Federal health officials are urging states to vaccinate all Americans over age 65 and those aged 16-64 who have a documented underlying health condition that makes them more vulnerable to COVID-19.

U.S. Department of Health and Human Services (HHS) Secretary Alex Azar and Centers for Disease Control and Prevention Director Robert Redfield, MD, made the recommendation in a briefing with reporters on Jan. 12, saying that the current vaccine supply was sufficient to meet demand for the next phase of immunization as recommended by the CDC’s Advisory Committee on Immunization Practices.

“We are ready for a transition that we outlined last September in the playbook we sent to states,” Mr. Azar said. Both he and U.S. Army General Gustave F. Perna, chief operations officer for Operation Warp Speed, said that confidence in the distribution system had led to the decision to urge wider access.

The federal government will also increase the number of sites eligible to receive vaccine – including some 13,000 federally qualified community health centers – and will not keep doses in reserve as insurance against issues that might prevent people from receiving a second dose on a timely basis. 

“We don’t need to hold back reserve doses,” Mr. Azar said, noting that if there were any “glitches in production” the federal government would move to fulfill obligations for second doses first and delay initial doses.
 

Azar: Use it or lose it

In a move that is sure to generate pushback, Mr. Azar said that states that don’t quickly administer vaccines will receive fewer doses in the future. That policy will not go into effect until later in February, which leaves open the possibility that it could be reversed by the incoming Biden administration.

“We have too much vaccine sitting in freezers at hospitals with hospitals not using it,” said Mr. Azar, who also blamed the slow administration process on a reporting lag and states being what he called “overly prescriptive” in who has been eligible to receive a shot.

“I would rather have people working to get appointments to get vaccinated than having vaccine going to waste sitting in freezers,” he told reporters.

Mr. Azar had already been pushing for broader vaccination, telling states to do so in an Operation Warp Speed briefing on Jan. 6. At that briefing, he also said that the federal government would be stepping up vaccination through an “early launch” of a federal partnership with 19 pharmacy chains, which will let states allocate vaccines directly to some 40,000 pharmacy sites.

Gen. Perna said during the Jan. 12 briefing that the aim is to further expand that to some 70,000 locations total.

The CDC reported that as of Jan. 11 some 25.4 million doses have been distributed, with 8.9 million administered. An additional 4.2 million doses were distributed to long-term care facilities, and 937,000 residents and staff have received a dose.
 

“Pace of administration”

Alaska, Connecticut, North Dakota, South Dakota, the District of Columbia, West Virginia, and the Northern Mariana Islands have administered the most vaccines per capita, according to the CDC. But even these locations have immunized only 4%-5% of their populations, the New York Times reports. At the bottom: Alabama, Arizona, Arkansas, Georgia, Mississippi, and South Carolina.

The federal government can encourage but not require states to move on to new phases of vaccination.

“States ultimately determine how they will proceed with vaccination,” said Marcus Plescia, MD, MPH, chief medical officer for the Association of State and Territorial Health Officials. “Most will be cautious about assuring there are doses for those needing a second dose,” he said in an interview.

Dr. Plescia said that ensuring a second dose is available is especially important for health care workers “who need to be confident that they are protected and not inadvertently transmitting the disease themselves.”

He added that “once we reach a steady state of supply and administration, the rate-limiting factor will be supply of vaccine.”

That supply could now be threatened if states don’t comply with a just-announced federal action that will change how doses are allocated.

Beginning in late February, vaccine allocations to states will be based on “the pace of administration reported by states,” and the size of the 65-and-older population, said Mr. Azar, who has previously criticized New York Governor Andrew Cuomo for fining hospitals that didn’t use up vaccine supply within a week.

“This new system gives states a strong incentive to ensure that all vaccinations are being promptly reported, which they currently are not,” he said.

Currently, allocations are based on a state’s or territory’s population.

Prepandemic, states were required to report vaccinations within 30 days. Since COVID-19 vaccines became available, the CDC has required reporting of shots within 72 hours.

Dr. Redfield said the requirement has caused some difficulty, and that the CDC is investigating why some states have reported using only 15% of doses while others have used 80%.

States have been scrambling to ramp up vaccinations.

Just ahead of the federal briefing, Gov. Cuomo tweeted that New York would be opening up vaccinations to anyone older than 65.

The Associated Press is reporting that some states have started mass vaccination sites.

Arizona has begun operating a 24/7 appointment-only vaccination program at State Farm Stadium outside of Phoenix, with the aim of immunizing 6,000 people each day, according to local radio station KJZZ.

California and Florida have also taken steps to use stadiums, while Michigan, New Jersey, New York, and Texas will use convention centers and fairgrounds, Axios has reported.

In Florida, Palm Beach County Health Director Alina Alonso, MD, told county commissioners on Jan. 12 that there isn’t enough vaccine to meet demand, WPTV reported. “We need to realize that there’s a shortage of vaccine. So it’s not the plan, it’s not our ability to do it. It’s simply supply and demand at this point,” Dr. Alonso said, according to the TV station report.

A version of this article first appeared on Medscape.com.

Federal health officials are urging states to vaccinate all Americans over age 65 and those aged 16-64 who have a documented underlying health condition that makes them more vulnerable to COVID-19.

U.S. Department of Health and Human Services (HHS) Secretary Alex Azar and Centers for Disease Control and Prevention Director Robert Redfield, MD, made the recommendation in a briefing with reporters on Jan. 12, saying that the current vaccine supply was sufficient to meet demand for the next phase of immunization as recommended by the CDC’s Advisory Committee on Immunization Practices.

“We are ready for a transition that we outlined last September in the playbook we sent to states,” Mr. Azar said. Both he and U.S. Army General Gustave F. Perna, chief operations officer for Operation Warp Speed, said that confidence in the distribution system had led to the decision to urge wider access.

The federal government will also increase the number of sites eligible to receive vaccine – including some 13,000 federally qualified community health centers – and will not keep doses in reserve as insurance against issues that might prevent people from receiving a second dose on a timely basis. 

“We don’t need to hold back reserve doses,” Mr. Azar said, noting that if there were any “glitches in production” the federal government would move to fulfill obligations for second doses first and delay initial doses.
 

Azar: Use it or lose it

In a move that is sure to generate pushback, Mr. Azar said that states that don’t quickly administer vaccines will receive fewer doses in the future. That policy will not go into effect until later in February, which leaves open the possibility that it could be reversed by the incoming Biden administration.

“We have too much vaccine sitting in freezers at hospitals with hospitals not using it,” said Mr. Azar, who also blamed the slow administration process on a reporting lag and states being what he called “overly prescriptive” in who has been eligible to receive a shot.

“I would rather have people working to get appointments to get vaccinated than having vaccine going to waste sitting in freezers,” he told reporters.

Mr. Azar had already been pushing for broader vaccination, telling states to do so in an Operation Warp Speed briefing on Jan. 6. At that briefing, he also said that the federal government would be stepping up vaccination through an “early launch” of a federal partnership with 19 pharmacy chains, which will let states allocate vaccines directly to some 40,000 pharmacy sites.

Gen. Perna said during the Jan. 12 briefing that the aim is to further expand that to some 70,000 locations total.

The CDC reported that as of Jan. 11 some 25.4 million doses have been distributed, with 8.9 million administered. An additional 4.2 million doses were distributed to long-term care facilities, and 937,000 residents and staff have received a dose.
 

“Pace of administration”

Alaska, Connecticut, North Dakota, South Dakota, the District of Columbia, West Virginia, and the Northern Mariana Islands have administered the most vaccines per capita, according to the CDC. But even these locations have immunized only 4%-5% of their populations, the New York Times reports. At the bottom: Alabama, Arizona, Arkansas, Georgia, Mississippi, and South Carolina.

The federal government can encourage but not require states to move on to new phases of vaccination.

“States ultimately determine how they will proceed with vaccination,” said Marcus Plescia, MD, MPH, chief medical officer for the Association of State and Territorial Health Officials. “Most will be cautious about assuring there are doses for those needing a second dose,” he said in an interview.

Dr. Plescia said that ensuring a second dose is available is especially important for health care workers “who need to be confident that they are protected and not inadvertently transmitting the disease themselves.”

He added that “once we reach a steady state of supply and administration, the rate-limiting factor will be supply of vaccine.”

That supply could now be threatened if states don’t comply with a just-announced federal action that will change how doses are allocated.

Beginning in late February, vaccine allocations to states will be based on “the pace of administration reported by states,” and the size of the 65-and-older population, said Mr. Azar, who has previously criticized New York Governor Andrew Cuomo for fining hospitals that didn’t use up vaccine supply within a week.

“This new system gives states a strong incentive to ensure that all vaccinations are being promptly reported, which they currently are not,” he said.

Currently, allocations are based on a state’s or territory’s population.

Prepandemic, states were required to report vaccinations within 30 days. Since COVID-19 vaccines became available, the CDC has required reporting of shots within 72 hours.

Dr. Redfield said the requirement has caused some difficulty, and that the CDC is investigating why some states have reported using only 15% of doses while others have used 80%.

States have been scrambling to ramp up vaccinations.

Just ahead of the federal briefing, Gov. Cuomo tweeted that New York would be opening up vaccinations to anyone older than 65.

The Associated Press is reporting that some states have started mass vaccination sites.

Arizona has begun operating a 24/7 appointment-only vaccination program at State Farm Stadium outside of Phoenix, with the aim of immunizing 6,000 people each day, according to local radio station KJZZ.

California and Florida have also taken steps to use stadiums, while Michigan, New Jersey, New York, and Texas will use convention centers and fairgrounds, Axios has reported.

