Infectious Diseases

The number of Americans hospitalized because of the flu has hit the highest levels the country has seen in at least a decade, the Centers for Disease Control and Prevention said.
 

But the number of deaths and outpatient visits for flu or flu-like illnesses was down slightly from the week before, the CDC said in its weekly FluView report.

There were almost 26,000 new hospital admissions involving laboratory-confirmed influenza over those 7 days, up by over 31% from the previous week, based on data from 5,000 hospitals in the HHS Protect system, which tracks and shares COVID-19 data.

The cumulative hospitalization rate for the 2022-2023 season is 26.0 per 100,000 people, the highest seen at this time of year since 2010-2011, the CDC said, based on data from its Influenza Hospitalization Surveillance Network, which includes hospitals in select counties in 13 states.

At this point in the 2019-2020 season, just before the COVID-19 pandemic began, the cumulative rate was 3.1 per 100,000 people, the CDC’s data show.

On the positive side, the proportion of outpatient visits for influenza-like illness dropped slightly to 7.2%, from 7.5% the week before. But these cases from the CDC’s Outpatient Influenza-like Illness Surveillance Network are not laboratory confirmed, so the data could include people with the flu, COVID-19, or respiratory syncytial virus. 

The number of confirmed flu deaths for the week of Nov. 27 to Dec. 3 also fell slightly from the last full week of November, 246 vs. 255, but the number of pediatric deaths rose from 2 to 7, and total deaths in children are already up to 21 for 2022-2023. That’s compared to 44 that were reported during all of the 2021-2022 season, the CDC said.

“So far this season, there have been at least 13 million illnesses, 120,000 hospitalizations, and 7,300 deaths from flu,” the agency estimated.

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

The number of Americans hospitalized because of the flu has hit the highest levels the country has seen in at least a decade, the Centers for Disease Control and Prevention said.
 

But the number of deaths and outpatient visits for flu or flu-like illnesses was down slightly from the week before, the CDC said in its weekly FluView report.

There were almost 26,000 new hospital admissions involving laboratory-confirmed influenza over those 7 days, up by over 31% from the previous week, based on data from 5,000 hospitals in the HHS Protect system, which tracks and shares COVID-19 data.

The cumulative hospitalization rate for the 2022-2023 season is 26.0 per 100,000 people, the highest seen at this time of year since 2010-2011, the CDC said, based on data from its Influenza Hospitalization Surveillance Network, which includes hospitals in select counties in 13 states.

At this point in the 2019-2020 season, just before the COVID-19 pandemic began, the cumulative rate was 3.1 per 100,000 people, the CDC’s data show.

On the positive side, the proportion of outpatient visits for influenza-like illness dropped slightly to 7.2%, from 7.5% the week before. But these cases from the CDC’s Outpatient Influenza-like Illness Surveillance Network are not laboratory confirmed, so the data could include people with the flu, COVID-19, or respiratory syncytial virus. 

The number of confirmed flu deaths for the week of Nov. 27 to Dec. 3 also fell slightly from the last full week of November, 246 vs. 255, but the number of pediatric deaths rose from 2 to 7, and total deaths in children are already up to 21 for 2022-2023. That’s compared to 44 that were reported during all of the 2021-2022 season, the CDC said.

“So far this season, there have been at least 13 million illnesses, 120,000 hospitalizations, and 7,300 deaths from flu,” the agency estimated.

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

The number of Americans hospitalized because of the flu has hit the highest levels the country has seen in at least a decade, the Centers for Disease Control and Prevention said.
 

But the number of deaths and outpatient visits for flu or flu-like illnesses was down slightly from the week before, the CDC said in its weekly FluView report.

There were almost 26,000 new hospital admissions involving laboratory-confirmed influenza over those 7 days, up by over 31% from the previous week, based on data from 5,000 hospitals in the HHS Protect system, which tracks and shares COVID-19 data.

The cumulative hospitalization rate for the 2022-2023 season is 26.0 per 100,000 people, the highest seen at this time of year since 2010-2011, the CDC said, based on data from its Influenza Hospitalization Surveillance Network, which includes hospitals in select counties in 13 states.

At this point in the 2019-2020 season, just before the COVID-19 pandemic began, the cumulative rate was 3.1 per 100,000 people, the CDC’s data show.

On the positive side, the proportion of outpatient visits for influenza-like illness dropped slightly to 7.2%, from 7.5% the week before. But these cases from the CDC’s Outpatient Influenza-like Illness Surveillance Network are not laboratory confirmed, so the data could include people with the flu, COVID-19, or respiratory syncytial virus. 

The number of confirmed flu deaths for the week of Nov. 27 to Dec. 3 also fell slightly from the last full week of November, 246 vs. 255, but the number of pediatric deaths rose from 2 to 7, and total deaths in children are already up to 21 for 2022-2023. That’s compared to 44 that were reported during all of the 2021-2022 season, the CDC said.

“So far this season, there have been at least 13 million illnesses, 120,000 hospitalizations, and 7,300 deaths from flu,” the agency estimated.

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

It was the last monoclonal antibody treatment standing. But less than 10 months after the U.S. Food and Drug Administration gave bebtelovimab its emergency use authorization (EUA) to fight COVID-19, it earlier this month de-authorized it, just as it had for other monoclonal antibody treatments, and for the same reason: The treatments were outwitted by the viral mutations.
 

Bebtelovimab couldn’t neutralize the Omicron subvariants BQ.1 and BQ.1.1, the cause of nearly 60% of COVID cases nationally as of November 30.

Next on the chopping block, some predict, will be Evusheld, the combination of tixagevimab and cilgavimab given as a preventive monoclonal antibody to people who are immunocompromised and at high risk of contracting COVID and to those who can’t take the vaccine. In October, the FDA warned that Evusheld was not neutralizing circulating COVID variants.

As the options for treating and preventing COVID decline, will companies rally quickly to develop new ones, or cut their losses in developing treatments that may work for only a few months, given the speed of viral mutations?

But although monoclonal antibody treatments are off the table, at least for now, antiviral drugs – including Paxlovid – are still very much available, and some say underused.

Others suggest it’s time to resurrect interest in convalescent plasma, a treatment used early in the pandemic before drugs or vaccines were here and still authorized for use in those who are immunosuppressed or receiving immunosuppressive treatment.

And on the prevention front, staying up to date with booster vaccines, masking, and taking other precautions should be stressed more, others say, regardless of the number of treatment options, and especially now, as cases rise and people gather for the winter holidays.
 

‘A major setback’

The bebtelovimab de-authorization was “a major setback,” but an understandable one, said Arturo Casadevall, MD, PhD, professor and chair of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health in Baltimore. “Monoclonal antibodies are great drugs. We are in an unfortunate situation in that they are vulnerable to changes in the virus” and can’t offer long-lasting protection.

Supplies of bebtelovimab will be retained, according to the FDA, in case variants susceptible to it return.

“What happened to bebtelovimab is no surprise,” agreed Amesh Adalja, MD, senior scholar at Johns Hopkins Center for Health Security. “This is what is going to happen when you are targeting a virus that mutates a lot.”

Monoclonal antibodies work by binding to the spike protein on the virus surface to prevent it from entering cells.

However, Dr. Adalja doesn’t view the disappearance of monoclonal antibody treatments as a major setback. Monoclonal antibodies were not the primary way COVID was treated, he said.

While he does believe it’s important that more monoclonal antibody treatments be developed, “I think it’s important to remember we still have Paxlovid while everyone is lamenting the loss of bebtelovimab.’’
 

Antivirals: What’s here, what’s coming

Compared with monoclonal antibodies, “Paxlovid remains a much easier drug to give,” Dr. Adalja told this news organization, because it is taken orally, not intravenously.

And it’s effective. In a recent study, researchers found that adults diagnosed with COVID given Paxlovid within 5 days of diagnosis had a 51% lower hospitalization rate within the next 30 days than those not given it. Another study shows it could also reduce a person’s risk of developing long COVID by 26%.

Paxlovid is underused, Dr. Adalja said, partly because the rebound potential got more press than the effectiveness. When a celebrity got rebound from Paxlovid, he said, that would make the news, overshadowing the research on its effectiveness.

Besides Paxlovid, the antivirals remdesivir (Veklury), given intravenously for 3 days, and molnupiravir (Lagevrio), taken orally, are also still available. Antivirals work by targeting specific parts of the virus to prevent it from multiplying.

In the lab, remdesivir, molnupiravir, and another antiviral, nirmatrelvir, all appear to be effective against both BQ.1.1 (a BA.5 subvariant) and XBB (a BA.2 subvariant), both rapidly rising in the United States, according to a report last week in the New England Journal of Medicine.

The researchers also tested several monoclonal antibodies and found they did not neutralize either of the subvariants BQ.1.1 and XBB.

A new oral antiviral, Xocova (ensitrelvir fumaric acid), from Japanese manufacturer Shionogi, received emergency approval in Japan on November 22. It’s taken once a day for 5 days. The goal is to expand access to it globally, according to the company.

Pardes Biosciences launched a phase 2 trial in September for its oral antiviral drug (PBI-0451), under study as a treatment and preventive for COVID. It expects data by the first quarter of 2023.

Pfizer, which makes Paxlovid, has partnered with Clear Creek Bio to develop another oral antiviral COVID drug.
 

Other approaches

A receptor protein known as ACE2 (angiotensin-converting enzyme 2) is the main “doorway” that SARS-CoV-2 uses to enter and infect cells.

Dana-Farber Cancer Institute scientists are developing a “decoy” drug that works by mimicking the ACE2 receptor on the surface of cells; when the virus tries to bind to it, the spike protein is destroyed. Human trials have not yet started.

Other researchers are investigating whether an already-approved drug used to treat a liver disease, Actigall (UDCA/ursodeoxycholic acid), could protect against COVID infection by reducing ACE2.

So far, the researchers have found in early research that people taking UDCA for liver conditions were less likely than those not taking the drug to have severe COVID. They also found that UDCA reduced SARS-CoV-2 infection in human lungs maintained outside the body.
 

Monoclonal antibody treatments?

After the FDA decision to withdraw the bebtelovimab EUA, which Eli Lilly said it agreed with, the company issued a statement, promising it wasn’t giving up on monoclonal antibody treatments.

“Lilly will continue to search and evaluate monoclonal antibodies to identify potential candidates for clinical development against new variants,” it read in part.

AstraZeneca, which makes Evusheld, is also continuing to work on monoclonal antibody development. According to a spokesperson, “We are also developing a new long-acting antibody combination – AZD5156 – which has been shown in the lab to neutralize emerging new variants and all known variants to date. We are working to accelerate the development of AZD5156 to make it available at the end of 2023.”

The AstraZeneca spokesperson said he could share no more information about what the combination would include.
 

