Myocarditis Risk Looms Over College Football’s COVID-19 Response

August 14, 2020

Risk of myocarditis — a heart condition with potentially permanent consequences — associated with COVID-19 may be the biggest obstacle to the fall football season.

At a Thursday telebriefing hosted by the Infectious Diseases Society of America, the National Collegiate Athletic Association’s (NCAA) chief medical officer said he was aware of 12 recent myocarditis cases affecting NCAA athletes.

Brian Hainline, MD, said previous NCAA guidance around cardiac health — a longstanding and important topic in the college sports world, as congenital anomalies have killed dozens of athletes over the years — has become “more rigid” during the pandemic.

Football players and others with fall seasons have been practicing throughout the summer with the expectation, or hope, of having games to play.

Hainline could hardly contain his frustration with the pandemic’s continuing spread in the U.S. “We fully expected in the spring not to be in this place come fall,” he told reporters on the call. “Where we are today, it’s exceptionally disappointing.”

Fears associated with myocarditis have in part driven the NCAA’s Big 10 and Pac 12 conferences to announce earlier this week they would postpone their upcoming football season until the spring.

But the other three “power” football conferences — Big 12, Southeastern Conference, and Atlantic Coast Conference — are still planning to play football in the fall, as is independent Notre Dame. They might end up postponing to the spring, too, Hainline said, but have not made final decisions yet.

The conferences are making different decisions while utilizing the same data the NCAA provided, Hainline said. The NCAA is an umbrella organization established by its member institutions to help govern them, but the conferences have final say on their football schedules.

Most NCAA fall sports have already been canceled or postponed until the spring in full, including football at lower levels. Big-time football can generate hundreds of millions of dollars for a school and its surrounding community — especially at larger programs such as Clemson University of the University of Alabama.

“From 2017 to 2018, the University of Oklahoma football program generated $102.3 million, and the University of Georgia a hefty $129 million, leaving the department with $84.1 million in revenue after operating expenses were accounted for,” Vox reported. “Many college athletic departments are highly dependent on those funds.”

If schools play football in the spring, Hainline said, the NCAA would then have to ponder how that would impact players’ ability to recover in time to play a normal 2021 fall season.

NCAA institutions will make further decisions about whether and when to play other sports — including men’s basketball, with a March Madness tournament that generates more than $800 million in television revenue alone annually, according to reports — based on COVID-19 testing figures and “where we are as a country,” Hainline said. https://tpc.googlesyndication.com/safeframe/1-0-37/html/container.html

Carlos del Rio, MD, of Emory University in Atlanta, told reporters on the call that many hospitals in his home state of Georgia are already at capacity. He questioned allowing schools to do anything that would further hamstring the capacity of the medical system in states such as Georgia, where the ACC’s Georgia Tech and SEC’s Georgia are still planning to play football in the fall.

Del Rio is concerned about athletes catching COVID-19 during organized sports activities such as practices and games, he said, but even more so about their safety away from sports. As millions of other students arrive in college towns this month, athletes are also likely to catch the disease during social gatherings, despite efforts to prevent it.

The potential for myocarditis is particularly concerning in the context of young athletes.

Also on the call was Colleen Kraft, MD, of Emory, who discussed the impact of myocarditis on people infected by COVID-19. While the statistics — about 20% of COVID-19 patients suffer myocarditis — do not sound awful, she said, that represents a large amount of human suffering.

Football is arguably the most contactful of all the major team sports. Distancing is antithetical to the game. If an infected player gets on the field, it’s highly likely to spread to others. Although COVID-19 is usually mild in young people, the prospect of lingering cardiac damage is not easily dismissed. Players who develop it could have their careers derailed, not to mention suffering permanent disability or even death.

Under some situations, the NCAA is considering adopting the bubble format that the National Basketball Association and National Hockey League have modeled over the last two weeks, which has worked better than many dared hope.

Major League Baseball, on the other hand, has tried to keep a normal traveling schedule with far less success; one team had a series of positive cases and hasn’t been able to play for weeks. The National Football League plans to follow baseball’s model when its season kicks off Sept. 10, and Major League Soccer is attempting a hybrid approach when its season restarts Sunday. https://tpc.googlesyndication.com/safeframe/1-0-37/html/container.html

But sports are of secondary concern, del Rio said, comparing disputes over whether to play college football to debating what time the band should play as the Titanic sunk.