In Florida, Palm Beach County Health Director Alina Alonso, MD, told county commissioners on Jan. 12 that there isn’t enough vaccine to meet demand, WPTV reported. “We need to realize that there’s a shortage of vaccine. So it’s not the plan, it’s not our ability to do it. It’s simply supply and demand at this point,” Dr. Alonso said, according to the TV station report.

A version of this article first appeared on Medscape.com.

Federal health officials are urging states to vaccinate all Americans over age 65 and those aged 16-64 who have a documented underlying health condition that makes them more vulnerable to COVID-19.

U.S. Department of Health and Human Services (HHS) Secretary Alex Azar and Centers for Disease Control and Prevention Director Robert Redfield, MD, made the recommendation in a briefing with reporters on Jan. 12, saying that the current vaccine supply was sufficient to meet demand for the next phase of immunization as recommended by the CDC’s Advisory Committee on Immunization Practices.

“We are ready for a transition that we outlined last September in the playbook we sent to states,” Mr. Azar said. Both he and U.S. Army General Gustave F. Perna, chief operations officer for Operation Warp Speed, said that confidence in the distribution system had led to the decision to urge wider access.

The federal government will also increase the number of sites eligible to receive vaccine – including some 13,000 federally qualified community health centers – and will not keep doses in reserve as insurance against issues that might prevent people from receiving a second dose on a timely basis. 

“We don’t need to hold back reserve doses,” Mr. Azar said, noting that if there were any “glitches in production” the federal government would move to fulfill obligations for second doses first and delay initial doses.
 

Azar: Use it or lose it

In a move that is sure to generate pushback, Mr. Azar said that states that don’t quickly administer vaccines will receive fewer doses in the future. That policy will not go into effect until later in February, which leaves open the possibility that it could be reversed by the incoming Biden administration.

“We have too much vaccine sitting in freezers at hospitals with hospitals not using it,” said Mr. Azar, who also blamed the slow administration process on a reporting lag and states being what he called “overly prescriptive” in who has been eligible to receive a shot.

“I would rather have people working to get appointments to get vaccinated than having vaccine going to waste sitting in freezers,” he told reporters.

Mr. Azar had already been pushing for broader vaccination, telling states to do so in an Operation Warp Speed briefing on Jan. 6. At that briefing, he also said that the federal government would be stepping up vaccination through an “early launch” of a federal partnership with 19 pharmacy chains, which will let states allocate vaccines directly to some 40,000 pharmacy sites.

Gen. Perna said during the Jan. 12 briefing that the aim is to further expand that to some 70,000 locations total.

The CDC reported that as of Jan. 11 some 25.4 million doses have been distributed, with 8.9 million administered. An additional 4.2 million doses were distributed to long-term care facilities, and 937,000 residents and staff have received a dose.
 

“Pace of administration”

Alaska, Connecticut, North Dakota, South Dakota, the District of Columbia, West Virginia, and the Northern Mariana Islands have administered the most vaccines per capita, according to the CDC. But even these locations have immunized only 4%-5% of their populations, the New York Times reports. At the bottom: Alabama, Arizona, Arkansas, Georgia, Mississippi, and South Carolina.

The federal government can encourage but not require states to move on to new phases of vaccination.

“States ultimately determine how they will proceed with vaccination,” said Marcus Plescia, MD, MPH, chief medical officer for the Association of State and Territorial Health Officials. “Most will be cautious about assuring there are doses for those needing a second dose,” he said in an interview.

Dr. Plescia said that ensuring a second dose is available is especially important for health care workers “who need to be confident that they are protected and not inadvertently transmitting the disease themselves.”

He added that “once we reach a steady state of supply and administration, the rate-limiting factor will be supply of vaccine.”

That supply could now be threatened if states don’t comply with a just-announced federal action that will change how doses are allocated.

Beginning in late February, vaccine allocations to states will be based on “the pace of administration reported by states,” and the size of the 65-and-older population, said Mr. Azar, who has previously criticized New York Governor Andrew Cuomo for fining hospitals that didn’t use up vaccine supply within a week.

“This new system gives states a strong incentive to ensure that all vaccinations are being promptly reported, which they currently are not,” he said.

Currently, allocations are based on a state’s or territory’s population.

Prepandemic, states were required to report vaccinations within 30 days. Since COVID-19 vaccines became available, the CDC has required reporting of shots within 72 hours.

Dr. Redfield said the requirement has caused some difficulty, and that the CDC is investigating why some states have reported using only 15% of doses while others have used 80%.

States have been scrambling to ramp up vaccinations.

Just ahead of the federal briefing, Gov. Cuomo tweeted that New York would be opening up vaccinations to anyone older than 65.

The Associated Press is reporting that some states have started mass vaccination sites.

Arizona has begun operating a 24/7 appointment-only vaccination program at State Farm Stadium outside of Phoenix, with the aim of immunizing 6,000 people each day, according to local radio station KJZZ.

California and Florida have also taken steps to use stadiums, while Michigan, New Jersey, New York, and Texas will use convention centers and fairgrounds, Axios has reported.

In Florida, Palm Beach County Health Director Alina Alonso, MD, told county commissioners on Jan. 12 that there isn’t enough vaccine to meet demand, WPTV reported. “We need to realize that there’s a shortage of vaccine. So it’s not the plan, it’s not our ability to do it. It’s simply supply and demand at this point,” Dr. Alonso said, according to the TV station report.

A version of this article first appeared on Medscape.com.

The findings of follicular-based papules, pustules, and scars led to the diagnosis of early folliculitis keloidalis nuchae (FKN).

FKN, also called acne keloidalis nuchae, is more common in patients with darker skin types (Fitzpatrick skin types IV-VI) and is the most common form of scarring alopecia in men of African descent. The pathogenesis is unclear, but the condition may arise from mechanical occlusion with a retained short hair that leads to follicular destruction. Patients should lengthen their hair to at least a quarter of an inch to minimize this process. Military personnel may receive a waiver from standard grooming requirements. FKN may also occur as a primary disorder arising from bacterial infection and subsequent vigorous inflammation.

For early disease, topical therapy with either clindamycin 1% lotion or chlorhexidine solution are acceptable options. Should these options and hair lengthening fail over 3 to 4 months, consider a 6- to 12-week course of doxycycline or minocycline 100 mg once or twice daily. Intralesional triamcinolone with 5 to 10 mg/mL injected into fixed papules every 4 to 8 weeks is another option to reduce scar formation. The most severe cases may require combination oral antibiotics, isotretinoin, or plastic surgery.

In this case, the patient grew out his hair and applied clindamycin 1% lotion twice daily for a year. As a result, he had no further disease.

‌

Text and photos courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. (Photo copyright retained.)

The findings of follicular-based papules, pustules, and scars led to the diagnosis of early folliculitis keloidalis nuchae (FKN).

FKN, also called acne keloidalis nuchae, is more common in patients with darker skin types (Fitzpatrick skin types IV-VI) and is the most common form of scarring alopecia in men of African descent. The pathogenesis is unclear, but the condition may arise from mechanical occlusion with a retained short hair that leads to follicular destruction. Patients should lengthen their hair to at least a quarter of an inch to minimize this process. Military personnel may receive a waiver from standard grooming requirements. FKN may also occur as a primary disorder arising from bacterial infection and subsequent vigorous inflammation.

For early disease, topical therapy with either clindamycin 1% lotion or chlorhexidine solution are acceptable options. Should these options and hair lengthening fail over 3 to 4 months, consider a 6- to 12-week course of doxycycline or minocycline 100 mg once or twice daily. Intralesional triamcinolone with 5 to 10 mg/mL injected into fixed papules every 4 to 8 weeks is another option to reduce scar formation. The most severe cases may require combination oral antibiotics, isotretinoin, or plastic surgery.

In this case, the patient grew out his hair and applied clindamycin 1% lotion twice daily for a year. As a result, he had no further disease.

‌

Text and photos courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. (Photo copyright retained.)

The findings of follicular-based papules, pustules, and scars led to the diagnosis of early folliculitis keloidalis nuchae (FKN).

FKN, also called acne keloidalis nuchae, is more common in patients with darker skin types (Fitzpatrick skin types IV-VI) and is the most common form of scarring alopecia in men of African descent. The pathogenesis is unclear, but the condition may arise from mechanical occlusion with a retained short hair that leads to follicular destruction. Patients should lengthen their hair to at least a quarter of an inch to minimize this process. Military personnel may receive a waiver from standard grooming requirements. FKN may also occur as a primary disorder arising from bacterial infection and subsequent vigorous inflammation.

For early disease, topical therapy with either clindamycin 1% lotion or chlorhexidine solution are acceptable options. Should these options and hair lengthening fail over 3 to 4 months, consider a 6- to 12-week course of doxycycline or minocycline 100 mg once or twice daily. Intralesional triamcinolone with 5 to 10 mg/mL injected into fixed papules every 4 to 8 weeks is another option to reduce scar formation. The most severe cases may require combination oral antibiotics, isotretinoin, or plastic surgery.

In this case, the patient grew out his hair and applied clindamycin 1% lotion twice daily for a year. As a result, he had no further disease.

‌

Text and photos courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. (Photo copyright retained.)

In these pandemic times, there is much discussion about public skepticism toward scientists and doctors. Many decry this distrust. They think people should accept what experts advise. After all, experts work hard to learn accurate facts to promote the public’s best interests.

Those who disagree and justify their reluctance – to be vaccinated against COVID-19, for instance – are unrepentant. First of all, they are not so sure experts are public spirited. Perhaps doctors have something to gain from illness and approve vaccines for political reasons, or assign certain diagnoses to get higher reimbursement.