A convalescent plasma comeback?

Although Paxlovid can help, there are many contraindications to it, such as drug-drug interactions, Dr. Casadevall told this news organization. And now that the monoclonal antibody treatments have been paused, convalescent plasma “is the only antibody-based therapy that is reliably available. Convalescent plasma includes thousands of different antibodies.”

With his colleagues, Dr. Casadevall evaluated plasma samples from 740 patients. Some had received booster vaccines and been infected with Omicron, others had received boosters and not been infected, and still others had not been vaccinated and became infected.

In a report (not yet peer-reviewed), they found the plasma from those who had been infected or boosted within the past 6 months neutralized the new Omicron variants BQ.1.1, XBB.1, and BF.7.
 

A push for boosters, masks

To get through the coming months, taking precautions like masking and distancing and staying up to date on booster vaccinations, especially for older adults, can make a difference, other experts say.

In a Twitter thread in early December, Peter Hotez, MD, PhD, professor of pediatrics and molecular virology and microbiology at Baylor College of Medicine, Houston, urged people to take COVID seriously as holiday parties and gatherings occur.

“The single most impactful thing you can do is get your bivalent booster,” he tweeted, as well as give your kids the booster, citing preliminary research that the bivalent mRNA booster broadens immunity against the Omicron subvariants.

For seniors, he said, ‘‘if you get breakthrough COVID, [it’s] really important to get Paxlovid.” Masks will help not only for COVID but also influenza, respiratory syncytial virus (RSV), and other conditions.

Mitigation measures have largely been abandoned, according to Eric Topol, MD, director of the Scripps Research Translational Institute, La Jolla, Calif., and editor-in-chief of Medscape. In an op-ed in the Los Angeles Times, and on his Twitter feed, he reminds people about masking and urges people to get the bivalent booster.

According to the Centers for Disease Control and Prevention, as of Dec. 8, only 13.5% of people aged 5 and older have gotten an updated booster, despite research that shows an increase in antibodies to BQ.1.1. Recent research has found that the bivalent booster increases antibodies to BQ.1.1 by up to 10-fold, Dr. Topol said.

Dr. Adalja is on advisory boards for Shionogi, GSK, and Pardes. Dr. Casadevall reports no relevant financial relationships.

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

It was the last monoclonal antibody treatment standing. But less than 10 months after the U.S. Food and Drug Administration gave bebtelovimab its emergency use authorization (EUA) to fight COVID-19, it earlier this month de-authorized it, just as it had for other monoclonal antibody treatments, and for the same reason: The treatments were outwitted by the viral mutations.
 

Bebtelovimab couldn’t neutralize the Omicron subvariants BQ.1 and BQ.1.1, the cause of nearly 60% of COVID cases nationally as of November 30.

Next on the chopping block, some predict, will be Evusheld, the combination of tixagevimab and cilgavimab given as a preventive monoclonal antibody to people who are immunocompromised and at high risk of contracting COVID and to those who can’t take the vaccine. In October, the FDA warned that Evusheld was not neutralizing circulating COVID variants.

As the options for treating and preventing COVID decline, will companies rally quickly to develop new ones, or cut their losses in developing treatments that may work for only a few months, given the speed of viral mutations?

But although monoclonal antibody treatments are off the table, at least for now, antiviral drugs – including Paxlovid – are still very much available, and some say underused.

Others suggest it’s time to resurrect interest in convalescent plasma, a treatment used early in the pandemic before drugs or vaccines were here and still authorized for use in those who are immunosuppressed or receiving immunosuppressive treatment.

And on the prevention front, staying up to date with booster vaccines, masking, and taking other precautions should be stressed more, others say, regardless of the number of treatment options, and especially now, as cases rise and people gather for the winter holidays.
 

‘A major setback’

The bebtelovimab de-authorization was “a major setback,” but an understandable one, said Arturo Casadevall, MD, PhD, professor and chair of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health in Baltimore. “Monoclonal antibodies are great drugs. We are in an unfortunate situation in that they are vulnerable to changes in the virus” and can’t offer long-lasting protection.

Supplies of bebtelovimab will be retained, according to the FDA, in case variants susceptible to it return.

“What happened to bebtelovimab is no surprise,” agreed Amesh Adalja, MD, senior scholar at Johns Hopkins Center for Health Security. “This is what is going to happen when you are targeting a virus that mutates a lot.”

Monoclonal antibodies work by binding to the spike protein on the virus surface to prevent it from entering cells.

However, Dr. Adalja doesn’t view the disappearance of monoclonal antibody treatments as a major setback. Monoclonal antibodies were not the primary way COVID was treated, he said.

While he does believe it’s important that more monoclonal antibody treatments be developed, “I think it’s important to remember we still have Paxlovid while everyone is lamenting the loss of bebtelovimab.’’
 

Antivirals: What’s here, what’s coming

Compared with monoclonal antibodies, “Paxlovid remains a much easier drug to give,” Dr. Adalja told this news organization, because it is taken orally, not intravenously.

And it’s effective. In a recent study, researchers found that adults diagnosed with COVID given Paxlovid within 5 days of diagnosis had a 51% lower hospitalization rate within the next 30 days than those not given it. Another study shows it could also reduce a person’s risk of developing long COVID by 26%.

Paxlovid is underused, Dr. Adalja said, partly because the rebound potential got more press than the effectiveness. When a celebrity got rebound from Paxlovid, he said, that would make the news, overshadowing the research on its effectiveness.

Besides Paxlovid, the antivirals remdesivir (Veklury), given intravenously for 3 days, and molnupiravir (Lagevrio), taken orally, are also still available. Antivirals work by targeting specific parts of the virus to prevent it from multiplying.

In the lab, remdesivir, molnupiravir, and another antiviral, nirmatrelvir, all appear to be effective against both BQ.1.1 (a BA.5 subvariant) and XBB (a BA.2 subvariant), both rapidly rising in the United States, according to a report last week in the New England Journal of Medicine.

The researchers also tested several monoclonal antibodies and found they did not neutralize either of the subvariants BQ.1.1 and XBB.

A new oral antiviral, Xocova (ensitrelvir fumaric acid), from Japanese manufacturer Shionogi, received emergency approval in Japan on November 22. It’s taken once a day for 5 days. The goal is to expand access to it globally, according to the company.

Pardes Biosciences launched a phase 2 trial in September for its oral antiviral drug (PBI-0451), under study as a treatment and preventive for COVID. It expects data by the first quarter of 2023.

Pfizer, which makes Paxlovid, has partnered with Clear Creek Bio to develop another oral antiviral COVID drug.
 

Other approaches

A receptor protein known as ACE2 (angiotensin-converting enzyme 2) is the main “doorway” that SARS-CoV-2 uses to enter and infect cells.

Dana-Farber Cancer Institute scientists are developing a “decoy” drug that works by mimicking the ACE2 receptor on the surface of cells; when the virus tries to bind to it, the spike protein is destroyed. Human trials have not yet started.

Other researchers are investigating whether an already-approved drug used to treat a liver disease, Actigall (UDCA/ursodeoxycholic acid), could protect against COVID infection by reducing ACE2.

So far, the researchers have found in early research that people taking UDCA for liver conditions were less likely than those not taking the drug to have severe COVID. They also found that UDCA reduced SARS-CoV-2 infection in human lungs maintained outside the body.
 

Monoclonal antibody treatments?

After the FDA decision to withdraw the bebtelovimab EUA, which Eli Lilly said it agreed with, the company issued a statement, promising it wasn’t giving up on monoclonal antibody treatments.

“Lilly will continue to search and evaluate monoclonal antibodies to identify potential candidates for clinical development against new variants,” it read in part.

AstraZeneca, which makes Evusheld, is also continuing to work on monoclonal antibody development. According to a spokesperson, “We are also developing a new long-acting antibody combination – AZD5156 – which has been shown in the lab to neutralize emerging new variants and all known variants to date. We are working to accelerate the development of AZD5156 to make it available at the end of 2023.”

The AstraZeneca spokesperson said he could share no more information about what the combination would include.
 

A convalescent plasma comeback?

Although Paxlovid can help, there are many contraindications to it, such as drug-drug interactions, Dr. Casadevall told this news organization. And now that the monoclonal antibody treatments have been paused, convalescent plasma “is the only antibody-based therapy that is reliably available. Convalescent plasma includes thousands of different antibodies.”

With his colleagues, Dr. Casadevall evaluated plasma samples from 740 patients. Some had received booster vaccines and been infected with Omicron, others had received boosters and not been infected, and still others had not been vaccinated and became infected.

In a report (not yet peer-reviewed), they found the plasma from those who had been infected or boosted within the past 6 months neutralized the new Omicron variants BQ.1.1, XBB.1, and BF.7.
 

A push for boosters, masks

To get through the coming months, taking precautions like masking and distancing and staying up to date on booster vaccinations, especially for older adults, can make a difference, other experts say.

In a Twitter thread in early December, Peter Hotez, MD, PhD, professor of pediatrics and molecular virology and microbiology at Baylor College of Medicine, Houston, urged people to take COVID seriously as holiday parties and gatherings occur.

“The single most impactful thing you can do is get your bivalent booster,” he tweeted, as well as give your kids the booster, citing preliminary research that the bivalent mRNA booster broadens immunity against the Omicron subvariants.

For seniors, he said, ‘‘if you get breakthrough COVID, [it’s] really important to get Paxlovid.” Masks will help not only for COVID but also influenza, respiratory syncytial virus (RSV), and other conditions.

Mitigation measures have largely been abandoned, according to Eric Topol, MD, director of the Scripps Research Translational Institute, La Jolla, Calif., and editor-in-chief of Medscape. In an op-ed in the Los Angeles Times, and on his Twitter feed, he reminds people about masking and urges people to get the bivalent booster.

According to the Centers for Disease Control and Prevention, as of Dec. 8, only 13.5% of people aged 5 and older have gotten an updated booster, despite research that shows an increase in antibodies to BQ.1.1. Recent research has found that the bivalent booster increases antibodies to BQ.1.1 by up to 10-fold, Dr. Topol said.

Dr. Adalja is on advisory boards for Shionogi, GSK, and Pardes. Dr. Casadevall reports no relevant financial relationships.

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

It was the last monoclonal antibody treatment standing. But less than 10 months after the U.S. Food and Drug Administration gave bebtelovimab its emergency use authorization (EUA) to fight COVID-19, it earlier this month de-authorized it, just as it had for other monoclonal antibody treatments, and for the same reason: The treatments were outwitted by the viral mutations.
 

Bebtelovimab couldn’t neutralize the Omicron subvariants BQ.1 and BQ.1.1, the cause of nearly 60% of COVID cases nationally as of November 30.