Said Kraft: “Our focus really needs be in the here and now, and doing things within our power to control the pandemic.”

https://www.medpagetoday.com/infectiousdisease/covid19/88060

Tune Up Telemedicine to Help Seniors

Simple communication strategies could help older adults being left behind by telemedicine, a group suggested.

“First and most important, you must assume that your older patients have at least mild hearing loss,” with clinically significant levels in about two-thirds by age 70, noted Carrie L. Nieman, MD, MPH, and Esther S. Oh, MD, PhD, both of Johns Hopkins Bloomberg School of Public Health in Baltimore.

In an opinion piece in the Annals of Internal Medicine, they offered suggestions to make telehealth encounters with older adults as effective as possible:

• Recommend headphones or a headset, or confirm patients are wearing their hearing aids or amplification device
• Use video whenever possible to allow lip reading and provide visual clues like gestures
• Focus the camera on your face with even lighting on it from the front to minimize shadows
• Use captioning when available for video-based encounters

You can also engage the patient to enlist an interpreter if concerned about not being heard or understood, Nieman and Oh added.

Raising your voice isn’t a good solution, given potential for distortion due to noise-cancelling software, Nieman and Oh pointed out. However, speaking slowly and clearly is, they said. Watch for cues that you’re not being understood, which can include nodding along, looking to loved ones to respond, or responding inappropriately.

“If a patient shows that he or she did not understand you, repeat your statement once but move quickly to rephrase if the patient did not understand the first two times,” they wrote. “The ‘teach-back’ technique can check a patient’s understanding and reiterate the main points and required actions. This should be paired with the provision of written summaries or instructions.”

Socioeconomic challenges can compound patients’ ability or willingness to use telemedicine, they noted. “Providers should be aware of patient preferences about how a telemedicine visit is conducted — for example, landline, cellphone, or computer-based interface — which may be driven in part by access to technology in a space conducive to a private exchange, as well as by internet, cellphone, or data plans and associated charges.”

A recent study indicated that more than one-third of seniors aren’t experienced enough with technology and/or have sight, hearing, or other disabilities that would interfere with a telemedicine encounter.

Another study of Medicare beneficiaries indicated that more than 40% had no access to a computer with a high-speed Internet connection at home and more than a quarter also didn’t have a smartphone with a wireless data plan.

Disclosures

Nieman disclosed support from the National Institute on Aging and relevant relationships with Access HEARS and the Hearing Loss Association of America.

Oh disclosed no relevant relationships with industry.

Primary Source

Annals of Internal Medicine

Source Reference: Nieman CL, Oh ES “Connecting with older adults via telemedicine” Ann Intern Med 2020; DOI: 10.7326/M20-1322.

https://www.medpagetoday.com/practicemanagement/telehealth/87989

Success Reported With Angioedema Med in Severe COVID-19

Hospitalized COVID-19 patients who received icatibant (Firazyr), the bradykinin inhibitor normally used for hereditary angioedema (HAE), had less need for oxygen supplementation compared to controls, a small retrospective study from the Netherlands found.

Of the nine total patients receiving icatibant, four were no longer oxygen dependent within 10 to 35 hours, and eight of nine saw a reduction in oxygen supplementation of 3 L/min or greater within 24 hours, reported Frank L. van de Veerdonk, MD, PhD, of Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues, writing in a research letter in JAMA Network Open.

Among controls, only three of 18 showed spontaneous reduction in oxygen supplementation of 3 L/min or greater within 24 hours.

However, three patients treated with icatibant also had a resurgence in the need for oxygen supplementation, the authors noted. They also added icatibant has a short half life of about 2 hours, which may have contributed to this resurgence.

Icatibant is a synthetic peptide drug approved by the FDA in 2011 for HAEs. Clinical evidence indicates vascular leakage contributes to pulmonary edema in COVID-19 patients, van de Veerdonk and colleagues explained. And SARS-CoV-2 enters cells via angiotensin converting enzyme 2 (ACE2), which is involved in degrading bradykinin.

“Loss of ACE2 might lead to plasma leakage and further activation of the plasma kallikrein-kinin system with more bradykinin formation that could contribute to pulmonary angioedema via stimulation of bradykinin 2 receptors,” the group wrote.

They therefore hypothesized that icatibant could make a difference, especially since pulmonary edema is a “prominent feature” of many patients with the virus.