In this contentious climate, peculiar treatments and unproved “cures” are claimed to deserve more respect than so-called experts are willing to grant them: hydroxychloroquine, bleach, and so on.

From my perspective, what is notable about such public disputes with medical experts is not that they exist but that they are public. In private, people have always argued with doctors. Most of those arguments don’t reach public notice. They are not interesting enough.

For instance, as I think back over the years, I can recall:

• A man who preferred to treat his eczema using topical yogurt. And not just any yogurt: only low-fat, plain Market Basket. He had tried them all.
• The woman with perioral scarring. She had let an unlicensed practitioner apply a painful acid on her face – he never told her what the acid was, and she hadn’t asked – as she lay on a neighbor’s living room floor to have her “skin cancer” treated.
• The man with an obvious melanoma on his chest. He did not want to treat it, because his faith healer in Milwaukee, whom he had never met in person, assured him that “it’s all taken care of.”

I could go on.

I cite these examples only because they are striking. They are far from unique.

People argue with doctors for the same reason they argue with anybody – because they think they know better. They may have heard otherwise from a friend, a magazine article, a blog, a different kind of practitioner.

Many such disagreements are never spoken out loud, because people who expect to argue usually don’t show up at their doctors’ offices. They either stay home or see a different kind of healer. If they do visit a doctor whose point of view differs from their own, most keep disagreements to themselves, because few people relish in-person confrontation. Instead they go home and ignore medical advice there.

Even when overt disagreements do erupt at a medical visit, the doctor can often find a way to convince the patient to reconsider, or somehow deflect the clash. The physician has to at least try to convince a patient who thinks his melanoma has “been taken care of” to have it removed. Whereas if someone really prefers low-fat yogurt to topical steroids, there is no need to win the argument. If the patient decides at some point that his eczema is out of control, he can call and request a prescription. He usually won’t.

For dermatologists, medical arguments rarely involve stakes high enough to force the doctor to try changing patients’ minds or discharging them from the practice. Had I stayed in my original field of pediatrics, I would have confronted patients who refused to vaccinate their children. I would have had to negotiate a compromise – vaccinate “more slowly” – or else part ways with the family.

I always advised medical students, when they found themselves argued with, to separate patients’ needs from their own egos. Being challenged in a small room can be challenging. Still, what matters is how the patient fares, not how the doctor feels.

Public disputes with scientists during the COVID-19 pandemic strike me as being motivated by the same factors behind private disputes in physicians’ offices: skepticism, resentment, suspicion, and – often underlying all these – fear.

Public disputes carried out over social media allow for posturing and aggression. A tweet is a better medium behind which to cloak opinions in the mantle of a noble cause, such as personal freedom. It is also easier to express derision and hostility toward opponents, expert or otherwise, from behind the screen of a Twitter handle.

Fortunately, in everyday medical practice, in-your-face disputes don’t happen very often.

You do remember them, though.
 

Dr. Rockoff, who wrote the Dermatology News column “Under My Skin,” is now semiretired, after 40 years of practice in Brookline, Mass. He served on the clinical faculty at Tufts University, Boston, and taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at online. Write to him at [email protected].

In these pandemic times, there is much discussion about public skepticism toward scientists and doctors. Many decry this distrust. They think people should accept what experts advise. After all, experts work hard to learn accurate facts to promote the public’s best interests.

Those who disagree and justify their reluctance – to be vaccinated against COVID-19, for instance – are unrepentant. First of all, they are not so sure experts are public spirited. Perhaps doctors have something to gain from illness and approve vaccines for political reasons, or assign certain diagnoses to get higher reimbursement.

In this contentious climate, peculiar treatments and unproved “cures” are claimed to deserve more respect than so-called experts are willing to grant them: hydroxychloroquine, bleach, and so on.

From my perspective, what is notable about such public disputes with medical experts is not that they exist but that they are public. In private, people have always argued with doctors. Most of those arguments don’t reach public notice. They are not interesting enough.

For instance, as I think back over the years, I can recall:

• A man who preferred to treat his eczema using topical yogurt. And not just any yogurt: only low-fat, plain Market Basket. He had tried them all.
• The woman with perioral scarring. She had let an unlicensed practitioner apply a painful acid on her face – he never told her what the acid was, and she hadn’t asked – as she lay on a neighbor’s living room floor to have her “skin cancer” treated.
• The man with an obvious melanoma on his chest. He did not want to treat it, because his faith healer in Milwaukee, whom he had never met in person, assured him that “it’s all taken care of.”

I could go on.

I cite these examples only because they are striking. They are far from unique.

People argue with doctors for the same reason they argue with anybody – because they think they know better. They may have heard otherwise from a friend, a magazine article, a blog, a different kind of practitioner.

Many such disagreements are never spoken out loud, because people who expect to argue usually don’t show up at their doctors’ offices. They either stay home or see a different kind of healer. If they do visit a doctor whose point of view differs from their own, most keep disagreements to themselves, because few people relish in-person confrontation. Instead they go home and ignore medical advice there.

Even when overt disagreements do erupt at a medical visit, the doctor can often find a way to convince the patient to reconsider, or somehow deflect the clash. The physician has to at least try to convince a patient who thinks his melanoma has “been taken care of” to have it removed. Whereas if someone really prefers low-fat yogurt to topical steroids, there is no need to win the argument. If the patient decides at some point that his eczema is out of control, he can call and request a prescription. He usually won’t.

For dermatologists, medical arguments rarely involve stakes high enough to force the doctor to try changing patients’ minds or discharging them from the practice. Had I stayed in my original field of pediatrics, I would have confronted patients who refused to vaccinate their children. I would have had to negotiate a compromise – vaccinate “more slowly” – or else part ways with the family.

I always advised medical students, when they found themselves argued with, to separate patients’ needs from their own egos. Being challenged in a small room can be challenging. Still, what matters is how the patient fares, not how the doctor feels.

Public disputes with scientists during the COVID-19 pandemic strike me as being motivated by the same factors behind private disputes in physicians’ offices: skepticism, resentment, suspicion, and – often underlying all these – fear.

Public disputes carried out over social media allow for posturing and aggression. A tweet is a better medium behind which to cloak opinions in the mantle of a noble cause, such as personal freedom. It is also easier to express derision and hostility toward opponents, expert or otherwise, from behind the screen of a Twitter handle.

Fortunately, in everyday medical practice, in-your-face disputes don’t happen very often.

You do remember them, though.
 

Dr. Rockoff, who wrote the Dermatology News column “Under My Skin,” is now semiretired, after 40 years of practice in Brookline, Mass. He served on the clinical faculty at Tufts University, Boston, and taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at online. Write to him at [email protected].

In these pandemic times, there is much discussion about public skepticism toward scientists and doctors. Many decry this distrust. They think people should accept what experts advise. After all, experts work hard to learn accurate facts to promote the public’s best interests.

Those who disagree and justify their reluctance – to be vaccinated against COVID-19, for instance – are unrepentant. First of all, they are not so sure experts are public spirited. Perhaps doctors have something to gain from illness and approve vaccines for political reasons, or assign certain diagnoses to get higher reimbursement.

In this contentious climate, peculiar treatments and unproved “cures” are claimed to deserve more respect than so-called experts are willing to grant them: hydroxychloroquine, bleach, and so on.

From my perspective, what is notable about such public disputes with medical experts is not that they exist but that they are public. In private, people have always argued with doctors. Most of those arguments don’t reach public notice. They are not interesting enough.

For instance, as I think back over the years, I can recall:

• A man who preferred to treat his eczema using topical yogurt. And not just any yogurt: only low-fat, plain Market Basket. He had tried them all.
• The woman with perioral scarring. She had let an unlicensed practitioner apply a painful acid on her face – he never told her what the acid was, and she hadn’t asked – as she lay on a neighbor’s living room floor to have her “skin cancer” treated.
• The man with an obvious melanoma on his chest. He did not want to treat it, because his faith healer in Milwaukee, whom he had never met in person, assured him that “it’s all taken care of.”

I could go on.

I cite these examples only because they are striking. They are far from unique.

People argue with doctors for the same reason they argue with anybody – because they think they know better. They may have heard otherwise from a friend, a magazine article, a blog, a different kind of practitioner.

Many such disagreements are never spoken out loud, because people who expect to argue usually don’t show up at their doctors’ offices. They either stay home or see a different kind of healer. If they do visit a doctor whose point of view differs from their own, most keep disagreements to themselves, because few people relish in-person confrontation. Instead they go home and ignore medical advice there.

Even when overt disagreements do erupt at a medical visit, the doctor can often find a way to convince the patient to reconsider, or somehow deflect the clash. The physician has to at least try to convince a patient who thinks his melanoma has “been taken care of” to have it removed. Whereas if someone really prefers low-fat yogurt to topical steroids, there is no need to win the argument. If the patient decides at some point that his eczema is out of control, he can call and request a prescription. He usually won’t.

For dermatologists, medical arguments rarely involve stakes high enough to force the doctor to try changing patients’ minds or discharging them from the practice. Had I stayed in my original field of pediatrics, I would have confronted patients who refused to vaccinate their children. I would have had to negotiate a compromise – vaccinate “more slowly” – or else part ways with the family.

I always advised medical students, when they found themselves argued with, to separate patients’ needs from their own egos. Being challenged in a small room can be challenging. Still, what matters is how the patient fares, not how the doctor feels.

Public disputes with scientists during the COVID-19 pandemic strike me as being motivated by the same factors behind private disputes in physicians’ offices: skepticism, resentment, suspicion, and – often underlying all these – fear.