Next on the chopping block, some predict, will be Evusheld, the combination of tixagevimab and cilgavimab given as a preventive monoclonal antibody to people who are immunocompromised and at high risk of contracting COVID and to those who can’t take the vaccine. In October, the FDA warned that Evusheld was not neutralizing circulating COVID variants.

As the options for treating and preventing COVID decline, will companies rally quickly to develop new ones, or cut their losses in developing treatments that may work for only a few months, given the speed of viral mutations?

But although monoclonal antibody treatments are off the table, at least for now, antiviral drugs – including Paxlovid – are still very much available, and some say underused.

Others suggest it’s time to resurrect interest in convalescent plasma, a treatment used early in the pandemic before drugs or vaccines were here and still authorized for use in those who are immunosuppressed or receiving immunosuppressive treatment.

And on the prevention front, staying up to date with booster vaccines, masking, and taking other precautions should be stressed more, others say, regardless of the number of treatment options, and especially now, as cases rise and people gather for the winter holidays.
 

‘A major setback’

The bebtelovimab de-authorization was “a major setback,” but an understandable one, said Arturo Casadevall, MD, PhD, professor and chair of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health in Baltimore. “Monoclonal antibodies are great drugs. We are in an unfortunate situation in that they are vulnerable to changes in the virus” and can’t offer long-lasting protection.

Supplies of bebtelovimab will be retained, according to the FDA, in case variants susceptible to it return.

“What happened to bebtelovimab is no surprise,” agreed Amesh Adalja, MD, senior scholar at Johns Hopkins Center for Health Security. “This is what is going to happen when you are targeting a virus that mutates a lot.”

Monoclonal antibodies work by binding to the spike protein on the virus surface to prevent it from entering cells.

However, Dr. Adalja doesn’t view the disappearance of monoclonal antibody treatments as a major setback. Monoclonal antibodies were not the primary way COVID was treated, he said.

While he does believe it’s important that more monoclonal antibody treatments be developed, “I think it’s important to remember we still have Paxlovid while everyone is lamenting the loss of bebtelovimab.’’
 

Antivirals: What’s here, what’s coming

Compared with monoclonal antibodies, “Paxlovid remains a much easier drug to give,” Dr. Adalja told this news organization, because it is taken orally, not intravenously.

And it’s effective. In a recent study, researchers found that adults diagnosed with COVID given Paxlovid within 5 days of diagnosis had a 51% lower hospitalization rate within the next 30 days than those not given it. Another study shows it could also reduce a person’s risk of developing long COVID by 26%.

Paxlovid is underused, Dr. Adalja said, partly because the rebound potential got more press than the effectiveness. When a celebrity got rebound from Paxlovid, he said, that would make the news, overshadowing the research on its effectiveness.

Besides Paxlovid, the antivirals remdesivir (Veklury), given intravenously for 3 days, and molnupiravir (Lagevrio), taken orally, are also still available. Antivirals work by targeting specific parts of the virus to prevent it from multiplying.

In the lab, remdesivir, molnupiravir, and another antiviral, nirmatrelvir, all appear to be effective against both BQ.1.1 (a BA.5 subvariant) and XBB (a BA.2 subvariant), both rapidly rising in the United States, according to a report last week in the New England Journal of Medicine.

The researchers also tested several monoclonal antibodies and found they did not neutralize either of the subvariants BQ.1.1 and XBB.

A new oral antiviral, Xocova (ensitrelvir fumaric acid), from Japanese manufacturer Shionogi, received emergency approval in Japan on November 22. It’s taken once a day for 5 days. The goal is to expand access to it globally, according to the company.

Pardes Biosciences launched a phase 2 trial in September for its oral antiviral drug (PBI-0451), under study as a treatment and preventive for COVID. It expects data by the first quarter of 2023.

Pfizer, which makes Paxlovid, has partnered with Clear Creek Bio to develop another oral antiviral COVID drug.
 

Other approaches

A receptor protein known as ACE2 (angiotensin-converting enzyme 2) is the main “doorway” that SARS-CoV-2 uses to enter and infect cells.

Dana-Farber Cancer Institute scientists are developing a “decoy” drug that works by mimicking the ACE2 receptor on the surface of cells; when the virus tries to bind to it, the spike protein is destroyed. Human trials have not yet started.

Other researchers are investigating whether an already-approved drug used to treat a liver disease, Actigall (UDCA/ursodeoxycholic acid), could protect against COVID infection by reducing ACE2.

So far, the researchers have found in early research that people taking UDCA for liver conditions were less likely than those not taking the drug to have severe COVID. They also found that UDCA reduced SARS-CoV-2 infection in human lungs maintained outside the body.
 

Monoclonal antibody treatments?

After the FDA decision to withdraw the bebtelovimab EUA, which Eli Lilly said it agreed with, the company issued a statement, promising it wasn’t giving up on monoclonal antibody treatments.

“Lilly will continue to search and evaluate monoclonal antibodies to identify potential candidates for clinical development against new variants,” it read in part.

AstraZeneca, which makes Evusheld, is also continuing to work on monoclonal antibody development. According to a spokesperson, “We are also developing a new long-acting antibody combination – AZD5156 – which has been shown in the lab to neutralize emerging new variants and all known variants to date. We are working to accelerate the development of AZD5156 to make it available at the end of 2023.”

The AstraZeneca spokesperson said he could share no more information about what the combination would include.
 

A convalescent plasma comeback?

Although Paxlovid can help, there are many contraindications to it, such as drug-drug interactions, Dr. Casadevall told this news organization. And now that the monoclonal antibody treatments have been paused, convalescent plasma “is the only antibody-based therapy that is reliably available. Convalescent plasma includes thousands of different antibodies.”

With his colleagues, Dr. Casadevall evaluated plasma samples from 740 patients. Some had received booster vaccines and been infected with Omicron, others had received boosters and not been infected, and still others had not been vaccinated and became infected.

In a report (not yet peer-reviewed), they found the plasma from those who had been infected or boosted within the past 6 months neutralized the new Omicron variants BQ.1.1, XBB.1, and BF.7.
 

A push for boosters, masks

To get through the coming months, taking precautions like masking and distancing and staying up to date on booster vaccinations, especially for older adults, can make a difference, other experts say.

In a Twitter thread in early December, Peter Hotez, MD, PhD, professor of pediatrics and molecular virology and microbiology at Baylor College of Medicine, Houston, urged people to take COVID seriously as holiday parties and gatherings occur.

“The single most impactful thing you can do is get your bivalent booster,” he tweeted, as well as give your kids the booster, citing preliminary research that the bivalent mRNA booster broadens immunity against the Omicron subvariants.

For seniors, he said, ‘‘if you get breakthrough COVID, [it’s] really important to get Paxlovid.” Masks will help not only for COVID but also influenza, respiratory syncytial virus (RSV), and other conditions.

Mitigation measures have largely been abandoned, according to Eric Topol, MD, director of the Scripps Research Translational Institute, La Jolla, Calif., and editor-in-chief of Medscape. In an op-ed in the Los Angeles Times, and on his Twitter feed, he reminds people about masking and urges people to get the bivalent booster.

According to the Centers for Disease Control and Prevention, as of Dec. 8, only 13.5% of people aged 5 and older have gotten an updated booster, despite research that shows an increase in antibodies to BQ.1.1. Recent research has found that the bivalent booster increases antibodies to BQ.1.1 by up to 10-fold, Dr. Topol said.

Dr. Adalja is on advisory boards for Shionogi, GSK, and Pardes. Dr. Casadevall reports no relevant financial relationships.

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

Treating adults who have chronic hepatitis C (CHC) with direct-acting antivirals (DAAs) was linked with a lower risk of death and poor liver outcomes, in a new study.

Eiichi Ogawa, MD, PhD, with the department of general internal medicine, Kyushu University Hospital in Fukuoka, Japan, led the retrospective study of 245,596 adults with CHC. In the new research, which was published in JAMA Internal Medicine, the authors analyzed data from the Optum Clinformatics Data Mart (CDM) database, 2010-2021.

It was important to do the study because of limited and conflicting information – mostly from case reports – on safety of the DAAs when they were approved for CHC in 2014, said coauthor Mindie H. Nguyen, MD, in an interview.
 

‘DAA treatment is safe’

“The main message is that DAA treatment is safe,” said Dr. Nguyen, of the division of gastroenterology and hepatology at Stanford (Calif.) University Medical Center in Palo Alto. In the early days of treatment, physicians were treating the sickest patients with the DAAs, which may have introduced patient selection bias and caused lasting misperceptions about poor safety, she noted.

“I really hope to dispel this myth,” she said, adding that this study also shows improved liver and nonliver outcomes.

Of the total cohort in this study, 40,654 patients had one or more prescriptions for a DAA (without interferon) and 204,942 patients had not been treated.
 

All-cause mortality reduced by 57%

DAA treatment, vs. no treatment, was linked with a large and significant reduction (57%) in all-cause mortality. That finding was particularly notable, because it was seen regardless of age, sex, race and ethnicity, comorbidities, alcohol use, and presence of hepatocellular carcinoma or cirrhosis.

The authors noted that patients without cirrhosis are a population previously considered to receive less benefit from an HCV cure than patients with cirrhosis.

DAAs were associated with lower risk of hepatocellular carcinoma and decompensation as well as risk of nonliver outcomes, including diabetes, cardiovascular disease (CVD), and chronic kidney disease (CKD).
 

Lower risk of poor nonliver outcomes

The researchers found that when they compared DAA-treated patients with untreated patients, the incidences per 1,000 person-years of having diabetes were 30.2 vs. 37.2 (P less than .001), and of having kidney disease was 31.1 vs. 34.1 (P less than .001), respectively.

“This retrospective cohort study provides valuable information to physicians,” Noel Deep, MD, chief medical officer at Aspirus Langlade Hospital in Antigo, Wis., said, in an interview.

The study’s size helps confirm DAAs’ safety and benefit, and previously unknown added benefits, in treating CHC, he continued.
 

Large study confirms, introduces DAA benefits

Dr. Deep, who was not part of the study, noted that DAAs now show much promise in efficacy and tolerability in most people with chronic hepatitis C, including those with concomitant conditions such as CKD.

“Previous studies did not have such large-scale nationwide data. [The findings of the new study] greatly enhance our knowledge of DAA treatment for chronic hepatitis C patients across the spectrum from noncirrhotic to compensated cirrhotic to decompensated cirrhotic,” Dr. Deep said. “The added benefit of improved outcomes for diabetes, CVD, CKD, and nonliver cancers truly surprised me.”

Dr. Deep pointed out some limitations of the study, including that, as the authors acknowledge, only privately insured patients were included so results may not be generalizable to the underinsured/uninsured “who might have other risk factors, poorer health, and fewer resources.”

