health funding allotted to California.

“I understand there’s a pandemic and it’s really bad and everybody is hurting,” said Carrie Madden of Chatsworth, California. Carrie and her sister have muscular dystrophy and their mother is a heart attack survivor who struggles with dementia.

Madden’s fears are compounded by the COVID-19 crisis, which has hit older people and those with chronic health conditions the hardest. She doesn’t want her mother, her sister or herself to end up in a nursing home or other long-term care facility — the settings with the most outbreaks of COVID-19.

“This is the wrong approach,” she said. “This will make disabled people end up in nursing homes.”

States across the country are eyeing Medicaid cuts to balance their budgets, in part because health care is usually the biggest portion of state spending, after education. They also project that more people will sign up for the public health care program, as the number of unemployed Americans hits astronomical heights. More than 20 million Americans filed for unemployment in April, raising the unemployment rate at least to 14.7%, the worst since the Great Depression of the 1930s.

New York approved Medicaid cuts that will take effect after the federal emergency ends, while Georgia has instructed all its agencies to reduce spending by 14%.

In California, where almost 2.9 million people have filed for unemployment in the past two months, Newsom described the proposed budget cuts as “prudent” and “strategic,” a huge pivot from the grand plans he unveiled earlier this year to expand health care to some of the neediest residents.

To address an estimated $54 billion deficit in the 2020-21 state budget, Newsom proposes a $205 million cut — or a 7% reduction in caregiver hours — to the In-Home Supportive Services program the Maddens rely on. The program, primarily funded by Medi-Cal, pays caregivers to make meals for people who need help to live independently, do their laundry, bathe them, administer medical treatments and keep their home clean.

The list of his other proposed cuts is lengthy: He would scale back or eliminate other programs intended to keep low-income seniors and people with disabilities in their own homes, such as adult day health care and support from social workers. He proposes to make it easier for the state to collect posthumous payback from deceased Medi-Cal enrollees 55 and older for a broad range of medical costs through the controversial “Estate Recovery Program.” He suggests reinstituting stricter income requirements for some older people and those with disabilities to qualify for free Medi-Cal.

And he is calling on lawmakers to remove $54.7 million in “optional” Medi-Cal benefits, such as adult podiatry care, eyeglasses, speech therapy and hearing exams — benefits that lawmakers recently restored after they were cut during the last recession.

“These don’t feel optional to people if they have had a stroke or need teeth to eat their food,” said Tricia Berke Vinson, an attorney with the Legal Aid Society of San Mateo County.

“I understand we are in a budget crisis,” she added. “I just don’t think it can be balanced on the old and the sick.”

Physicians, dentists and other health care providers who treat Medi-Cal patients also stand to lose $1.2 billion in supplemental Medi-Cal payments that flow from Proposition 56, a tobacco tax that voters approved in 2016.

The Democratic governor’s proposal includes an automatic “trigger” to restore the cuts if the state gets more federal COVID relief dollars, shifting the responsibility to Congress to negotiate another stimulus package.

Whether lawmakers will make the sweeping Medi-Cal cuts the governor has proposed is uncertain. For example, the state Senate plan preserves Medi-Cal funding and assumes Congress will pass another stimulus bill.

Both houses of the legislature must come to an agreement and present their version of the budget to the governor for consideration by June 15.

“Save these programs and you save lives and money,” said Assembly member Jim Wood (D-Santa Rosa), chair of the Assembly Health Committee. “Cut these programs and costs will increase and lives will be lost.”

Health care experts and some lawmakers also fear Newsom’s approach could jeopardize billions of dollars in emergency federal health funding already allotted to California.

States that drop Medicaid enrollees or reduce benefits risk losing out on additional federal health payments authorized by Congress this spring, said Edwin Park, an expert on Medicaid and a professor at Georgetown University McCourt School of Public Policy.

“The federal government has said you can’t cut eligibility or disenroll or cut benefits,” Park said. He noted that New York lawmakers delayed their state Medicaid cuts until after the federal emergency ends to ensure they still receive the added federal help now.

The Centers for Medicare & Medicaid Services did not respond to requests for comment. Guidance posted on its website suggests states must keep Medicaid programs intact.

California is expected to receive $5.1 billion in additional federal funding for Medi-Cal through June 30, 2021, according to the proposed budget Newsom released in mid-May.

The Newsom administration is not convinced its Medi-Cal budget cuts will cost the state the additional federal money already approved by Congress.

“There’s never a guarantee until we have that conversation with the federal government. So until then, it’s hard for us to tell what the fed’s going to do,” said Yang Lee, an analyst at the state Department of Finance.