Public disputes carried out over social media allow for posturing and aggression. A tweet is a better medium behind which to cloak opinions in the mantle of a noble cause, such as personal freedom. It is also easier to express derision and hostility toward opponents, expert or otherwise, from behind the screen of a Twitter handle.

Fortunately, in everyday medical practice, in-your-face disputes don’t happen very often.

You do remember them, though.
 

Dr. Rockoff, who wrote the Dermatology News column “Under My Skin,” is now semiretired, after 40 years of practice in Brookline, Mass. He served on the clinical faculty at Tufts University, Boston, and taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at online. Write to him at [email protected].

The United States has allocated more than 641,000 monoclonal antibody treatments for outpatients to ease pressure on strained hospitals, but officials from Operation Warp Speed report that more than half of that reserve sits unused as clinicians grapple with best practices.

There are space and personnel limitations in hospitals right now, Janet Woodcock, MD, therapeutics lead on Operation Warp Speed, acknowledges in an interview with this news organization. “Special areas and procedures must be set up.” And the operation is in the process of broadening availability beyond hospitals, she points out.

But for frontline clinicians, questions about treatment efficacy and the logistics of administering intravenous drugs to infectious outpatients loom large.

More than 50 monoclonal antibody products that target SARS-CoV-2 are now in development. The U.S. Food and Drug Administration has already issued Emergency Use Authorization (EUA) for two such drugs on the basis of phase 2 trial data – bamlanivimab, made by Eli Lilly, and a cocktail of casirivimab plus imdevimab, made by Regeneron – and another two-antibody cocktail from AstraZeneca, AZD7442, has started phase 3 clinical trials. The Regeneron combination was used to treat President Donald Trump when he contracted COVID-19 in October.

Monoclonal antibody drugs are based on the natural antibodies that the body uses to fight infections. They work by binding to a specific target and then blocking its action or flagging it for destruction by other parts of the immune system. Both bamlanivimab and the casirivimab plus imdevimab combination target the spike protein of the virus and stop it from attaching to and entering human cells.
 

Targeting the spike protein out of the hospital

The antibody drugs covered by EUAs do not cure COVID-19, but they have been shown to reduce hospitalizations and visits to the emergency department for patients at high risk for disease progression. They are approved to treat patients older than 12 years with mild to moderate COVID-19 who are at high risk of progressing to severe disease or hospitalization. They are not authorized for use in patients who have been hospitalized or who are on ventilators. The hope is that antibody drugs will reduce the number of severe cases of COVID-19 and ease pressure on overstretched hospitals.

Most COVID-19 patients are outpatients, so we need something to keep them from getting worse.

This is important because it targets the greatest need in COVID-19 therapeutics, says Rajesh Gandhi, MD, an infectious disease physician at Harvard Medical School in Boston, who is a member of two panels evaluating COVID-19 treatments: one for the Infectious Disease Society of America and the other for the National Institutes of Health. “Up to now, most of the focus has been on hospitalized patients,” he says, but “most COVID-19 patients are outpatients, so we need something to keep them from getting worse.”

Both panels have said that, despite the EUAs, more evidence is needed to be sure of the efficacy of the drugs and to determine which patients will benefit the most from them.

These aren’t the mature data from drug development that guideline groups are accustomed to working with, Dr. Woodcock points out. “But this is an emergency and the data taken as a whole are pretty convincing,” she says. “As I look at the totality of the evidence, monoclonal antibodies will have a big effect in keeping people out of the hospital and helping them recover faster.”

High-risk patients are eligible for treatment, especially those older than 65 years and those with comorbidities who are younger. Access to the drugs is increasing for clinicians who are able to infuse safely or work with a site that will.

In the Boston area, several hospitals, including Massachusetts General where Dr. Gandhi works, have set up infusion centers where newly diagnosed patients can get the antibody treatment if their doctor thinks it will benefit them. And Coram, a provider of at-home infusion therapy owned by the CVS pharmacy chain, is running a pilot program offering the Eli Lilly drug to people in seven cities – including Boston, Chicago, Los Angeles, and Tampa – and their surrounding communities with a physician referral.

Getting that referral could be tricky, however, for patients without a primary care physician or for those whose doctor isn’t already connected to one of the institutions providing the infusions. The hospitals are sending out communications on how patients and physicians can get the therapy, but Dr. Gandhi says that making information about access available should be a priority. The window for the effective treatment is small – the drugs appear to work best before patients begin to make their own antibodies, says Dr. Gandhi – so it’s vital that doctors act quickly if they have a patient who is eligible.

And rolling out the new therapies to patients around the world will be a major logistical undertaking.

The first hurdle will be making enough of them to go around. Case numbers are skyrocketing around the globe, and producing the drugs is a complex time- and labor-intensive process that requires specialized facilities. Antibodies are produced by cell lines in bioreactors, so a plant that churns out generic aspirin tablets can’t simply be converted into an antibody factory.

“These types of drugs are manufactured in a sterile injectables plant, which is different from a plant where oral solids are made,” says Kim Crabtree, senior director of pharma portfolio management for Henry Schein Medical, a medical supplies distributor. “Those are not as plentiful as a standard pill factory.”

The doses required are also relatively high – 1.2 g of each antibody in Regeneron’s cocktail – which will further strain production capacity. Leah Lipsich, PhD, vice president of strategic program direction at Regeneron, says the company is prepared for high demand and has been able to respond, thanks to its rapid development and manufacturing technology, known as VelociSuite, which allows it to rapidly scale-up from discovery to productions in weeks instead of months.

“We knew supply would be a huge problem for COVID-19, but because we had such confidence in our technology, we went immediately from research-scale to our largest-scale manufacturing,” she says. “We’ve been manufacturing our cocktail for months now.”

The company has also partnered with Roche, the biggest manufacturer and vendor of monoclonal antibodies in the world, to manufacture and supply the drugs. Once full manufacturing capacity is reached in 2021, the companies expect to produce at least 2 million doses a year.

Then there is the issue of getting the drugs from the factories to the places they will be used.

Antibodies are temperature sensitive and need to be refrigerated during transport and storage, so a cold-chain-compliant supply chain is required. Fortunately, they can be kept at standard refrigerator temperatures, ranging from 2° C to 8° C, rather than the ultra-low temperatures required by some COVID-19 vaccines.
 

Two million doses a year

Medical logistics companies have a lot of experience dealing with products like these and are well prepared to handle the new antibody drugs. “There are quite a few products like these on the market, and the supply chain is used to shipping them,” Ms. Crabtree says.

They will be shipped to distribution centers in refrigerated trucks, repacked into smaller lots that can sustain the correct temperature for 24 hours, and then sent to their final destination, often in something as simple as a Styrofoam cooler filled with dry ice.

The expected rise in demand shouldn’t be too much of an issue for distributors either, says Ms. Crabtree; they have built systems that can deal with short-term surges in volume. The annual flu vaccine, for example, involves shipping a lot of product in a very short time, usually from August to November. “The distribution system is used to seasonal variations and peaks in demand,” she says.

The next question is how the treatments will be administered. Although most patients who will receive monoclonal antibodies will be ambulatory and not hospitalized, the administration requires intravenous infusion. Hospitals, of course, have a lot of experience with intravenous drugs, but typically give them only to inpatients. Most other monoclonal antibody drugs – such as those for cancer and autoimmune disorders – are given in specialized suites in doctor’s offices or in stand-alone infusion clinics.

That means that the places best suited to treat COVID-19 patients with antibodies are those that regularly deal with people who are immunocompromised, and such patients should not be interacting with people who have an infectious disease. “How do we protect the staff and other patients?” Dr. Gandhi asks.
 

Protecting staff and other patients

This is not an insurmountable obstacle, he points out, but it is one that requires careful thought and planning to accommodate COVID-19 patients without unduly disrupting life-saving treatments for other patients. It might involve, for example, treating COVID-19 patients in sequestered parts of the clinic or at different times of day, with even greater attention paid to cleaning, he explains. “We now have many months of experience with infection control, so we know how to do this; it’s just a question of logistics.”

But even once all the details around manufacturing, transporting, and administering the drugs are sorted out, there is still the issue of how they will be distributed fairly and equitably.

Despite multiple companies working to produce an array of different antibody drugs, demand is still expected to exceed supply for many months. “With more than 200,000 new cases a day in the United States, there won’t be enough antibodies to treat all of the high-risk patients,” says Dr. Gandhi. “Most of us are worried that demand will far outstrip supply. People are talking about lotteries to determine who gets them.”

The Department of Health and Human Services will continue to distribute the drugs to states on the basis of their COVID-19 burdens, and the states will then decide how much to provide to each health care facility.

Although the HHS goal is to ensure that the drugs reach as many patients as possible, no matter where they live and regardless of their income, there are still concerns that larger facilities serving more affluent areas will end up being favored, if only because they are the ones best equipped to deal with the drugs right now.

“We are all aware that this has affected certain communities more, so we need to make sure that the drugs are used equitably and made available to the communities that were hardest hit,” says Dr. Gandhi. The ability to monitor drug distribution should be built into the rollout, so that institutions and governments will have some sense of whether they are being doled out evenly, he adds.

Equity in distribution will be an issue for the rest of the world as well. Currently, 80% of monoclonal antibodies are sold in Canada, Europe, and the United States; few, if any, are available in low- and middle-income countries. The treatments are expensive: the cost of producing one g of marketed monoclonal antibodies is between $95 and $200, which does not include the cost of R&D, packaging, shipping, or administration. The median price for antibody treatment not related to COVID-19 runs from $15,000 to $200,000 per year in the United States.