He added: “The data also may not be reflective of the outcomes in Asians who were, in my opinion, also underrepresented in this study.”

The authors cited the insurance claims database they used as a strength of the study, due to it containing information on 61 million people from across all regions of the United States.

Dr. Ogawa reports grants from Gilead Sciences outside the submitted work. Coauthor Dr. Nguyen reports institutional grants and advisory board fees from Gilead Sciences outside the submitted work. Another coauthor reports speaking/consulting fees from Gilead and Merck Sharp & Dohme outside the submitted work. No other disclosures were reported.

The Stanford Center for Population Health Sciences (PHS) supported this study by providing access to the PHS Data Core.

Dr. Deep reports no relevant financial relationships. He serves on the editorial advisory board of Internal Medicine News.
 

Treating adults who have chronic hepatitis C (CHC) with direct-acting antivirals (DAAs) was linked with a lower risk of death and poor liver outcomes, in a new study.

Eiichi Ogawa, MD, PhD, with the department of general internal medicine, Kyushu University Hospital in Fukuoka, Japan, led the retrospective study of 245,596 adults with CHC. In the new research, which was published in JAMA Internal Medicine, the authors analyzed data from the Optum Clinformatics Data Mart (CDM) database, 2010-2021.

It was important to do the study because of limited and conflicting information – mostly from case reports – on safety of the DAAs when they were approved for CHC in 2014, said coauthor Mindie H. Nguyen, MD, in an interview.
 

‘DAA treatment is safe’

“The main message is that DAA treatment is safe,” said Dr. Nguyen, of the division of gastroenterology and hepatology at Stanford (Calif.) University Medical Center in Palo Alto. In the early days of treatment, physicians were treating the sickest patients with the DAAs, which may have introduced patient selection bias and caused lasting misperceptions about poor safety, she noted.

“I really hope to dispel this myth,” she said, adding that this study also shows improved liver and nonliver outcomes.

Of the total cohort in this study, 40,654 patients had one or more prescriptions for a DAA (without interferon) and 204,942 patients had not been treated.
 

All-cause mortality reduced by 57%

DAA treatment, vs. no treatment, was linked with a large and significant reduction (57%) in all-cause mortality. That finding was particularly notable, because it was seen regardless of age, sex, race and ethnicity, comorbidities, alcohol use, and presence of hepatocellular carcinoma or cirrhosis.

The authors noted that patients without cirrhosis are a population previously considered to receive less benefit from an HCV cure than patients with cirrhosis.

DAAs were associated with lower risk of hepatocellular carcinoma and decompensation as well as risk of nonliver outcomes, including diabetes, cardiovascular disease (CVD), and chronic kidney disease (CKD).
 

Lower risk of poor nonliver outcomes

The researchers found that when they compared DAA-treated patients with untreated patients, the incidences per 1,000 person-years of having diabetes were 30.2 vs. 37.2 (P less than .001), and of having kidney disease was 31.1 vs. 34.1 (P less than .001), respectively.

“This retrospective cohort study provides valuable information to physicians,” Noel Deep, MD, chief medical officer at Aspirus Langlade Hospital in Antigo, Wis., said, in an interview.

The study’s size helps confirm DAAs’ safety and benefit, and previously unknown added benefits, in treating CHC, he continued.
 

Large study confirms, introduces DAA benefits

Dr. Deep, who was not part of the study, noted that DAAs now show much promise in efficacy and tolerability in most people with chronic hepatitis C, including those with concomitant conditions such as CKD.

“Previous studies did not have such large-scale nationwide data. [The findings of the new study] greatly enhance our knowledge of DAA treatment for chronic hepatitis C patients across the spectrum from noncirrhotic to compensated cirrhotic to decompensated cirrhotic,” Dr. Deep said. “The added benefit of improved outcomes for diabetes, CVD, CKD, and nonliver cancers truly surprised me.”

Dr. Deep pointed out some limitations of the study, including that, as the authors acknowledge, only privately insured patients were included so results may not be generalizable to the underinsured/uninsured “who might have other risk factors, poorer health, and fewer resources.”

He added: “The data also may not be reflective of the outcomes in Asians who were, in my opinion, also underrepresented in this study.”

The authors cited the insurance claims database they used as a strength of the study, due to it containing information on 61 million people from across all regions of the United States.

Dr. Ogawa reports grants from Gilead Sciences outside the submitted work. Coauthor Dr. Nguyen reports institutional grants and advisory board fees from Gilead Sciences outside the submitted work. Another coauthor reports speaking/consulting fees from Gilead and Merck Sharp & Dohme outside the submitted work. No other disclosures were reported.

The Stanford Center for Population Health Sciences (PHS) supported this study by providing access to the PHS Data Core.

Dr. Deep reports no relevant financial relationships. He serves on the editorial advisory board of Internal Medicine News.
 

Treating adults who have chronic hepatitis C (CHC) with direct-acting antivirals (DAAs) was linked with a lower risk of death and poor liver outcomes, in a new study.

Eiichi Ogawa, MD, PhD, with the department of general internal medicine, Kyushu University Hospital in Fukuoka, Japan, led the retrospective study of 245,596 adults with CHC. In the new research, which was published in JAMA Internal Medicine, the authors analyzed data from the Optum Clinformatics Data Mart (CDM) database, 2010-2021.

It was important to do the study because of limited and conflicting information – mostly from case reports – on safety of the DAAs when they were approved for CHC in 2014, said coauthor Mindie H. Nguyen, MD, in an interview.
 

‘DAA treatment is safe’

“The main message is that DAA treatment is safe,” said Dr. Nguyen, of the division of gastroenterology and hepatology at Stanford (Calif.) University Medical Center in Palo Alto. In the early days of treatment, physicians were treating the sickest patients with the DAAs, which may have introduced patient selection bias and caused lasting misperceptions about poor safety, she noted.

“I really hope to dispel this myth,” she said, adding that this study also shows improved liver and nonliver outcomes.

Of the total cohort in this study, 40,654 patients had one or more prescriptions for a DAA (without interferon) and 204,942 patients had not been treated.
 

All-cause mortality reduced by 57%

DAA treatment, vs. no treatment, was linked with a large and significant reduction (57%) in all-cause mortality. That finding was particularly notable, because it was seen regardless of age, sex, race and ethnicity, comorbidities, alcohol use, and presence of hepatocellular carcinoma or cirrhosis.

The authors noted that patients without cirrhosis are a population previously considered to receive less benefit from an HCV cure than patients with cirrhosis.

DAAs were associated with lower risk of hepatocellular carcinoma and decompensation as well as risk of nonliver outcomes, including diabetes, cardiovascular disease (CVD), and chronic kidney disease (CKD).
 

Lower risk of poor nonliver outcomes

The researchers found that when they compared DAA-treated patients with untreated patients, the incidences per 1,000 person-years of having diabetes were 30.2 vs. 37.2 (P less than .001), and of having kidney disease was 31.1 vs. 34.1 (P less than .001), respectively.

“This retrospective cohort study provides valuable information to physicians,” Noel Deep, MD, chief medical officer at Aspirus Langlade Hospital in Antigo, Wis., said, in an interview.

The study’s size helps confirm DAAs’ safety and benefit, and previously unknown added benefits, in treating CHC, he continued.
 

Large study confirms, introduces DAA benefits

Dr. Deep, who was not part of the study, noted that DAAs now show much promise in efficacy and tolerability in most people with chronic hepatitis C, including those with concomitant conditions such as CKD.

“Previous studies did not have such large-scale nationwide data. [The findings of the new study] greatly enhance our knowledge of DAA treatment for chronic hepatitis C patients across the spectrum from noncirrhotic to compensated cirrhotic to decompensated cirrhotic,” Dr. Deep said. “The added benefit of improved outcomes for diabetes, CVD, CKD, and nonliver cancers truly surprised me.”

Dr. Deep pointed out some limitations of the study, including that, as the authors acknowledge, only privately insured patients were included so results may not be generalizable to the underinsured/uninsured “who might have other risk factors, poorer health, and fewer resources.”

He added: “The data also may not be reflective of the outcomes in Asians who were, in my opinion, also underrepresented in this study.”

The authors cited the insurance claims database they used as a strength of the study, due to it containing information on 61 million people from across all regions of the United States.

Dr. Ogawa reports grants from Gilead Sciences outside the submitted work. Coauthor Dr. Nguyen reports institutional grants and advisory board fees from Gilead Sciences outside the submitted work. Another coauthor reports speaking/consulting fees from Gilead and Merck Sharp & Dohme outside the submitted work. No other disclosures were reported.

The Stanford Center for Population Health Sciences (PHS) supported this study by providing access to the PHS Data Core.

Dr. Deep reports no relevant financial relationships. He serves on the editorial advisory board of Internal Medicine News.
 

WASHINGTON – “We don’t get to use the ‘eliminate’ word all that often with a disease that’s taking thousands or tens of thousands – or worldwide, hundreds of thousands – of lives every year, but we have that opportunity with hepatitis C.”

So said Francis S. Collins, MD, PhD, special projects advisor to the Executive Office of the President of the United States, and former director of the National Institutes of Health, speaking at a special session outlining ambitious goals for a national plan to eliminate hepatitis C virus (HCV) infections by the year 2050.

The session was held at the annual meeting of the American Association for the Study of Liver Diseases.
 

A public health crisis

Dr. Collins labeled HCV a public health crisis, citing statistics from the Centers for Disease Control and Prevention that show that the rate of reported acute HCV infection cases increased 400% between 2010 and 2020, with the highest rates among young adults aged 20-39 years.

In addition, an estimated 2.4 million people in the United States are living with chronic HCV infections, but as many as 40% of these people are unaware of their infection, despite broad recommendations for the screening of all adults aged 18 years and older, he said.

“Our goal is to try to do something to change this,” Dr. Collins said. He noted that for the past 8 years we have had highly effective oral agents that don’t just treat the disease but cure it – 95%-97% of the time, with only 8-12 weeks of oral therapy and relatively few side effects.

“A wonderful story, one of the most exciting stories that’s come out of biomedical research in the last couple of decades,” he said.

Yet Dr. Collins also acknowledged that the task of developing a national plan is daunting, despite that pharmaceutical triumph.

National pharmacy claims data show that the number of persons treated for HCV with direct-acting antiviral agents (DAAs) in the United States declined from a high of 164,247 in 2015 to 83,740 in 2020.

Furthermore, CDC data from 2019 and 2020 show that, of persons with a diagnosis of HCV infection, only 23% of those on Medicaid, 28% of those on Medicare, and 35% of those with private insurance were treated for their infections.

“We have a huge gap here between the ability to know you have the disease and to get treatment, and we don’t see the numbers here for the uninsured, or people in prisons, but they’re probably much worse,” he said.
 