Newsom’s administration predicts about 2 million Californians will sign up for Medi-Cal by July as a result of the pandemic, bringing the program’s enrollment to 14.5 million, more than one-third of all Californians.

The administration anticipates $3.1 billion in added costs to cover the new enrollees. The Legislative Analyst’s Office believes that figure is $750 million too high, in part because new sign-ups will primarily be younger and healthier individuals who do not need as much care as low-income seniors and people with disabilities.

For many current enrollees, Newsom’s proposals would cut into multiple benefits.

Cynde Soto, 63, said it felt like “someone had punched me in the gut” when she heard about the governor’s plan to cut the In-Home Supportive Services budget. As a quadriplegic, the Long Beach resident worries state cutbacks could force her into a nursing home. On top of that, she fears she might lose her Medi-Cal dental and vision care if Newsom’s other cuts are approved.

“I’ve had nightmares about it. I don’t know what I’m going to do,” Soto said. “Why do we always get hit first?”

This KHN story first published on California Healthline, a service of the California Health Care Foundation.

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California Cost and Quality Insurance Medi-Cal Medicaid States

COVID-19 Disparities State Budgets

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Egypt reports first decline in new coronavirus cases for a week

FILE PHOTO: A family rides a motorbike in front of National Hepatology and Tropical Medicine Research Institute amid concerns about the spread of the coronavirus disease (COVID-19), in Cairo, in Egypt May 26, 2020. REUTERS/Staff

CAIRO (Reuters) – Egypt confirmed 1,399 new cases of the novel coronavirus on Monday, the health ministry said, its first decline for a week.

That is down from 1,536 reported the day before, but still almost double the number on the same day a week ago.

Egypt has reported a total of 26,384 cases, of which 6,297 have recovered and 1,005 died, the ministry said.

Reporting by Nayera Abdalla and Ulf Laessing; Editing by Richard Chang

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Wildlife groups pressure Big Pharma to curb crab blood addiction

ZURICH (Reuters) – Wildlife advocates are pushing drugmakers to curb the use of horseshoe crab blood by switching to a synthetic alternative for safety tests, including those needed before a COVID-19 vaccine can be used on humans.

FILE PHOTO: Atlantic horseshoe crabs come ashore by the thousands to spawn and lay their eggs on Pickering beach, a national horseshoe crab sanctuary near Little Creek, Delaware in this picture taken May 20, 2008. REUTERS/Mike Segar (UNITED STATES)/File Photo

Fishermen net hundreds of thousands of the creatures off the U.S. East Coast and Asia every year, draining their prized milky-blue blood for use in medical safety tests that detect bacterial contamination in intravenous drugs or implants.

The National Audubon Society, Defenders of Wildlife and other groups called for greater use of a man-made option, called recombinant Factor C (rFC), in a statement released on Monday by umbrella organization the Horseshoe Crab Recovery Coalition.

They say this shift could save 100,000 horseshoe crabs annually on the U.S. East Coast alone and help threatened migratory birds that depend on crab eggs for survival.

“It is unfortunate that biomedical research still relies on the harvesting of a vulnerable wild animal population when there is a simple, effective, sustainable replacement,” said Ryan Phelan, a campaigner with California-based conservation group Revive & Restore.

However, the testing industry’s impact on the U.S. crab population is disputed, with varying estimates of how many die during bleeding or after they are returned to the ocean.

Swiss biotech company Lonza, a leader in the field, said that good stewardship had led to “stable to increasing” populations.

Regulatory hurdles to rFC also remain, with U.S. standards group U.S. Pharmacopeia (USP) last week scrapping plans to put the synthetic test on an equal footing with industry-standard crab blood trials.

While Europe is moving to recognize the synthetic as comparable, USP announced on Friday that more data was needed to support such a move.

Adoption has lagged, in part, because drug regulators have demanded that rFC endotoxin tests undergo extra validations – adding time and cost – to prove they match the accuracy of crab blood.

So far, only two drugs, both from Eli Lily, have been approved after relying on rFC for final endotoxin tests.

Eli Lilly, which has switched 90% of its safety testing to rFC since 2016, on Monday told Reuters that it supports the wildlife groups’ aims to get more companies to follow suit.

The wildlife groups pledged to target U.S. legislators and regulators to spur action.

COPPER-RICH BLOOD

Horseshoe crabs’ copper-rich blood has helped the species to survive for 450 million years – and made it a source of one of the drug industry’s most unusual raw materials because it clots in the presence of bacterial endotoxins.