Regeneron’s Dr. Lipsich says that the company has not yet set a price for its antibody cocktail. The government paid $450 million for its 300,000 doses, but that price includes the costs of research, manufacturing, and distribution, so is not a useful indicator of the eventual per-dose price. “We’re not in a position to talk about how it will be priced yet, but we will do our best to make it affordable and accessible to all,” she says.

There are some projects underway to ensure that the drugs are made available in poorer countries. In April, the COVID-19 Therapeutics Accelerator – an initiative launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard to speed-up the response to the global pandemic – reserved manufacturing capacity with Fujifilm Diosynth Biotechnologies in Denmark for future monoclonal antibody therapies that will supply low- and middle-income countries. In October, the initiative announced that Eli Lilly would use that reserved capacity to produce its antibody drug starting in April 2021.

In the meantime, Lilly will make some of its product manufactured in other facilities available to lower-income countries. To help keep costs down, the company’s collaborators have agreed to waive their royalties on antibodies distributed in low- and middle-income countries.

“Everyone is looking carefully at how the drugs are distributed to ensure all will get access,” said Dr. Lipsich.

A version of this article first appeared on Medscape.com.

The United States has allocated more than 641,000 monoclonal antibody treatments for outpatients to ease pressure on strained hospitals, but officials from Operation Warp Speed report that more than half of that reserve sits unused as clinicians grapple with best practices.

There are space and personnel limitations in hospitals right now, Janet Woodcock, MD, therapeutics lead on Operation Warp Speed, acknowledges in an interview with this news organization. “Special areas and procedures must be set up.” And the operation is in the process of broadening availability beyond hospitals, she points out.

But for frontline clinicians, questions about treatment efficacy and the logistics of administering intravenous drugs to infectious outpatients loom large.

More than 50 monoclonal antibody products that target SARS-CoV-2 are now in development. The U.S. Food and Drug Administration has already issued Emergency Use Authorization (EUA) for two such drugs on the basis of phase 2 trial data – bamlanivimab, made by Eli Lilly, and a cocktail of casirivimab plus imdevimab, made by Regeneron – and another two-antibody cocktail from AstraZeneca, AZD7442, has started phase 3 clinical trials. The Regeneron combination was used to treat President Donald Trump when he contracted COVID-19 in October.

Monoclonal antibody drugs are based on the natural antibodies that the body uses to fight infections. They work by binding to a specific target and then blocking its action or flagging it for destruction by other parts of the immune system. Both bamlanivimab and the casirivimab plus imdevimab combination target the spike protein of the virus and stop it from attaching to and entering human cells.
 

Targeting the spike protein out of the hospital

The antibody drugs covered by EUAs do not cure COVID-19, but they have been shown to reduce hospitalizations and visits to the emergency department for patients at high risk for disease progression. They are approved to treat patients older than 12 years with mild to moderate COVID-19 who are at high risk of progressing to severe disease or hospitalization. They are not authorized for use in patients who have been hospitalized or who are on ventilators. The hope is that antibody drugs will reduce the number of severe cases of COVID-19 and ease pressure on overstretched hospitals.

Most COVID-19 patients are outpatients, so we need something to keep them from getting worse.

This is important because it targets the greatest need in COVID-19 therapeutics, says Rajesh Gandhi, MD, an infectious disease physician at Harvard Medical School in Boston, who is a member of two panels evaluating COVID-19 treatments: one for the Infectious Disease Society of America and the other for the National Institutes of Health. “Up to now, most of the focus has been on hospitalized patients,” he says, but “most COVID-19 patients are outpatients, so we need something to keep them from getting worse.”

Both panels have said that, despite the EUAs, more evidence is needed to be sure of the efficacy of the drugs and to determine which patients will benefit the most from them.

These aren’t the mature data from drug development that guideline groups are accustomed to working with, Dr. Woodcock points out. “But this is an emergency and the data taken as a whole are pretty convincing,” she says. “As I look at the totality of the evidence, monoclonal antibodies will have a big effect in keeping people out of the hospital and helping them recover faster.”

High-risk patients are eligible for treatment, especially those older than 65 years and those with comorbidities who are younger. Access to the drugs is increasing for clinicians who are able to infuse safely or work with a site that will.

In the Boston area, several hospitals, including Massachusetts General where Dr. Gandhi works, have set up infusion centers where newly diagnosed patients can get the antibody treatment if their doctor thinks it will benefit them. And Coram, a provider of at-home infusion therapy owned by the CVS pharmacy chain, is running a pilot program offering the Eli Lilly drug to people in seven cities – including Boston, Chicago, Los Angeles, and Tampa – and their surrounding communities with a physician referral.

Getting that referral could be tricky, however, for patients without a primary care physician or for those whose doctor isn’t already connected to one of the institutions providing the infusions. The hospitals are sending out communications on how patients and physicians can get the therapy, but Dr. Gandhi says that making information about access available should be a priority. The window for the effective treatment is small – the drugs appear to work best before patients begin to make their own antibodies, says Dr. Gandhi – so it’s vital that doctors act quickly if they have a patient who is eligible.

And rolling out the new therapies to patients around the world will be a major logistical undertaking.

The first hurdle will be making enough of them to go around. Case numbers are skyrocketing around the globe, and producing the drugs is a complex time- and labor-intensive process that requires specialized facilities. Antibodies are produced by cell lines in bioreactors, so a plant that churns out generic aspirin tablets can’t simply be converted into an antibody factory.

“These types of drugs are manufactured in a sterile injectables plant, which is different from a plant where oral solids are made,” says Kim Crabtree, senior director of pharma portfolio management for Henry Schein Medical, a medical supplies distributor. “Those are not as plentiful as a standard pill factory.”

The doses required are also relatively high – 1.2 g of each antibody in Regeneron’s cocktail – which will further strain production capacity. Leah Lipsich, PhD, vice president of strategic program direction at Regeneron, says the company is prepared for high demand and has been able to respond, thanks to its rapid development and manufacturing technology, known as VelociSuite, which allows it to rapidly scale-up from discovery to productions in weeks instead of months.

“We knew supply would be a huge problem for COVID-19, but because we had such confidence in our technology, we went immediately from research-scale to our largest-scale manufacturing,” she says. “We’ve been manufacturing our cocktail for months now.”

The company has also partnered with Roche, the biggest manufacturer and vendor of monoclonal antibodies in the world, to manufacture and supply the drugs. Once full manufacturing capacity is reached in 2021, the companies expect to produce at least 2 million doses a year.

Then there is the issue of getting the drugs from the factories to the places they will be used.

Antibodies are temperature sensitive and need to be refrigerated during transport and storage, so a cold-chain-compliant supply chain is required. Fortunately, they can be kept at standard refrigerator temperatures, ranging from 2° C to 8° C, rather than the ultra-low temperatures required by some COVID-19 vaccines.
 

Two million doses a year

Medical logistics companies have a lot of experience dealing with products like these and are well prepared to handle the new antibody drugs. “There are quite a few products like these on the market, and the supply chain is used to shipping them,” Ms. Crabtree says.

They will be shipped to distribution centers in refrigerated trucks, repacked into smaller lots that can sustain the correct temperature for 24 hours, and then sent to their final destination, often in something as simple as a Styrofoam cooler filled with dry ice.

The expected rise in demand shouldn’t be too much of an issue for distributors either, says Ms. Crabtree; they have built systems that can deal with short-term surges in volume. The annual flu vaccine, for example, involves shipping a lot of product in a very short time, usually from August to November. “The distribution system is used to seasonal variations and peaks in demand,” she says.

The next question is how the treatments will be administered. Although most patients who will receive monoclonal antibodies will be ambulatory and not hospitalized, the administration requires intravenous infusion. Hospitals, of course, have a lot of experience with intravenous drugs, but typically give them only to inpatients. Most other monoclonal antibody drugs – such as those for cancer and autoimmune disorders – are given in specialized suites in doctor’s offices or in stand-alone infusion clinics.

That means that the places best suited to treat COVID-19 patients with antibodies are those that regularly deal with people who are immunocompromised, and such patients should not be interacting with people who have an infectious disease. “How do we protect the staff and other patients?” Dr. Gandhi asks.
 

Protecting staff and other patients

This is not an insurmountable obstacle, he points out, but it is one that requires careful thought and planning to accommodate COVID-19 patients without unduly disrupting life-saving treatments for other patients. It might involve, for example, treating COVID-19 patients in sequestered parts of the clinic or at different times of day, with even greater attention paid to cleaning, he explains. “We now have many months of experience with infection control, so we know how to do this; it’s just a question of logistics.”

But even once all the details around manufacturing, transporting, and administering the drugs are sorted out, there is still the issue of how they will be distributed fairly and equitably.

Despite multiple companies working to produce an array of different antibody drugs, demand is still expected to exceed supply for many months. “With more than 200,000 new cases a day in the United States, there won’t be enough antibodies to treat all of the high-risk patients,” says Dr. Gandhi. “Most of us are worried that demand will far outstrip supply. People are talking about lotteries to determine who gets them.”

The Department of Health and Human Services will continue to distribute the drugs to states on the basis of their COVID-19 burdens, and the states will then decide how much to provide to each health care facility.

Although the HHS goal is to ensure that the drugs reach as many patients as possible, no matter where they live and regardless of their income, there are still concerns that larger facilities serving more affluent areas will end up being favored, if only because they are the ones best equipped to deal with the drugs right now.

“We are all aware that this has affected certain communities more, so we need to make sure that the drugs are used equitably and made available to the communities that were hardest hit,” says Dr. Gandhi. The ability to monitor drug distribution should be built into the rollout, so that institutions and governments will have some sense of whether they are being doled out evenly, he adds.