Obstacles abound, as do ways to overcome them

Current barriers to treatment include the aforementioned lack of awareness of infection, a “clunky” two-step diagnosis requiring an antibody test followed by an RNA or core antigen test necessitating three visits often separated by several weeks, and the high cost of treatment (around $90,000 per patient).

In addition, insurers commonly require proof that patients remain sober for extended periods, insist that treatment monitoring be performed by specialists only, and often approve treatment only for those patients who have documented evidence of liver damage.

“Does that make sense to you?” Dr. Collins asked. “You’ve got a cure for a liver disease, and you have to wait and show that the liver’s been damaged before you receive it? That just doesn’t fit,” he said.

Dr. Collins also pointed out that we’re dealing with hard-to-reach populations (underserved, uninsured, justice-involved), and people who are in tough times. “Anything that you put in the way as a barrier is going to make this worse in terms of its ability to be implemented,” he said.

To demonstrate how a coordinated HCV-elimination program could work, Dr. Collins pointed to a Medicaid cohort study in Louisiana conducted from July 2019 through December 2021, in which 8,867 patients started on therapy, 7,763 (88%) completed therapy, and 5,882 (66%) returned for testing. Of those tested, 5,285 (90%) had sustained virologic responses.

Another model of a hepatitis C elimination program was provided by the Veterans Health Administration. They received funding for an effort for all veterans, and in the space of 7 years were able to reach out even to some of their difficult-to-reach populations and achieve high diagnosis and treatment rates in a way that could be a model for what we would want to do across the nation, Dr. Collins noted.
 

Doing the math

Also at the session, Jagpreet Chhatwal, PhD, director of the Massachusetts General Hospital Institute for Technology Assessment and associate professor of radiology at Harvard Medical School, Boston, described outcomes projected by a mathematical simulation model of the HCV epidemic that he and his colleagues developed.

The HEP-SIM (Hepatitis C Disease Burden Simulation) model evaluates HCV prevalence trends, the number needed to screen and treat to eliminate HCV, HCV-associated clinical outcomes, the cost of an elimination program, and the cost savings that could be realized from preventing long-term complications.

The model seeks to determine whether the upfront costs of a national HCV elimination program could be offset by savings down the road. Specifically, it assumes that within the next 5 years 1.31 million individuals would be diagnosed with HCV and projects that within that time frame 1.52 million would need to be treated to meet HCV elimination goals.

The model shows that, compared with the status quo, a concerted campaign of screening and treatment would prevent more than 10,000 HCV-related deaths by 2030, and 91,000 deaths by 2050.

A coordinated screening program is also projected to prevent 17,000 cases of hepatocellular carcinoma by 2030 and 108,000 cases by 2050, as well as avert 29,000 cases of decompensated cirrhosis by 2030 and 93,000 such cases by 2050.

The cost savings associated with an HCV elimination plan would also be substantial, Dr. Chhatwal said.

According to the model, over the next decade the cumulative costs associated with HCV would decline by $14.2 billion, compared with the status quo. Nearly 80% of those savings ($11.2 billion) would be in Medicare and Medicaid.

The total projected savings from 2024 through 2050 – in disease management, testing, treatment, and pragmatic costs – are estimated at $59.3 billion, Dr. Chhatwal said.

“This is unprecedented,” he said. “We’re not just eliminating a disease as a public health threat but also saving money, which is not a common thing. That gives us a lot of impetus to implement such a program.”
 

Getting it done

Rachael L. Fleurence, PhD, MSc, a health economist currently serving as a senior advisor in the Executive Office of the President, summarized efforts to build a national HCV elimination program with input from federal health care agencies, state health leaders, patients, advocacy groups, drug manufacturers, and insurers.

She noted that a large component and focus of the program will be working on diagnostic test development but also accelerating bringing tests into the United States that are currently unavailable here. “These include point-of-care RNA diagnostic tests, as well as core antigen laboratory tests,” she said.

The program will be designed to offer broad access to curative anti-HCV drugs through a national subscription model that would make DAAs available to Medicaid recipients, justice-involved populations, the uninsured, and American Indians and Alaskan Natives who receive care through the Indian Health Service.

“On the Medicare and commercial insurance fronts, we’re still exploring different approaches, including potentially a co-pay assistance for Medicare beneficiaries, as well as working with commercial insurers to reduce barriers to access,” she said.

The program would also involve screening strategies extending to more settings, especially for high-risk populations, expanding the number of providers allowed to screen and treat HCV infections through telehealth, ensuring incentives for providers, and increasing the number of community health workers and case workers to improve linkage to care.

The next steps for the program would include funding to support the NIH’s RADx diagnostics program to accelerate access to testing, planning for the subscription model for DAA purchase, and launching pilot programs with the CDC, the Health Resources and Services Administration, the Substance Abuse and Mental Health Services Administration, and the Indian Health Service.
 

A call to action

Dr. Collins ended this portion of the program with an exhortation to AASLD members to do their part.

“We need your help,” Dr. Collins said. “This is a bold initiative, but it’s an opportunity. It’s even a responsibility. If we can actually succeed at this kind of outreach and save lives, and at the same time save money, how can we not do that?”

Dr. Collins, Dr. Chhatwal, and Dr. Fleurence each reported having no financial conflicts.

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

WASHINGTON – “We don’t get to use the ‘eliminate’ word all that often with a disease that’s taking thousands or tens of thousands – or worldwide, hundreds of thousands – of lives every year, but we have that opportunity with hepatitis C.”

So said Francis S. Collins, MD, PhD, special projects advisor to the Executive Office of the President of the United States, and former director of the National Institutes of Health, speaking at a special session outlining ambitious goals for a national plan to eliminate hepatitis C virus (HCV) infections by the year 2050.

The session was held at the annual meeting of the American Association for the Study of Liver Diseases.
 

A public health crisis

Dr. Collins labeled HCV a public health crisis, citing statistics from the Centers for Disease Control and Prevention that show that the rate of reported acute HCV infection cases increased 400% between 2010 and 2020, with the highest rates among young adults aged 20-39 years.

In addition, an estimated 2.4 million people in the United States are living with chronic HCV infections, but as many as 40% of these people are unaware of their infection, despite broad recommendations for the screening of all adults aged 18 years and older, he said.

“Our goal is to try to do something to change this,” Dr. Collins said. He noted that for the past 8 years we have had highly effective oral agents that don’t just treat the disease but cure it – 95%-97% of the time, with only 8-12 weeks of oral therapy and relatively few side effects.

“A wonderful story, one of the most exciting stories that’s come out of biomedical research in the last couple of decades,” he said.

Yet Dr. Collins also acknowledged that the task of developing a national plan is daunting, despite that pharmaceutical triumph.

National pharmacy claims data show that the number of persons treated for HCV with direct-acting antiviral agents (DAAs) in the United States declined from a high of 164,247 in 2015 to 83,740 in 2020.

Furthermore, CDC data from 2019 and 2020 show that, of persons with a diagnosis of HCV infection, only 23% of those on Medicaid, 28% of those on Medicare, and 35% of those with private insurance were treated for their infections.

“We have a huge gap here between the ability to know you have the disease and to get treatment, and we don’t see the numbers here for the uninsured, or people in prisons, but they’re probably much worse,” he said.
 

Obstacles abound, as do ways to overcome them

Current barriers to treatment include the aforementioned lack of awareness of infection, a “clunky” two-step diagnosis requiring an antibody test followed by an RNA or core antigen test necessitating three visits often separated by several weeks, and the high cost of treatment (around $90,000 per patient).

In addition, insurers commonly require proof that patients remain sober for extended periods, insist that treatment monitoring be performed by specialists only, and often approve treatment only for those patients who have documented evidence of liver damage.

“Does that make sense to you?” Dr. Collins asked. “You’ve got a cure for a liver disease, and you have to wait and show that the liver’s been damaged before you receive it? That just doesn’t fit,” he said.

Dr. Collins also pointed out that we’re dealing with hard-to-reach populations (underserved, uninsured, justice-involved), and people who are in tough times. “Anything that you put in the way as a barrier is going to make this worse in terms of its ability to be implemented,” he said.

To demonstrate how a coordinated HCV-elimination program could work, Dr. Collins pointed to a Medicaid cohort study in Louisiana conducted from July 2019 through December 2021, in which 8,867 patients started on therapy, 7,763 (88%) completed therapy, and 5,882 (66%) returned for testing. Of those tested, 5,285 (90%) had sustained virologic responses.

Another model of a hepatitis C elimination program was provided by the Veterans Health Administration. They received funding for an effort for all veterans, and in the space of 7 years were able to reach out even to some of their difficult-to-reach populations and achieve high diagnosis and treatment rates in a way that could be a model for what we would want to do across the nation, Dr. Collins noted.
 

Doing the math

Also at the session, Jagpreet Chhatwal, PhD, director of the Massachusetts General Hospital Institute for Technology Assessment and associate professor of radiology at Harvard Medical School, Boston, described outcomes projected by a mathematical simulation model of the HCV epidemic that he and his colleagues developed.

The HEP-SIM (Hepatitis C Disease Burden Simulation) model evaluates HCV prevalence trends, the number needed to screen and treat to eliminate HCV, HCV-associated clinical outcomes, the cost of an elimination program, and the cost savings that could be realized from preventing long-term complications.

The model seeks to determine whether the upfront costs of a national HCV elimination program could be offset by savings down the road. Specifically, it assumes that within the next 5 years 1.31 million individuals would be diagnosed with HCV and projects that within that time frame 1.52 million would need to be treated to meet HCV elimination goals.

The model shows that, compared with the status quo, a concerted campaign of screening and treatment would prevent more than 10,000 HCV-related deaths by 2030, and 91,000 deaths by 2050.

A coordinated screening program is also projected to prevent 17,000 cases of hepatocellular carcinoma by 2030 and 108,000 cases by 2050, as well as avert 29,000 cases of decompensated cirrhosis by 2030 and 93,000 such cases by 2050.

The cost savings associated with an HCV elimination plan would also be substantial, Dr. Chhatwal said.

According to the model, over the next decade the cumulative costs associated with HCV would decline by $14.2 billion, compared with the status quo. Nearly 80% of those savings ($11.2 billion) would be in Medicare and Medicaid.

The total projected savings from 2024 through 2050 – in disease management, testing, treatment, and pragmatic costs – are estimated at $59.3 billion, Dr. Chhatwal said.

“This is unprecedented,” he said. “We’re not just eliminating a disease as a public health threat but also saving money, which is not a common thing. That gives us a lot of impetus to implement such a program.”
 

Getting it done

Rachael L. Fleurence, PhD, MSc, a health economist currently serving as a senior advisor in the Executive Office of the President, summarized efforts to build a national HCV elimination program with input from federal health care agencies, state health leaders, patients, advocacy groups, drug manufacturers, and insurers.