Patients were given icatibant if they tested positive for SARS-CoV-2 via polymerase chain reaction assay, had oxygen saturation of less than 90% without supplemental oxygen, needed 3 L/min supplemental oxygen or more, and had a CT severity score of 7 or greater. For each of these patients, two controls were identified retrospectively based on sex, age, BMI, and day of illness, for a total of 18 controls.

Icatibant was given in three 30-mg injections at intervals of 6 hours.

Mean age for icatibant patients was 55; for controls it was 58. Most were men.

There were no severe adverse events, nor a “clear association” with D-dimer concentrations and fever, the authors noted.

The study’s small size and lack of randomization or prospective assignment were important limitations, van de Veerdonk and colleagues acknowledged. Also, the report lacked data on COVID-19 severity other than patients’ oxygen requirements. Nevertheless, the authors said, the findings warrant further investigation of treatments targeting the kallikrein-kinin system in similar patients.

Primary Source

JAMA Network Open

Source Reference: van de Veerdonk FL, et al “Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19” JAMA Netw Open. 2020; DOI: 10.1001/jamanetworkopen.2020.17708.

https://www.medpagetoday.com/infectiousdisease/covid19/88076

U.S. teams up with McKesson for COVID-19 vaccine distribution, Trump says

The U.S. federal government is partnering with McKesson (NYSE:MCK) on vaccine distribution, once a vaccine for the coronavirus is approved and available, President Trump said in a White House press briefing.

https://seekingalpha.com/news/3605882-u-s-teams-up-mckesson-for-covidminus-19-vaccine-distribution-trump-says

Covid-19 clinical trials fail to enroll diverse populations, despite awareness efforts

It’s been well-established that Covid-19, at least in the United States, has disproportionately affected people of color. And yet clinical trials of treatments and vaccines for Covid-19 have so far failed to enroll diverse populations that actually reflect society. 

Hala Borno is an oncologist at the University of California, San Francisco. She’s been studying the gap between real-world demographics and clinical trial enrollment. She recently called into STAT’s podcast, “The Readout LOUD,” to discuss the issue of diversity and inclusion in Covid-19 clinical trials.

You just co-authored a study in Contemporary Clinical Trials Communications, looking at the racial and ethnic makeup of Covid-19 trials and comparing it to what we know about the actual burden of disease in the U.S. What did you find out in that research?

We looked at the studies that were published that specifically were examining the effects of a Covid-19 treatment among affected populations. And we wanted to look at the studies that were recruiting from the United States. Among the studies we identified, 50% were observational, so real-world analyses of Covid-19 treatments and patient outcomes. And 50% were randomized clinical trials, so prospective trials looking at efficacy. And what we observed was striking.

A third of the studies did not report race or ethnicity data. One study did not even collect race data among participants. And we also observed that Black patients were underrepresented in all studies relative to the burden of disease among the Black communities in which these studies took place.

So when you step back and you think about these findings, we observe that today, in the year 2020, in the context of a horrific pandemic that has shone the spotlight on racial-ethnic disparities in the United States, still, investigators are not uniformly collecting or reporting race-ethnicity data in published clinical research to treat the disease that is disproportionately burdening racial or ethnic minorities. And that is outrageous.

The data that we’ve seen so far on Covid-19 vaccines isn’t any better in terms of racial and ethnic diversity. What’s at risk if clinical trial sponsors don’t enroll populations that reflect the reality of Covid-19?

When you step back and think about what is clinical research trying to do, it’s trying to develop empiric evidence that the intervention is effective. But not only that, it also has to demonstrate empiric evidence that the intervention is safe. And when you do not recruit patients to the clinical studies that are ultimately going to receive this intervention in the real world, then you may miss an important signal of efficacy or an important signal of toxicity, which could be devastating.

I think that if we do not ensure diversity in these Covid-19 clinical research studies, we may ultimately render interventions, whether it be drug or vaccines, that do not uniformly demonstrate efficacy across populations, or have side effects that we only capture later on.:

Some people from underrepresented populations, particularly Black people and Native Americans, distrust the medical establishment because of a long history of injustice. How can investigators build trust in communities that have had previous bad experiences with medical research?

This issue always comes up: Is there a contribution of hereditary mistrust? Is there a contribution of fears of experimentation? I think it’s important to think about those components when you think about recruitment to clinical trials, especially among racial-ethnic minorities. But the bottom line is, there’s been a lot of data that show that racial-ethnic minorities specifically … have shown a great interest to participate in clinical research when offered and actually have pretty high rates of acceptance to clinical research when offered opportunities. … We should acknowledge our history of exploitation in experimental research is horrific and we should learn lessons from it. But we should not prevent it from offering diverse populations opportunities for clinical research.