Equity in distribution will be an issue for the rest of the world as well. Currently, 80% of monoclonal antibodies are sold in Canada, Europe, and the United States; few, if any, are available in low- and middle-income countries. The treatments are expensive: the cost of producing one g of marketed monoclonal antibodies is between $95 and $200, which does not include the cost of R&D, packaging, shipping, or administration. The median price for antibody treatment not related to COVID-19 runs from $15,000 to $200,000 per year in the United States.

Regeneron’s Dr. Lipsich says that the company has not yet set a price for its antibody cocktail. The government paid $450 million for its 300,000 doses, but that price includes the costs of research, manufacturing, and distribution, so is not a useful indicator of the eventual per-dose price. “We’re not in a position to talk about how it will be priced yet, but we will do our best to make it affordable and accessible to all,” she says.

There are some projects underway to ensure that the drugs are made available in poorer countries. In April, the COVID-19 Therapeutics Accelerator – an initiative launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard to speed-up the response to the global pandemic – reserved manufacturing capacity with Fujifilm Diosynth Biotechnologies in Denmark for future monoclonal antibody therapies that will supply low- and middle-income countries. In October, the initiative announced that Eli Lilly would use that reserved capacity to produce its antibody drug starting in April 2021.

In the meantime, Lilly will make some of its product manufactured in other facilities available to lower-income countries. To help keep costs down, the company’s collaborators have agreed to waive their royalties on antibodies distributed in low- and middle-income countries.

“Everyone is looking carefully at how the drugs are distributed to ensure all will get access,” said Dr. Lipsich.

A version of this article first appeared on Medscape.com.

The United States has allocated more than 641,000 monoclonal antibody treatments for outpatients to ease pressure on strained hospitals, but officials from Operation Warp Speed report that more than half of that reserve sits unused as clinicians grapple with best practices.

There are space and personnel limitations in hospitals right now, Janet Woodcock, MD, therapeutics lead on Operation Warp Speed, acknowledges in an interview with this news organization. “Special areas and procedures must be set up.” And the operation is in the process of broadening availability beyond hospitals, she points out.

But for frontline clinicians, questions about treatment efficacy and the logistics of administering intravenous drugs to infectious outpatients loom large.

More than 50 monoclonal antibody products that target SARS-CoV-2 are now in development. The U.S. Food and Drug Administration has already issued Emergency Use Authorization (EUA) for two such drugs on the basis of phase 2 trial data – bamlanivimab, made by Eli Lilly, and a cocktail of casirivimab plus imdevimab, made by Regeneron – and another two-antibody cocktail from AstraZeneca, AZD7442, has started phase 3 clinical trials. The Regeneron combination was used to treat President Donald Trump when he contracted COVID-19 in October.

Monoclonal antibody drugs are based on the natural antibodies that the body uses to fight infections. They work by binding to a specific target and then blocking its action or flagging it for destruction by other parts of the immune system. Both bamlanivimab and the casirivimab plus imdevimab combination target the spike protein of the virus and stop it from attaching to and entering human cells.
 

Targeting the spike protein out of the hospital

The antibody drugs covered by EUAs do not cure COVID-19, but they have been shown to reduce hospitalizations and visits to the emergency department for patients at high risk for disease progression. They are approved to treat patients older than 12 years with mild to moderate COVID-19 who are at high risk of progressing to severe disease or hospitalization. They are not authorized for use in patients who have been hospitalized or who are on ventilators. The hope is that antibody drugs will reduce the number of severe cases of COVID-19 and ease pressure on overstretched hospitals.

Most COVID-19 patients are outpatients, so we need something to keep them from getting worse.

This is important because it targets the greatest need in COVID-19 therapeutics, says Rajesh Gandhi, MD, an infectious disease physician at Harvard Medical School in Boston, who is a member of two panels evaluating COVID-19 treatments: one for the Infectious Disease Society of America and the other for the National Institutes of Health. “Up to now, most of the focus has been on hospitalized patients,” he says, but “most COVID-19 patients are outpatients, so we need something to keep them from getting worse.”

Both panels have said that, despite the EUAs, more evidence is needed to be sure of the efficacy of the drugs and to determine which patients will benefit the most from them.

These aren’t the mature data from drug development that guideline groups are accustomed to working with, Dr. Woodcock points out. “But this is an emergency and the data taken as a whole are pretty convincing,” she says. “As I look at the totality of the evidence, monoclonal antibodies will have a big effect in keeping people out of the hospital and helping them recover faster.”

High-risk patients are eligible for treatment, especially those older than 65 years and those with comorbidities who are younger. Access to the drugs is increasing for clinicians who are able to infuse safely or work with a site that will.

In the Boston area, several hospitals, including Massachusetts General where Dr. Gandhi works, have set up infusion centers where newly diagnosed patients can get the antibody treatment if their doctor thinks it will benefit them. And Coram, a provider of at-home infusion therapy owned by the CVS pharmacy chain, is running a pilot program offering the Eli Lilly drug to people in seven cities – including Boston, Chicago, Los Angeles, and Tampa – and their surrounding communities with a physician referral.

Getting that referral could be tricky, however, for patients without a primary care physician or for those whose doctor isn’t already connected to one of the institutions providing the infusions. The hospitals are sending out communications on how patients and physicians can get the therapy, but Dr. Gandhi says that making information about access available should be a priority. The window for the effective treatment is small – the drugs appear to work best before patients begin to make their own antibodies, says Dr. Gandhi – so it’s vital that doctors act quickly if they have a patient who is eligible.

And rolling out the new therapies to patients around the world will be a major logistical undertaking.

The first hurdle will be making enough of them to go around. Case numbers are skyrocketing around the globe, and producing the drugs is a complex time- and labor-intensive process that requires specialized facilities. Antibodies are produced by cell lines in bioreactors, so a plant that churns out generic aspirin tablets can’t simply be converted into an antibody factory.

“These types of drugs are manufactured in a sterile injectables plant, which is different from a plant where oral solids are made,” says Kim Crabtree, senior director of pharma portfolio management for Henry Schein Medical, a medical supplies distributor. “Those are not as plentiful as a standard pill factory.”

The doses required are also relatively high – 1.2 g of each antibody in Regeneron’s cocktail – which will further strain production capacity. Leah Lipsich, PhD, vice president of strategic program direction at Regeneron, says the company is prepared for high demand and has been able to respond, thanks to its rapid development and manufacturing technology, known as VelociSuite, which allows it to rapidly scale-up from discovery to productions in weeks instead of months.

“We knew supply would be a huge problem for COVID-19, but because we had such confidence in our technology, we went immediately from research-scale to our largest-scale manufacturing,” she says. “We’ve been manufacturing our cocktail for months now.”

The company has also partnered with Roche, the biggest manufacturer and vendor of monoclonal antibodies in the world, to manufacture and supply the drugs. Once full manufacturing capacity is reached in 2021, the companies expect to produce at least 2 million doses a year.

Then there is the issue of getting the drugs from the factories to the places they will be used.

Antibodies are temperature sensitive and need to be refrigerated during transport and storage, so a cold-chain-compliant supply chain is required. Fortunately, they can be kept at standard refrigerator temperatures, ranging from 2° C to 8° C, rather than the ultra-low temperatures required by some COVID-19 vaccines.
 

Two million doses a year

Medical logistics companies have a lot of experience dealing with products like these and are well prepared to handle the new antibody drugs. “There are quite a few products like these on the market, and the supply chain is used to shipping them,” Ms. Crabtree says.

They will be shipped to distribution centers in refrigerated trucks, repacked into smaller lots that can sustain the correct temperature for 24 hours, and then sent to their final destination, often in something as simple as a Styrofoam cooler filled with dry ice.

The expected rise in demand shouldn’t be too much of an issue for distributors either, says Ms. Crabtree; they have built systems that can deal with short-term surges in volume. The annual flu vaccine, for example, involves shipping a lot of product in a very short time, usually from August to November. “The distribution system is used to seasonal variations and peaks in demand,” she says.

The next question is how the treatments will be administered. Although most patients who will receive monoclonal antibodies will be ambulatory and not hospitalized, the administration requires intravenous infusion. Hospitals, of course, have a lot of experience with intravenous drugs, but typically give them only to inpatients. Most other monoclonal antibody drugs – such as those for cancer and autoimmune disorders – are given in specialized suites in doctor’s offices or in stand-alone infusion clinics.

That means that the places best suited to treat COVID-19 patients with antibodies are those that regularly deal with people who are immunocompromised, and such patients should not be interacting with people who have an infectious disease. “How do we protect the staff and other patients?” Dr. Gandhi asks.
 

Protecting staff and other patients

This is not an insurmountable obstacle, he points out, but it is one that requires careful thought and planning to accommodate COVID-19 patients without unduly disrupting life-saving treatments for other patients. It might involve, for example, treating COVID-19 patients in sequestered parts of the clinic or at different times of day, with even greater attention paid to cleaning, he explains. “We now have many months of experience with infection control, so we know how to do this; it’s just a question of logistics.”

But even once all the details around manufacturing, transporting, and administering the drugs are sorted out, there is still the issue of how they will be distributed fairly and equitably.

Despite multiple companies working to produce an array of different antibody drugs, demand is still expected to exceed supply for many months. “With more than 200,000 new cases a day in the United States, there won’t be enough antibodies to treat all of the high-risk patients,” says Dr. Gandhi. “Most of us are worried that demand will far outstrip supply. People are talking about lotteries to determine who gets them.”

The Department of Health and Human Services will continue to distribute the drugs to states on the basis of their COVID-19 burdens, and the states will then decide how much to provide to each health care facility.