She noted that a large component and focus of the program will be working on diagnostic test development but also accelerating bringing tests into the United States that are currently unavailable here. “These include point-of-care RNA diagnostic tests, as well as core antigen laboratory tests,” she said.

The program will be designed to offer broad access to curative anti-HCV drugs through a national subscription model that would make DAAs available to Medicaid recipients, justice-involved populations, the uninsured, and American Indians and Alaskan Natives who receive care through the Indian Health Service.

“On the Medicare and commercial insurance fronts, we’re still exploring different approaches, including potentially a co-pay assistance for Medicare beneficiaries, as well as working with commercial insurers to reduce barriers to access,” she said.

The program would also involve screening strategies extending to more settings, especially for high-risk populations, expanding the number of providers allowed to screen and treat HCV infections through telehealth, ensuring incentives for providers, and increasing the number of community health workers and case workers to improve linkage to care.

The next steps for the program would include funding to support the NIH’s RADx diagnostics program to accelerate access to testing, planning for the subscription model for DAA purchase, and launching pilot programs with the CDC, the Health Resources and Services Administration, the Substance Abuse and Mental Health Services Administration, and the Indian Health Service.
 

A call to action

Dr. Collins ended this portion of the program with an exhortation to AASLD members to do their part.

“We need your help,” Dr. Collins said. “This is a bold initiative, but it’s an opportunity. It’s even a responsibility. If we can actually succeed at this kind of outreach and save lives, and at the same time save money, how can we not do that?”

Dr. Collins, Dr. Chhatwal, and Dr. Fleurence each reported having no financial conflicts.

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

WASHINGTON – “We don’t get to use the ‘eliminate’ word all that often with a disease that’s taking thousands or tens of thousands – or worldwide, hundreds of thousands – of lives every year, but we have that opportunity with hepatitis C.”

So said Francis S. Collins, MD, PhD, special projects advisor to the Executive Office of the President of the United States, and former director of the National Institutes of Health, speaking at a special session outlining ambitious goals for a national plan to eliminate hepatitis C virus (HCV) infections by the year 2050.

The session was held at the annual meeting of the American Association for the Study of Liver Diseases.
 

A public health crisis

Dr. Collins labeled HCV a public health crisis, citing statistics from the Centers for Disease Control and Prevention that show that the rate of reported acute HCV infection cases increased 400% between 2010 and 2020, with the highest rates among young adults aged 20-39 years.

In addition, an estimated 2.4 million people in the United States are living with chronic HCV infections, but as many as 40% of these people are unaware of their infection, despite broad recommendations for the screening of all adults aged 18 years and older, he said.

“Our goal is to try to do something to change this,” Dr. Collins said. He noted that for the past 8 years we have had highly effective oral agents that don’t just treat the disease but cure it – 95%-97% of the time, with only 8-12 weeks of oral therapy and relatively few side effects.

“A wonderful story, one of the most exciting stories that’s come out of biomedical research in the last couple of decades,” he said.

Yet Dr. Collins also acknowledged that the task of developing a national plan is daunting, despite that pharmaceutical triumph.

National pharmacy claims data show that the number of persons treated for HCV with direct-acting antiviral agents (DAAs) in the United States declined from a high of 164,247 in 2015 to 83,740 in 2020.

Furthermore, CDC data from 2019 and 2020 show that, of persons with a diagnosis of HCV infection, only 23% of those on Medicaid, 28% of those on Medicare, and 35% of those with private insurance were treated for their infections.

“We have a huge gap here between the ability to know you have the disease and to get treatment, and we don’t see the numbers here for the uninsured, or people in prisons, but they’re probably much worse,” he said.
 

Obstacles abound, as do ways to overcome them

Current barriers to treatment include the aforementioned lack of awareness of infection, a “clunky” two-step diagnosis requiring an antibody test followed by an RNA or core antigen test necessitating three visits often separated by several weeks, and the high cost of treatment (around $90,000 per patient).

In addition, insurers commonly require proof that patients remain sober for extended periods, insist that treatment monitoring be performed by specialists only, and often approve treatment only for those patients who have documented evidence of liver damage.

“Does that make sense to you?” Dr. Collins asked. “You’ve got a cure for a liver disease, and you have to wait and show that the liver’s been damaged before you receive it? That just doesn’t fit,” he said.

Dr. Collins also pointed out that we’re dealing with hard-to-reach populations (underserved, uninsured, justice-involved), and people who are in tough times. “Anything that you put in the way as a barrier is going to make this worse in terms of its ability to be implemented,” he said.

To demonstrate how a coordinated HCV-elimination program could work, Dr. Collins pointed to a Medicaid cohort study in Louisiana conducted from July 2019 through December 2021, in which 8,867 patients started on therapy, 7,763 (88%) completed therapy, and 5,882 (66%) returned for testing. Of those tested, 5,285 (90%) had sustained virologic responses.

Another model of a hepatitis C elimination program was provided by the Veterans Health Administration. They received funding for an effort for all veterans, and in the space of 7 years were able to reach out even to some of their difficult-to-reach populations and achieve high diagnosis and treatment rates in a way that could be a model for what we would want to do across the nation, Dr. Collins noted.
 

Doing the math

Also at the session, Jagpreet Chhatwal, PhD, director of the Massachusetts General Hospital Institute for Technology Assessment and associate professor of radiology at Harvard Medical School, Boston, described outcomes projected by a mathematical simulation model of the HCV epidemic that he and his colleagues developed.

The HEP-SIM (Hepatitis C Disease Burden Simulation) model evaluates HCV prevalence trends, the number needed to screen and treat to eliminate HCV, HCV-associated clinical outcomes, the cost of an elimination program, and the cost savings that could be realized from preventing long-term complications.

The model seeks to determine whether the upfront costs of a national HCV elimination program could be offset by savings down the road. Specifically, it assumes that within the next 5 years 1.31 million individuals would be diagnosed with HCV and projects that within that time frame 1.52 million would need to be treated to meet HCV elimination goals.

The model shows that, compared with the status quo, a concerted campaign of screening and treatment would prevent more than 10,000 HCV-related deaths by 2030, and 91,000 deaths by 2050.

A coordinated screening program is also projected to prevent 17,000 cases of hepatocellular carcinoma by 2030 and 108,000 cases by 2050, as well as avert 29,000 cases of decompensated cirrhosis by 2030 and 93,000 such cases by 2050.

The cost savings associated with an HCV elimination plan would also be substantial, Dr. Chhatwal said.

According to the model, over the next decade the cumulative costs associated with HCV would decline by $14.2 billion, compared with the status quo. Nearly 80% of those savings ($11.2 billion) would be in Medicare and Medicaid.

The total projected savings from 2024 through 2050 – in disease management, testing, treatment, and pragmatic costs – are estimated at $59.3 billion, Dr. Chhatwal said.

“This is unprecedented,” he said. “We’re not just eliminating a disease as a public health threat but also saving money, which is not a common thing. That gives us a lot of impetus to implement such a program.”
 

Getting it done

Rachael L. Fleurence, PhD, MSc, a health economist currently serving as a senior advisor in the Executive Office of the President, summarized efforts to build a national HCV elimination program with input from federal health care agencies, state health leaders, patients, advocacy groups, drug manufacturers, and insurers.

She noted that a large component and focus of the program will be working on diagnostic test development but also accelerating bringing tests into the United States that are currently unavailable here. “These include point-of-care RNA diagnostic tests, as well as core antigen laboratory tests,” she said.

The program will be designed to offer broad access to curative anti-HCV drugs through a national subscription model that would make DAAs available to Medicaid recipients, justice-involved populations, the uninsured, and American Indians and Alaskan Natives who receive care through the Indian Health Service.

“On the Medicare and commercial insurance fronts, we’re still exploring different approaches, including potentially a co-pay assistance for Medicare beneficiaries, as well as working with commercial insurers to reduce barriers to access,” she said.

The program would also involve screening strategies extending to more settings, especially for high-risk populations, expanding the number of providers allowed to screen and treat HCV infections through telehealth, ensuring incentives for providers, and increasing the number of community health workers and case workers to improve linkage to care.

The next steps for the program would include funding to support the NIH’s RADx diagnostics program to accelerate access to testing, planning for the subscription model for DAA purchase, and launching pilot programs with the CDC, the Health Resources and Services Administration, the Substance Abuse and Mental Health Services Administration, and the Indian Health Service.
 

A call to action

Dr. Collins ended this portion of the program with an exhortation to AASLD members to do their part.

“We need your help,” Dr. Collins said. “This is a bold initiative, but it’s an opportunity. It’s even a responsibility. If we can actually succeed at this kind of outreach and save lives, and at the same time save money, how can we not do that?”

Dr. Collins, Dr. Chhatwal, and Dr. Fleurence each reported having no financial conflicts.

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

The dire shortage of pediatric hospital beds plaguing the nation in the fall of 2022 is a byproduct of financial decisions made by hospitals over the past decade, as they shuttered children’s wards, which often operate in the red, and expanded the number of beds available for more profitable endeavors like joint replacements and cancer care.

To cope with the flood of young patients sickened by a sweeping convergence of nasty bugs – especially respiratory syncytial virus, influenza, and coronavirus – medical centers nationwide have deployed triage tents, delayed elective surgeries, and transferred critically ill children out of state.

A major factor in the bed shortage is a years-long trend among hospitals of eliminating pediatric units, which tend to be less profitable than adult units, said Mark Wietecha, MS, MBA, CEO of the Children’s Hospital Association. Hospitals optimize revenue by striving to keep their beds 100% full – and filled with patients whose conditions command generous insurance reimbursements.

“It really has to do with dollars,” said Scott Krugman, MD, MS, vice chair of pediatrics at the Herman and Walter Samuelson Children’s Hospital at Sinai in Baltimore. “Hospitals rely on high-volume, high-reimbursement procedures from good payers to make money. There’s no incentive for hospitals to provide money-losing services.”

The number of pediatric inpatient units in hospitals fell 19% from 2008 to 2018, according to a study published in 2021 in the journal Pediatrics. Just this year, hospitals have closed pediatric units in Boston and Springfield, Mass.; Richmond, Va.; and Tulsa, Okla.

The current surge in dangerous respiratory illnesses among children is yet another example of how COVID-19 has upended the health care system. The lockdowns and isolation that marked the first years of the pandemic left kids largely unexposed – and still vulnerable – to viruses other than COVID for two winters, and doctors are now essentially treating multiple years’ worth of respiratory ailments.

The pandemic also accelerated changes in the health care industry that have left many communities with fewer hospital beds available for children who are acutely ill, along with fewer doctors and nurses to care for them.