Drained from live crabs, the blood has long been the standard to detect contamination in shots, infusions and medical devices.

Companies including Lonza and Charles River Laboratories are the biggest crab bleeders, supplying many of the 70 million annual endotoxin tests in a roughly $1 billion market.

More recently, man-made rFC from Lonza, France’s bioMerieux and others has emerged an alternative, and they have been pushing to gain market share, though Charles River has opposed recognition, sparking an industry battle.

FILE PHOTO: Atlantic horseshoe crabs burrow in the sand on Pickering beach, a national horseshoe crab sanctuary near Little Creek, Delaware, May 20, 2008. REUTERS/Mike Segar (UNITED STATES)/File Photo

Eli Lilly on Monday announced that it had begun testing a COVID-19 antibody in humans with all the safety testing done with rFC, said Jay Bolden, a Lilly biologist whose hobby as a birdwatcher spurred him to lead his company’s switch to the synthetic.

There is sufficient scientific evidence, including from more than 40,000 samples tested by Lilly so far, to support the synthetic’s comparability with crab blood, Bolden added.

“And that data is out there, and it’s either not being looked at or it’s being ignored,” he told Reuters. “There’s no reason the USP should be asking for more data.”

Reporting by John Miller; Editing by Pravin Char and David Goodman

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Researchers develop new method to measure hydroxychloroquine levels in SLE patients

Researchers at Uppsala University and Uppsala University Hospital have developed a new method to measure levels of the medication hydroxychloroquine in patients with rheumatic disease systemic lupus erythematosus (SLE).

The analysis method may also be useful in other areas, such as in the treatment of COVID-19. The study is being published in Arthritis Research and Therapy.

Hydroxychloroquine was originally used to treat malaria but has also proven effective with SLE and rheumatoid arthritis (RA). Today it is recommended to all SLE patients since it protects against flares of the disease. Tests are now being conducted to see if it can also be used to treat COVID-19.

A disadvantage of hydroxychloroquine is its side effects which can be avoided, however, if the dosage is adjusted for each patient.

To achieve the protective effect against flares in SLE while also minimizing the risk of side effects, Uppsala researchers have now developed a method that can be used in the medical care system to measure hydroxychloroquine levels in the blood of SLE patients.

The method is based on high-resolution mass spectrometry and has been used at Uppsala University Hospital since December 2019.

First, the researchers went through available data on hydroxychloroquine measurements. They saw that results from measurements on whole blood, plasma, and serum were not comparable with each other.

“It was shown that there were major differences between different reports, and there seemed to be very large individual differences,” says Kim Kultima, Associate Professor at the Department of Medical Sciences at Uppsala University and also active at Clinical Chemistry and Pharmacology at Uppsala University Hospital.

For this reason, his research team conducted a study together with the research team in rheumatology that compared the levels of hydroxychloroquine in plasma, serum, and whole blood in SLE patients.

They concluded that the levels in whole blood were about twice as high as in serum and plasma. Whole blood analyses were also the most dependable.

One striking result, and very important insight, was that levels in whole blood for patients prescribed the same dosage could differ by up to 15 times between individuals. This indicates a large individual variation in how the medication is metabolized.”

Kim Kultima, Associate Professor, Department of Medical Sciences, Uppsala University

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One problem pointed out by the study is that the services for electronic information on medicinal products in Sweden (FASS) provides concentrations of hydroxychloroquine in plasma.

The researchers judge that these values provide an inaccurate and inappropriate picture for monitoring medication levels in patients.

“We also have to be very careful about drawing hasty conclusions about whether hydroxychloroquine is effective with COVID-19. What we know today is that the analysis method will hopefully lead to better data for providing the right dosages to SLE patients who are prescribed the medication.”

In collaboration with doctors at the Infectious Disease Clinic and within intensive care at Uppsala University Hospital, there are plans and preparations in place to be able to measure the levels of the medication in the blood of COVID-19 patients if the substance proves effective.

Source:

Uppsala University

Journal reference:

Carlsson, H., et al. (2020) Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS—evaluation of whole blood, plasma, and serum as sample matrices. Arthritis Research & Therapy. doi.org/10.1186/s13075-020-02211-1.

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Researchers use optical mapping system to observe the effect of hydroxychloroquine

The malaria drug hydroxychloroquine, which has been promoted as a potential treatment for Covid-19, is known to have potentially serious effects on heart rhythms.

Now, a team of researchers has used an optical mapping system to observe exactly how the drug creates serious disturbances in the electrical signals that govern heartbeat.