Although the HHS goal is to ensure that the drugs reach as many patients as possible, no matter where they live and regardless of their income, there are still concerns that larger facilities serving more affluent areas will end up being favored, if only because they are the ones best equipped to deal with the drugs right now.

“We are all aware that this has affected certain communities more, so we need to make sure that the drugs are used equitably and made available to the communities that were hardest hit,” says Dr. Gandhi. The ability to monitor drug distribution should be built into the rollout, so that institutions and governments will have some sense of whether they are being doled out evenly, he adds.

Equity in distribution will be an issue for the rest of the world as well. Currently, 80% of monoclonal antibodies are sold in Canada, Europe, and the United States; few, if any, are available in low- and middle-income countries. The treatments are expensive: the cost of producing one g of marketed monoclonal antibodies is between $95 and $200, which does not include the cost of R&D, packaging, shipping, or administration. The median price for antibody treatment not related to COVID-19 runs from $15,000 to $200,000 per year in the United States.

Regeneron’s Dr. Lipsich says that the company has not yet set a price for its antibody cocktail. The government paid $450 million for its 300,000 doses, but that price includes the costs of research, manufacturing, and distribution, so is not a useful indicator of the eventual per-dose price. “We’re not in a position to talk about how it will be priced yet, but we will do our best to make it affordable and accessible to all,” she says.

There are some projects underway to ensure that the drugs are made available in poorer countries. In April, the COVID-19 Therapeutics Accelerator – an initiative launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard to speed-up the response to the global pandemic – reserved manufacturing capacity with Fujifilm Diosynth Biotechnologies in Denmark for future monoclonal antibody therapies that will supply low- and middle-income countries. In October, the initiative announced that Eli Lilly would use that reserved capacity to produce its antibody drug starting in April 2021.

In the meantime, Lilly will make some of its product manufactured in other facilities available to lower-income countries. To help keep costs down, the company’s collaborators have agreed to waive their royalties on antibodies distributed in low- and middle-income countries.

“Everyone is looking carefully at how the drugs are distributed to ensure all will get access,” said Dr. Lipsich.

A version of this article first appeared on Medscape.com.

The United States added over 171,000 new COVID-19 cases in children during the week ending Jan. 7, but that figure is lower than 3 of the previous 4 weeks, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

Despite an increase compared with the week ending Dec. 31, the most recent weekly total is down from the high of 182,000 cases reported for the week ending Dec. 17, based on data collected from the health department websites of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

Those jurisdictions have recorded a total of almost 2.3 million COVID-19 cases in children since the beginning of the pandemic, which amounts to 12.5% of reported cases among all ages. The 171,000 child cases for the most recent week represented 12.9% of the more than 1.3 million cases nationwide, the AAP and CHA said in their latest weekly update.

The United States now has a rate of 3,055 COVID-19 cases per 100,000 children in the population, the report shows, with 31 states above that figure and 14 states reporting rates above 4,500 per 100,000 children.

Severe illness, however, continues to be rare among children. So far, children represent 1.8% of all hospitalizations in the jurisdictions reporting such data (24 states and New York City), and just 0.9% of infected children have been hospitalized. There have been 188 deaths among children in 42 states and New York City, which makes up just 0.06% of the total for all ages in those jurisdictions, the AAP and CHA reported.

There are 13 states that have reported no coronavirus-related deaths in children, while Texas (34), New York City (21), Arizona (17), and Illinois (11) are the only jurisdictions with 10 or more. Nevada has the highest proportion of child deaths to all deaths at 0.2%, with Arizona and Nebraska next at 0.18%, according to the AAP/CHA report.

[email protected]

The United States added over 171,000 new COVID-19 cases in children during the week ending Jan. 7, but that figure is lower than 3 of the previous 4 weeks, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

Despite an increase compared with the week ending Dec. 31, the most recent weekly total is down from the high of 182,000 cases reported for the week ending Dec. 17, based on data collected from the health department websites of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

Those jurisdictions have recorded a total of almost 2.3 million COVID-19 cases in children since the beginning of the pandemic, which amounts to 12.5% of reported cases among all ages. The 171,000 child cases for the most recent week represented 12.9% of the more than 1.3 million cases nationwide, the AAP and CHA said in their latest weekly update.

The United States now has a rate of 3,055 COVID-19 cases per 100,000 children in the population, the report shows, with 31 states above that figure and 14 states reporting rates above 4,500 per 100,000 children.

Severe illness, however, continues to be rare among children. So far, children represent 1.8% of all hospitalizations in the jurisdictions reporting such data (24 states and New York City), and just 0.9% of infected children have been hospitalized. There have been 188 deaths among children in 42 states and New York City, which makes up just 0.06% of the total for all ages in those jurisdictions, the AAP and CHA reported.

There are 13 states that have reported no coronavirus-related deaths in children, while Texas (34), New York City (21), Arizona (17), and Illinois (11) are the only jurisdictions with 10 or more. Nevada has the highest proportion of child deaths to all deaths at 0.2%, with Arizona and Nebraska next at 0.18%, according to the AAP/CHA report.

[email protected]

The United States added over 171,000 new COVID-19 cases in children during the week ending Jan. 7, but that figure is lower than 3 of the previous 4 weeks, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

Despite an increase compared with the week ending Dec. 31, the most recent weekly total is down from the high of 182,000 cases reported for the week ending Dec. 17, based on data collected from the health department websites of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

Those jurisdictions have recorded a total of almost 2.3 million COVID-19 cases in children since the beginning of the pandemic, which amounts to 12.5% of reported cases among all ages. The 171,000 child cases for the most recent week represented 12.9% of the more than 1.3 million cases nationwide, the AAP and CHA said in their latest weekly update.

The United States now has a rate of 3,055 COVID-19 cases per 100,000 children in the population, the report shows, with 31 states above that figure and 14 states reporting rates above 4,500 per 100,000 children.

Severe illness, however, continues to be rare among children. So far, children represent 1.8% of all hospitalizations in the jurisdictions reporting such data (24 states and New York City), and just 0.9% of infected children have been hospitalized. There have been 188 deaths among children in 42 states and New York City, which makes up just 0.06% of the total for all ages in those jurisdictions, the AAP and CHA reported.

There are 13 states that have reported no coronavirus-related deaths in children, while Texas (34), New York City (21), Arizona (17), and Illinois (11) are the only jurisdictions with 10 or more. Nevada has the highest proportion of child deaths to all deaths at 0.2%, with Arizona and Nebraska next at 0.18%, according to the AAP/CHA report.

[email protected]

Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.

And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.

“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.

Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).

Observational registry study shows 43% reduction in primary outcome

The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.

The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.

Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.

Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).

Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.

Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.

“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”

Noncompliance to DOAC therapy a concern

In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”

However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.

“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”

Methods ‘severely flawed’

John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.

“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”

Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.

Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.

Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.

Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.

And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.

“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.

Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).

Observational registry study shows 43% reduction in primary outcome

The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.

The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.

Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.

Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).

Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.

Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.

“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”

Noncompliance to DOAC therapy a concern

In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”

However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.

“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”

Methods ‘severely flawed’

John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.

“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”

Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.

Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.

Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.

Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.

And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.

“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.

Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).

Observational registry study shows 43% reduction in primary outcome

The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.

The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.

Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.

Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).

Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.

Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.

“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”

Noncompliance to DOAC therapy a concern

In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”

However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.

“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”

Methods ‘severely flawed’

John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.

“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”

Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.

Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.

Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.

Click here to read this supplement 

CME/CE CREDITS: 1.5 CREDITS

After reviewing the learning objectives and reading the supplement, please complete the Activity Evaluation/Credit Request form online at www.cmesurvey.site/MDDJFP

Click here to read this supplement 

CME/CE CREDITS: 1.5 CREDITS

After reviewing the learning objectives and reading the supplement, please complete the Activity Evaluation/Credit Request form online at www.cmesurvey.site/MDDJFP

Click here to read this supplement 

CME/CE CREDITS: 1.5 CREDITS

After reviewing the learning objectives and reading the supplement, please complete the Activity Evaluation/Credit Request form online at www.cmesurvey.site/MDDJFP

Malpractice lawsuits related to colonoscopy continue to pose challenges for practitioners, and a new analysis reveals that errors related to sedation are more likely to be awarded to plaintiffs. Primary care physicians and surgeons are often codefendants, which emphasizes the importance of interdisciplinary care in colonoscopy.

Cases involving informed consent were more likely to be ruled for the defendant, while those tied to medication error favored the plaintiff, according to an analysis of cases from the Westlaw legal database. The study, led by Krishan S. Patel and Sushil Ahlawat of Rutgers New Jersey Medical School, Newark, was published in the Journal of Clinical Gastroenterology.

According to the authors, 55% of physicians face a malpractice suit at some point in their careers, and gastroenterology ranks as the sixth most common specialty named in malpractice suits. Every year, about 13% of gastroenterologists confront malpractice allegations, and colonoscopy is the most common reason.

The researchers searched the Westlaw legal database for malpractice cases involving colonoscopy or sigmoidoscopy, identifying 305 cases between 1980 and 2017. The average patient age was 54.9 years, and 52.8% of cases were brought by female patients. The most cases were from New York (21.0%), followed by California (13.4%), Pennsylvania (13.1%), Massachusetts (12.5%), and New Jersey (7.9%). Gastroenterologists were named in 71.1% of cases, internists in 25.6%, and surgeons in 14.8%.

A little more than half (51.8%) of cases were ruled in favor of the defendant, and 25% for the plaintiff; 17% were settled, and 6% had a mixed outcome. Payouts ranged from $30,000 to $500,000,000, with a median of $995,000.