When intensive care units were flooded with older COVID patients in 2020, some hospitals began using children’s beds to treat adults. Many of those pediatric beds haven’t been restored, said Daniel Rauch, MD, chair of the American Academy of Pediatrics’ committee on hospital care.

In addition, the relentless pace of the pandemic has spurred more than 230,000 health care providers – including doctors, nurses, and physician assistants – to quit. Before the pandemic, about 10% of nurses left their jobs every year; the rate has risen to about 20%, Dr. Wietecha said. He estimates that pediatric hospitals are unable to maintain as many as 10% of their beds because of staffing shortages.

“There is just not enough space for all the kids who need beds,” said Megan Ranney, MD, MPH, who works in several emergency departments in Providence, R.I., including Hasbro Children’s Hospital. The number of children seeking emergency care in recent weeks was 25% higher than the hospital’s previous record.

“We have doctors who are cleaning beds so we can get children into them faster,” said Dr. Ranney, a deputy dean at Brown University’s School of Public Health.

There’s not great money in treating kids. About 40% of U.S. children are covered by Medicaid, a joint federal-state program for low-income patients and people with disabilities. Base Medicaid rates are typically more than 20% below those paid by Medicare, the government insurance program for older adults, and are even lower when compared with private insurance. While specialty care for a range of common adult procedures, from knee and hip replacements to heart surgeries and cancer treatments, generates major profits for medical centers, hospitals complain they typically lose money on inpatient pediatric care.

When Tufts Children’s Hospital closed 41 pediatric beds this summer, hospital officials assured residents that young patients could receive care at nearby Boston Children’s Hospital. Now, Boston Children’s is delaying some elective surgeries to make room for kids who are acutely ill.

Dr. Rauch noted that children’s hospitals, which specialize in treating rare and serious conditions such as pediatric cancer, cystic fibrosis, and heart defects, simply aren’t designed to handle this season’s crush of kids acutely ill with respiratory bugs.

Even before the autumn’s viral trifecta, pediatric units were straining to absorb rising numbers of young people in acute mental distress. Stories abound of children in mental crises being marooned for weeks in emergency departments while awaiting transfer to a pediatric psychiatric unit. On a good day, Dr. Ranney said, 20% of pediatric emergency room beds at Hasbro Children’s Hospital are occupied by children experiencing mental health issues.

In hopes of adding pediatric capacity, the American Academy of Pediatrics joined the Children’s Hospital Association last month in calling on the White House to declare a national emergency due to child respiratory infections and provide additional resources to help cover the costs of care. The Biden administration has said that the flexibility hospital systems and providers have been given during the pandemic to sidestep certain staffing requirements also applies to RSV and flu.

Doernbecher Children’s Hospital at Oregon Health & Science University has shifted to “crisis standards of care,” enabling intensive care nurses to treat more patients than they’re usually assigned. Hospitals in Atlanta, Pittsburgh, and Aurora, Colorado, meanwhile, have resorted to treating young patients in overflow tents in parking lots.

Alex Kon, MD, a pediatric critical care physician at Community Medical Center in Missoula, Mont., said providers there have made plans to care for older kids in the adult intensive care unit, and to divert ambulances to other facilities when necessary. With only three pediatric ICUs in the state, that means young patients may be flown as far as Seattle or Spokane, Wash., or Idaho.

Hollis Lillard took her 1-year-old son, Calder, to an Army hospital in Northern Virginia last month after he experienced several days of fever, coughing, and labored breathing. They spent 7 anguished hours in the emergency room before the hospital found an open bed and transferred them by ambulance to Walter Reed National Military Medical Center in Maryland.

With proper therapy and instructions for home care, Calder’s virus was readily treatable: He recovered after he was given oxygen and treated with steroids, which fight inflammation, and albuterol, which counteracts bronchospasms. He was discharged the next day.

Although hospitalizations for RSV are falling, rates remain well above the norm for this time of year. And hospitals may not get much relief.

People can be infected with RSV more than once a year, and Dr. Krugman worries about a resurgence in the months to come. Because of the coronavirus, which competes with other viruses, “the usual seasonal pattern of viruses has gone out the window,” he said.

Like RSV, influenza arrived early this season. Both viruses usually peak around January. Three strains of flu are circulating and have caused an estimated 8.7 million illnesses, 78,000 hospitalizations, and 4,500 deaths, according to the Centers for Disease Control and Prevention.

Dr. Krugman doubts the health care industry will learn any quick lessons from the current crisis. “Unless there is a radical change in how we pay for pediatric hospital care,” Dr. Krugman said, “the bed shortage is only going to get worse.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The dire shortage of pediatric hospital beds plaguing the nation in the fall of 2022 is a byproduct of financial decisions made by hospitals over the past decade, as they shuttered children’s wards, which often operate in the red, and expanded the number of beds available for more profitable endeavors like joint replacements and cancer care.

To cope with the flood of young patients sickened by a sweeping convergence of nasty bugs – especially respiratory syncytial virus, influenza, and coronavirus – medical centers nationwide have deployed triage tents, delayed elective surgeries, and transferred critically ill children out of state.

A major factor in the bed shortage is a years-long trend among hospitals of eliminating pediatric units, which tend to be less profitable than adult units, said Mark Wietecha, MS, MBA, CEO of the Children’s Hospital Association. Hospitals optimize revenue by striving to keep their beds 100% full – and filled with patients whose conditions command generous insurance reimbursements.

“It really has to do with dollars,” said Scott Krugman, MD, MS, vice chair of pediatrics at the Herman and Walter Samuelson Children’s Hospital at Sinai in Baltimore. “Hospitals rely on high-volume, high-reimbursement procedures from good payers to make money. There’s no incentive for hospitals to provide money-losing services.”

The number of pediatric inpatient units in hospitals fell 19% from 2008 to 2018, according to a study published in 2021 in the journal Pediatrics. Just this year, hospitals have closed pediatric units in Boston and Springfield, Mass.; Richmond, Va.; and Tulsa, Okla.

The current surge in dangerous respiratory illnesses among children is yet another example of how COVID-19 has upended the health care system. The lockdowns and isolation that marked the first years of the pandemic left kids largely unexposed – and still vulnerable – to viruses other than COVID for two winters, and doctors are now essentially treating multiple years’ worth of respiratory ailments.

The pandemic also accelerated changes in the health care industry that have left many communities with fewer hospital beds available for children who are acutely ill, along with fewer doctors and nurses to care for them.

When intensive care units were flooded with older COVID patients in 2020, some hospitals began using children’s beds to treat adults. Many of those pediatric beds haven’t been restored, said Daniel Rauch, MD, chair of the American Academy of Pediatrics’ committee on hospital care.

In addition, the relentless pace of the pandemic has spurred more than 230,000 health care providers – including doctors, nurses, and physician assistants – to quit. Before the pandemic, about 10% of nurses left their jobs every year; the rate has risen to about 20%, Dr. Wietecha said. He estimates that pediatric hospitals are unable to maintain as many as 10% of their beds because of staffing shortages.

“There is just not enough space for all the kids who need beds,” said Megan Ranney, MD, MPH, who works in several emergency departments in Providence, R.I., including Hasbro Children’s Hospital. The number of children seeking emergency care in recent weeks was 25% higher than the hospital’s previous record.

“We have doctors who are cleaning beds so we can get children into them faster,” said Dr. Ranney, a deputy dean at Brown University’s School of Public Health.

There’s not great money in treating kids. About 40% of U.S. children are covered by Medicaid, a joint federal-state program for low-income patients and people with disabilities. Base Medicaid rates are typically more than 20% below those paid by Medicare, the government insurance program for older adults, and are even lower when compared with private insurance. While specialty care for a range of common adult procedures, from knee and hip replacements to heart surgeries and cancer treatments, generates major profits for medical centers, hospitals complain they typically lose money on inpatient pediatric care.

When Tufts Children’s Hospital closed 41 pediatric beds this summer, hospital officials assured residents that young patients could receive care at nearby Boston Children’s Hospital. Now, Boston Children’s is delaying some elective surgeries to make room for kids who are acutely ill.

Dr. Rauch noted that children’s hospitals, which specialize in treating rare and serious conditions such as pediatric cancer, cystic fibrosis, and heart defects, simply aren’t designed to handle this season’s crush of kids acutely ill with respiratory bugs.

Even before the autumn’s viral trifecta, pediatric units were straining to absorb rising numbers of young people in acute mental distress. Stories abound of children in mental crises being marooned for weeks in emergency departments while awaiting transfer to a pediatric psychiatric unit. On a good day, Dr. Ranney said, 20% of pediatric emergency room beds at Hasbro Children’s Hospital are occupied by children experiencing mental health issues.

In hopes of adding pediatric capacity, the American Academy of Pediatrics joined the Children’s Hospital Association last month in calling on the White House to declare a national emergency due to child respiratory infections and provide additional resources to help cover the costs of care. The Biden administration has said that the flexibility hospital systems and providers have been given during the pandemic to sidestep certain staffing requirements also applies to RSV and flu.

Doernbecher Children’s Hospital at Oregon Health & Science University has shifted to “crisis standards of care,” enabling intensive care nurses to treat more patients than they’re usually assigned. Hospitals in Atlanta, Pittsburgh, and Aurora, Colorado, meanwhile, have resorted to treating young patients in overflow tents in parking lots.

Alex Kon, MD, a pediatric critical care physician at Community Medical Center in Missoula, Mont., said providers there have made plans to care for older kids in the adult intensive care unit, and to divert ambulances to other facilities when necessary. With only three pediatric ICUs in the state, that means young patients may be flown as far as Seattle or Spokane, Wash., or Idaho.

Hollis Lillard took her 1-year-old son, Calder, to an Army hospital in Northern Virginia last month after he experienced several days of fever, coughing, and labored breathing. They spent 7 anguished hours in the emergency room before the hospital found an open bed and transferred them by ambulance to Walter Reed National Military Medical Center in Maryland.

With proper therapy and instructions for home care, Calder’s virus was readily treatable: He recovered after he was given oxygen and treated with steroids, which fight inflammation, and albuterol, which counteracts bronchospasms. He was discharged the next day.

Although hospitalizations for RSV are falling, rates remain well above the norm for this time of year. And hospitals may not get much relief.

People can be infected with RSV more than once a year, and Dr. Krugman worries about a resurgence in the months to come. Because of the coronavirus, which competes with other viruses, “the usual seasonal pattern of viruses has gone out the window,” he said.

Like RSV, influenza arrived early this season. Both viruses usually peak around January. Three strains of flu are circulating and have caused an estimated 8.7 million illnesses, 78,000 hospitalizations, and 4,500 deaths, according to the Centers for Disease Control and Prevention.