The research, reported May 29 in the journal Heart Rhythm, found that the drug made it “surprisingly easy” to trigger worrisome arrhythmias in two types of animal hearts by altering the timing of the electrical waves that control heartbeat.

While the findings of animal studies can’t necessarily be generalized to humans, the videos created by the research team clearly show how the drug can cause cardiac electrical signals to become dysfunctional.

We have illustrated experimentally how the drug actually changes the waves in the heart, and how that can initiate an arrhythmia. We have demonstrated that with optical mapping, which allows us to see exactly how the waveform is changing. This gives us a visual demonstration of how the drug can alter the wave propagation in the heart.”

Flavio Fenton, Study Corresponding Author and Professor, School of Physics, Georgia Institute of Technology

What the team saw was an elongation of the T wave, a portion of the heart cycle during which voltages normally dissipate in preparation for the next beat.

By extending the QT portion of one wave cycle, the drug sets the stage for disturbances in the next wave, potentially creating an arrhythmia. Such disturbances can transition to fibrillation that interferes with the heart’s ability to pump.

The ability to easily trigger disturbances known as “long QT” reinforces cautions about using hydroxychloroquine (HCQ) in humans – particularly in those who may have heart damage from Covid-19, cautioned Dr. Shahriar Iravanian, a co-author of the paper and a cardiologist in the Division of Cardiology, Section of Electrophysiology, at Emory University Hospital.

“The hearts used in the study are small and very resistant to this form of arrhythmia,” Iravanian said. “If we had not seen any HCQ-induced arrhythmias in this model, the results would not have been reassuring.

However, in reality, we observed that HCQ readily induced arrhythmia in those hearts. This finding is very concerning and, in combination with the clinical reports of sudden death and arrhythmia in Covid-19 patients taking HCQ, suggests that the drug should be considered a potentially harmful medication and its use in Covid-19 patients be restricted to clinical trial settings.”

Georgia Tech postdoctoral fellow Ilija Uzelac administered HCQ to the animal hearts – one from a guinea pig and one from a rabbit – while quantifying wave patterns changing across the hearts using a high-powered, LED-based optical mapping system. Voltage-sensitive fluorescent dyes made the electrical waves visible as they moved across the surface of the hearts.

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“The effect of the arrhythmia and the long QT was quite obvious,” said Uzelac. “HCQ shifts the wavelengths to larger values, and when we quantified the dispersion of the electrical current in portions of the heart, we saw the extension of the voltage across the tissue.

The change was very dramatic comparing the waveforms in the heart with and without the HCQ.”

The drug concentration used in the study was at the high end of what’s being recommended for humans. HCQ normally takes a few days to accumulate in the body, so the researchers used a higher initial dose to simulate the drug’s effect over time.

In a normal heartbeat, an electrical wave is generated in specialized cells of a heart’s right atrium. The wave propagates through the entire atria and then to the ventricles.

As the wave moves through the heart, the electrical potential created causes calcium ions to be released, which stimulates contraction of the heart muscle in a coordinated pattern.

Drugs such as HCQ modify the properties of these ion channels and inhibit the flow of potassium currents, which prolongs the length of the electrical waves and creates spatial variations in their properties. Ultimately, that can lead to the development of dangerously rapid and dysfunctional heart rhythms.

“The wavelength becomes less homogeneous and that affects the propagation of additional waves, producing sections of the heart where the waves do not propagate well,” Fenton said. “In the worst case, there are multiple waves going in different directions.

Every section of the heart is contracting at a different time, so the heart is just quivering. At that point, it can no longer pump blood throughout the body.”

Patients taking HCQ for diseases such as lupus and rheumatoid arthritis rarely suffer from arrythmia because the doses they take are smaller than those being recommended for Covid-19 patients, Iravanian said.

“Covid-19 patients are different and are at a much higher risk of HCQ-induced arrhythmia,” he said. “Not only is the proposed dose of HCQ for Covid-19 patients two to three times the usual dose, but Covid-19 has effects on the heart and lowers potassium levels, further increasing the risk of arrythmias.”

Fenton and his colleagues have already begun a new study to evaluate the effects of HCQ with the antibiotic azithromycin, which has been suggested as a companion treatment. Azithromycin can also cause the long QT effect, potentially increasing the impact on Covid-19 patients.

Source:

Georgia Institute of Technology

Journal reference:

Uzelac, L., et al. (2020) Fatal arrhythmias: Another reason why doctors remain cautious about chloroquine/ hydroxychloroquine for treating COVID-19. Heart Rhythm. doi.org/10.1016/j.hrthm.2020.05.030.

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