We’ve heard a lot of drug manufacturers and government health agencies talk about the importance of enrolling diverse populations in the large-scale Covid-19 studies that are underway right now or planned for later this year. Is there a way to hold them accountable for those promises?

That’s a really important question. When you think about accountability for a disease that is affecting the entire world, it’s really hard to think through an international strategy for accountability. In the United States, we have had certain mandates to promote diversity and inclusion. For example, the 1993 NIH Revitalization Act mandated the inclusion of women and racial-ethnic minorities in publicly funded clinical trials. However, this mandate did not really come out with a clear protocol or guidance into how to achieve this. 

The reality is it’s challenging to hold investigators accountable. But I think one thing is, is crucial: At a minimum, we should ensure that they are collecting race data uniformly and reporting race data as they present the data and the outcomes of their interventions.

Outside Covid-19, a lot of your work is focused on improving participation in cancer clinical trials among racial and ethnic minorities. Has there been progress in that world that might point to a way forward?

Yeah, I think there have been a lot of different strategies that have shown promise. When you think about recruitment, there are two major buckets to think through. One is an outreach strategy: What is the strategy out in the communities that can promote diversity and inclusion in clinical trials? And then what is the strategy within sites that are recruiting patients to clinical trials? That is the inner reach strategy and there are different interventions in both categories.

For example, at the University of California, San Francisco, where I practice, I work with the Lazarex Cancer Foundation to help deliver a financial reimbursement program for cancer patients enrolling in therapeutic clinical trials. That is a strategy to help reduce some of the indirect costs associated with participating in clinical research in order to ensure that the most financially vulnerable patients can enroll into clinical trials and don’t bear the greatest financial burdens of that participation.

There are different strategies, but they need to be tailored to the problems that you’re isolating, whether it be getting diverse patients to your site to recruit or just ensuring the diversity that you’re seeing at your site is getting on trials.

Covid-19 clinical trials are failing to enroll diverse populations, despite awareness efforts

Verona Pharma to trial lung drug ensifentrine for COVID-19

Verona Pharma is to develop its lung drug ensifentrine for patients with COVID-19, joining the legions of drug companies repurposing their medicines to fight the pandemic.

Based in the UK and US, Verona is due to start a phase 3 trial of ensifentrine in chronic obstructive pulmonary disease (COPD) later this year after encouraging results in phase 2.

But president and CEO David Zaccardelli said the company has received clearance from the FDA to begin a pilot clinical trial in patients hospitalised with COVID-19.

The randomised double-blind, placebo-controlled study will test ensifentrine delivered through a pressurised metered-dose inhaler at the University of Alabama at Birmingham, Zaccardelli said in an update accompanying the firm’s half year results.

He added: “Clinical data from prior studies of ensifentrine in other respiratory diseases have demonstrated ensifentrine improves lung function and reduces cellular markers of inflammation in the lungs.

“We believe ensifentrine, with its novel mechanism of action, has the potential to improve oxygenation and lung function assisting recovery from COVID-19.”

But the pandemic has impacted development of ensifentrine – in March the company postponed the start of the second multiple dose part of the phase 2 study, with an inhaled formulation in patients with moderate to severe COPD.

This trial is slated to start in the third quarter and the company says it has sufficient funding for the phase 3 trial ensifentrine, which will test a nebulised formulation of the drug.

In July, Verona raised around £159 million ($200 million) with a private placement to fund phase 3 development, keeping around £145 million ($183 million) after deducting agent fees and expenses.

Like many biotechs Verona is loss-making as it does not have a marketed product and nearly all revenues are directed towards R&D and operating costs.

In the first six months, the company reported a loss after tax of £16.9 million ($22.2 million), compared with £14.4 million ($18.9 million) in the corresponding period last year.

Ensifentrine, which could be used in other respiratory diseases such as asthma and cystic fibrosis, combines bronchodilator and anti-inflammatory properties in one compound.

It works by inhibiting phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) enzymes – a very different mechanism of action from approved drug classes to treat COPD such as corticosteroids, beta2-agonists and anti-muscarinic drugs.

Zaccardelli took over as CEO in February, replacing Jan-Anders Karlsson, who retired after eight years to pursue non-executive roles.

Verona Pharma to trial lung drug ensifentrine for COVID-19