There were multiple causes of litigation listed in 83.6% of cases. The most frequent causes were delayed treatment (65.9%), delayed diagnosis (65.6%), procedural error/negligence (44.3%), and failure to refer/reorder tests (25.6%).

Of 135 cases alleging procedural negligence, 90 (67%) named perforation. Among 79 cases that cited a failure to refer and order appropriate tests, 97% claimed the defendant missed a cancerous lesion. In cases alleging missed cancers, 31% were in the cecum, and 23% in the anus.

A logistic regression analysis of factors associated with a verdict for the defendant found “lack of informed consent” to be an independent predictor of defendant verdict (odds ratio, 4.05; P = .004). “Medication error” was associated with reduced defendant success (OR, 0.17; P=.023). There were nonsignificant trends between reduced odds of a verdict for the defendant and lawsuits that named “delay in diagnosis” (OR, 0.35; P = .060) and “failure to refer” (OR, 0.51; P = .074).

The authors sound a dire note about the number of malpractice suits brought against gastroenterologists, but Lawrence Kosinski, MD, is more sanguine. He notes that gastroenterologists have low insurance premiums, compared with other specialties, but recognizes that colonoscopies are a significant source of risk.

Dr. Kosinski, who is chief medical officer at SonarMD and formerly a managing partner at the Illinois Gastroenterology Group, said in an interview that the study is revealing. “It comes out in the article: Acts of omission are more dangerous to the physician than acts of commission. Not finding that cancer, not acting on that malignant polyp, not pursuing it, is much more likely to get you in trouble than taking it off and perforating a colon,” said Dr. Kosinski, who was not involved in the study.

To gastroenterologists seeking to reduce their risks, he offered advice: You shouldn’t assume that the patient has read the information provided. Risks of anesthesia and the procedure should be directly communicated. It’s also important to document the procedure, including pictures of the cecum and rectal retroflexion. Finally, don’t rush. “This isn’t a race. Clean the colon, make sure you don’t miss something. If that person pops up in 3 years with a cancer, someone may go after you,” said Dr. Kosinski.

No source of funding was disclosed. Dr. Kosinski has no relevant financial disclosures.

Malpractice lawsuits related to colonoscopy continue to pose challenges for practitioners, and a new analysis reveals that errors related to sedation are more likely to be awarded to plaintiffs. Primary care physicians and surgeons are often codefendants, which emphasizes the importance of interdisciplinary care in colonoscopy.

Cases involving informed consent were more likely to be ruled for the defendant, while those tied to medication error favored the plaintiff, according to an analysis of cases from the Westlaw legal database. The study, led by Krishan S. Patel and Sushil Ahlawat of Rutgers New Jersey Medical School, Newark, was published in the Journal of Clinical Gastroenterology.

According to the authors, 55% of physicians face a malpractice suit at some point in their careers, and gastroenterology ranks as the sixth most common specialty named in malpractice suits. Every year, about 13% of gastroenterologists confront malpractice allegations, and colonoscopy is the most common reason.

The researchers searched the Westlaw legal database for malpractice cases involving colonoscopy or sigmoidoscopy, identifying 305 cases between 1980 and 2017. The average patient age was 54.9 years, and 52.8% of cases were brought by female patients. The most cases were from New York (21.0%), followed by California (13.4%), Pennsylvania (13.1%), Massachusetts (12.5%), and New Jersey (7.9%). Gastroenterologists were named in 71.1% of cases, internists in 25.6%, and surgeons in 14.8%.

A little more than half (51.8%) of cases were ruled in favor of the defendant, and 25% for the plaintiff; 17% were settled, and 6% had a mixed outcome. Payouts ranged from $30,000 to $500,000,000, with a median of $995,000.

There were multiple causes of litigation listed in 83.6% of cases. The most frequent causes were delayed treatment (65.9%), delayed diagnosis (65.6%), procedural error/negligence (44.3%), and failure to refer/reorder tests (25.6%).

Of 135 cases alleging procedural negligence, 90 (67%) named perforation. Among 79 cases that cited a failure to refer and order appropriate tests, 97% claimed the defendant missed a cancerous lesion. In cases alleging missed cancers, 31% were in the cecum, and 23% in the anus.

A logistic regression analysis of factors associated with a verdict for the defendant found “lack of informed consent” to be an independent predictor of defendant verdict (odds ratio, 4.05; P = .004). “Medication error” was associated with reduced defendant success (OR, 0.17; P=.023). There were nonsignificant trends between reduced odds of a verdict for the defendant and lawsuits that named “delay in diagnosis” (OR, 0.35; P = .060) and “failure to refer” (OR, 0.51; P = .074).

The authors sound a dire note about the number of malpractice suits brought against gastroenterologists, but Lawrence Kosinski, MD, is more sanguine. He notes that gastroenterologists have low insurance premiums, compared with other specialties, but recognizes that colonoscopies are a significant source of risk.

Dr. Kosinski, who is chief medical officer at SonarMD and formerly a managing partner at the Illinois Gastroenterology Group, said in an interview that the study is revealing. “It comes out in the article: Acts of omission are more dangerous to the physician than acts of commission. Not finding that cancer, not acting on that malignant polyp, not pursuing it, is much more likely to get you in trouble than taking it off and perforating a colon,” said Dr. Kosinski, who was not involved in the study.

To gastroenterologists seeking to reduce their risks, he offered advice: You shouldn’t assume that the patient has read the information provided. Risks of anesthesia and the procedure should be directly communicated. It’s also important to document the procedure, including pictures of the cecum and rectal retroflexion. Finally, don’t rush. “This isn’t a race. Clean the colon, make sure you don’t miss something. If that person pops up in 3 years with a cancer, someone may go after you,” said Dr. Kosinski.

No source of funding was disclosed. Dr. Kosinski has no relevant financial disclosures.

Malpractice lawsuits related to colonoscopy continue to pose challenges for practitioners, and a new analysis reveals that errors related to sedation are more likely to be awarded to plaintiffs. Primary care physicians and surgeons are often codefendants, which emphasizes the importance of interdisciplinary care in colonoscopy.

Cases involving informed consent were more likely to be ruled for the defendant, while those tied to medication error favored the plaintiff, according to an analysis of cases from the Westlaw legal database. The study, led by Krishan S. Patel and Sushil Ahlawat of Rutgers New Jersey Medical School, Newark, was published in the Journal of Clinical Gastroenterology.

According to the authors, 55% of physicians face a malpractice suit at some point in their careers, and gastroenterology ranks as the sixth most common specialty named in malpractice suits. Every year, about 13% of gastroenterologists confront malpractice allegations, and colonoscopy is the most common reason.

The researchers searched the Westlaw legal database for malpractice cases involving colonoscopy or sigmoidoscopy, identifying 305 cases between 1980 and 2017. The average patient age was 54.9 years, and 52.8% of cases were brought by female patients. The most cases were from New York (21.0%), followed by California (13.4%), Pennsylvania (13.1%), Massachusetts (12.5%), and New Jersey (7.9%). Gastroenterologists were named in 71.1% of cases, internists in 25.6%, and surgeons in 14.8%.

A little more than half (51.8%) of cases were ruled in favor of the defendant, and 25% for the plaintiff; 17% were settled, and 6% had a mixed outcome. Payouts ranged from $30,000 to $500,000,000, with a median of $995,000.

There were multiple causes of litigation listed in 83.6% of cases. The most frequent causes were delayed treatment (65.9%), delayed diagnosis (65.6%), procedural error/negligence (44.3%), and failure to refer/reorder tests (25.6%).

Of 135 cases alleging procedural negligence, 90 (67%) named perforation. Among 79 cases that cited a failure to refer and order appropriate tests, 97% claimed the defendant missed a cancerous lesion. In cases alleging missed cancers, 31% were in the cecum, and 23% in the anus.

A logistic regression analysis of factors associated with a verdict for the defendant found “lack of informed consent” to be an independent predictor of defendant verdict (odds ratio, 4.05; P = .004). “Medication error” was associated with reduced defendant success (OR, 0.17; P=.023). There were nonsignificant trends between reduced odds of a verdict for the defendant and lawsuits that named “delay in diagnosis” (OR, 0.35; P = .060) and “failure to refer” (OR, 0.51; P = .074).

The authors sound a dire note about the number of malpractice suits brought against gastroenterologists, but Lawrence Kosinski, MD, is more sanguine. He notes that gastroenterologists have low insurance premiums, compared with other specialties, but recognizes that colonoscopies are a significant source of risk.

Dr. Kosinski, who is chief medical officer at SonarMD and formerly a managing partner at the Illinois Gastroenterology Group, said in an interview that the study is revealing. “It comes out in the article: Acts of omission are more dangerous to the physician than acts of commission. Not finding that cancer, not acting on that malignant polyp, not pursuing it, is much more likely to get you in trouble than taking it off and perforating a colon,” said Dr. Kosinski, who was not involved in the study.

To gastroenterologists seeking to reduce their risks, he offered advice: You shouldn’t assume that the patient has read the information provided. Risks of anesthesia and the procedure should be directly communicated. It’s also important to document the procedure, including pictures of the cecum and rectal retroflexion. Finally, don’t rush. “This isn’t a race. Clean the colon, make sure you don’t miss something. If that person pops up in 3 years with a cancer, someone may go after you,” said Dr. Kosinski.

No source of funding was disclosed. Dr. Kosinski has no relevant financial disclosures.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

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To claim credits for this activity, please visit: www.gihealthfoundation.org/EVAL-PRIMESUPPLEMENT

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CME CREDITS: 1 CREDIT

To claim credits for this activity, please visit: www.gihealthfoundation.org/EVAL-PRIMESUPPLEMENT