Dr. Krugman doubts the health care industry will learn any quick lessons from the current crisis. “Unless there is a radical change in how we pay for pediatric hospital care,” Dr. Krugman said, “the bed shortage is only going to get worse.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The dire shortage of pediatric hospital beds plaguing the nation in the fall of 2022 is a byproduct of financial decisions made by hospitals over the past decade, as they shuttered children’s wards, which often operate in the red, and expanded the number of beds available for more profitable endeavors like joint replacements and cancer care.

To cope with the flood of young patients sickened by a sweeping convergence of nasty bugs – especially respiratory syncytial virus, influenza, and coronavirus – medical centers nationwide have deployed triage tents, delayed elective surgeries, and transferred critically ill children out of state.

A major factor in the bed shortage is a years-long trend among hospitals of eliminating pediatric units, which tend to be less profitable than adult units, said Mark Wietecha, MS, MBA, CEO of the Children’s Hospital Association. Hospitals optimize revenue by striving to keep their beds 100% full – and filled with patients whose conditions command generous insurance reimbursements.

“It really has to do with dollars,” said Scott Krugman, MD, MS, vice chair of pediatrics at the Herman and Walter Samuelson Children’s Hospital at Sinai in Baltimore. “Hospitals rely on high-volume, high-reimbursement procedures from good payers to make money. There’s no incentive for hospitals to provide money-losing services.”

The number of pediatric inpatient units in hospitals fell 19% from 2008 to 2018, according to a study published in 2021 in the journal Pediatrics. Just this year, hospitals have closed pediatric units in Boston and Springfield, Mass.; Richmond, Va.; and Tulsa, Okla.

The current surge in dangerous respiratory illnesses among children is yet another example of how COVID-19 has upended the health care system. The lockdowns and isolation that marked the first years of the pandemic left kids largely unexposed – and still vulnerable – to viruses other than COVID for two winters, and doctors are now essentially treating multiple years’ worth of respiratory ailments.

The pandemic also accelerated changes in the health care industry that have left many communities with fewer hospital beds available for children who are acutely ill, along with fewer doctors and nurses to care for them.

When intensive care units were flooded with older COVID patients in 2020, some hospitals began using children’s beds to treat adults. Many of those pediatric beds haven’t been restored, said Daniel Rauch, MD, chair of the American Academy of Pediatrics’ committee on hospital care.

In addition, the relentless pace of the pandemic has spurred more than 230,000 health care providers – including doctors, nurses, and physician assistants – to quit. Before the pandemic, about 10% of nurses left their jobs every year; the rate has risen to about 20%, Dr. Wietecha said. He estimates that pediatric hospitals are unable to maintain as many as 10% of their beds because of staffing shortages.

“There is just not enough space for all the kids who need beds,” said Megan Ranney, MD, MPH, who works in several emergency departments in Providence, R.I., including Hasbro Children’s Hospital. The number of children seeking emergency care in recent weeks was 25% higher than the hospital’s previous record.

“We have doctors who are cleaning beds so we can get children into them faster,” said Dr. Ranney, a deputy dean at Brown University’s School of Public Health.

There’s not great money in treating kids. About 40% of U.S. children are covered by Medicaid, a joint federal-state program for low-income patients and people with disabilities. Base Medicaid rates are typically more than 20% below those paid by Medicare, the government insurance program for older adults, and are even lower when compared with private insurance. While specialty care for a range of common adult procedures, from knee and hip replacements to heart surgeries and cancer treatments, generates major profits for medical centers, hospitals complain they typically lose money on inpatient pediatric care.

When Tufts Children’s Hospital closed 41 pediatric beds this summer, hospital officials assured residents that young patients could receive care at nearby Boston Children’s Hospital. Now, Boston Children’s is delaying some elective surgeries to make room for kids who are acutely ill.

Dr. Rauch noted that children’s hospitals, which specialize in treating rare and serious conditions such as pediatric cancer, cystic fibrosis, and heart defects, simply aren’t designed to handle this season’s crush of kids acutely ill with respiratory bugs.

Even before the autumn’s viral trifecta, pediatric units were straining to absorb rising numbers of young people in acute mental distress. Stories abound of children in mental crises being marooned for weeks in emergency departments while awaiting transfer to a pediatric psychiatric unit. On a good day, Dr. Ranney said, 20% of pediatric emergency room beds at Hasbro Children’s Hospital are occupied by children experiencing mental health issues.

In hopes of adding pediatric capacity, the American Academy of Pediatrics joined the Children’s Hospital Association last month in calling on the White House to declare a national emergency due to child respiratory infections and provide additional resources to help cover the costs of care. The Biden administration has said that the flexibility hospital systems and providers have been given during the pandemic to sidestep certain staffing requirements also applies to RSV and flu.

Doernbecher Children’s Hospital at Oregon Health & Science University has shifted to “crisis standards of care,” enabling intensive care nurses to treat more patients than they’re usually assigned. Hospitals in Atlanta, Pittsburgh, and Aurora, Colorado, meanwhile, have resorted to treating young patients in overflow tents in parking lots.

Alex Kon, MD, a pediatric critical care physician at Community Medical Center in Missoula, Mont., said providers there have made plans to care for older kids in the adult intensive care unit, and to divert ambulances to other facilities when necessary. With only three pediatric ICUs in the state, that means young patients may be flown as far as Seattle or Spokane, Wash., or Idaho.

Hollis Lillard took her 1-year-old son, Calder, to an Army hospital in Northern Virginia last month after he experienced several days of fever, coughing, and labored breathing. They spent 7 anguished hours in the emergency room before the hospital found an open bed and transferred them by ambulance to Walter Reed National Military Medical Center in Maryland.

With proper therapy and instructions for home care, Calder’s virus was readily treatable: He recovered after he was given oxygen and treated with steroids, which fight inflammation, and albuterol, which counteracts bronchospasms. He was discharged the next day.

Although hospitalizations for RSV are falling, rates remain well above the norm for this time of year. And hospitals may not get much relief.

People can be infected with RSV more than once a year, and Dr. Krugman worries about a resurgence in the months to come. Because of the coronavirus, which competes with other viruses, “the usual seasonal pattern of viruses has gone out the window,” he said.

Like RSV, influenza arrived early this season. Both viruses usually peak around January. Three strains of flu are circulating and have caused an estimated 8.7 million illnesses, 78,000 hospitalizations, and 4,500 deaths, according to the Centers for Disease Control and Prevention.

Dr. Krugman doubts the health care industry will learn any quick lessons from the current crisis. “Unless there is a radical change in how we pay for pediatric hospital care,” Dr. Krugman said, “the bed shortage is only going to get worse.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Several years into the pandemic, COVID-19 continues to deeply impact our society; at the time of publication of this review, 98.8 million cases in the United States have been reported to the Centers for Disease Control and Prevention (CDC).¹ Although many people recover well from infection, there is mounting concern regarding long-term sequelae of COVID-19. These long-term symptoms have been termed long COVID, among other names.

What exactly is long COVID?

The CDC and National Institutes of Health define long COVID as new or ongoing health problems experienced ≥ 4 weeks after initial infection.² Evidence suggests that even people who have mild initial COVID-19 symptoms are at risk for long COVID.

Available data about long COVID are imperfect, however; much about the condition remains poorly understood. For example, there is little evidence regarding the effect of vaccination and viral variants on the prevalence of long ­COVID. A recent study of more than 13 million people from the US Department of Veterans Affairs database did demonstrate that vaccination against SARS-CoV-2 lowered the risk for long ­COVID by only about 15%.³

Persistent symptoms associated with long COVID often lead to disability and decreased quality of life. Furthermore, long COVID is a challenge to treat because there is a paucity of evidence to guide COVID-19 treatment beyond initial infection.

The prevalence of long COVID symptoms appears to increase with age.

Because many patients who have ongoing COVID-19 symptoms will be seen in primary care, it is important to understand how to manage and support them. In this article, we discuss current understanding of long COVID epidemiology, symptoms that can persist 4 weeks after initial infection, and potential treatment options.

Prevalence and diagnosis

The prevalence of long COVID is not well defined because many epidemiologic studies rely on self-reporting. The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.⁴ Other studies variously cite 5% to 85% of people who have had a diagnosis of COVID-19 as experiencing long COVID, although that rate more consistently appears to be 10% to 30%.⁵

Copyright Brian Stauffer

A study of adult patients in France found that self-reported symptoms of long COVID, 10 to 12 months after the first wave of the pandemic (May through November 2020), were associated with the belief of having had COVID-19 but not necessarily with having tested positive for anti-SARS-CoV-2 antibodies,⁶ which indicates prior COVID-19. This complicates research on long COVID because, first, there is no specific test to confirm a diagnosis of long COVID and, second, studies often rely on self-reporting of earlier COVID-19.

Continue to: As such, long COVID...

As such, long COVID is diagnosed primarily through a medical history and physical examination. The medical history provides a guide as to whether additional testing is warranted to evaluate for known complications of COVID-19, such as deep vein thrombosis, pulmonary embolism, myocarditis, and pulmonary fibrosis. As of October 1, 2021, a new International Classification of Disease (10th Revision) code went into effect for post ­COVID condition, unspecified (U09.9).⁷

The prevalence of long COVID symptoms appears to increase with age. Among patients whose disease was diagnosed using code U09.9, most were 36 to 64 years of age; children and adults ages 22 years or younger constituted only 10.5% of diagnoses.⁷ Long COVID symptoms might also be more prevalent among women and in people with a preexisting chronic comorbidity.^2,7

Symptoms can be numerous, severe or mild, and lasting

Initially, there was no widely accepted definition of long COVID; follow-up in early studies ranged from 21 days to 2 years after initial infection (or from discharge, for hospitalized patients).⁸ Differences in descriptions that have been used on surveys to self-report symptoms make it a challenge to clearly summarize the frequency of each aspect of long COVID.

Long COVID can be mild or debilitating; severity can fluctuate. Common symptoms include fatigue, dyspnea or other breathing difficulties, headache, and cognitive dysfunction, but as many as 203 lasting symptoms have been reported.^2,8-12 From October 1, 2021, through January 31, 2022, the most common accompanying manifestations of long COVID were difficulty breathing, cough, and fatigue.⁷ Long COVID can affect multiple organ systems,^13,14 with symptoms varying by organ system affected. Regardless of the need for hospitalization initially, having had COVID-19 significantly increases the risk for subsequent death at 30 days and at 6 months after initial infection.¹⁵

The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.

Symptoms of long COVID have been reported as long as 2 years after initial infection.⁸ When Davis and colleagues studied the onset and progression of reported symptoms of long COVID,⁹ they determined that, among patients who reported recovery from COVID-19 in < 90 days, symptoms peaked at approximately Week 2 of infection. In comparison, patients who reported not having recovered in < 90 days had (1) symptoms that peaked later (2 months) and (2) on average, more symptoms (mean, 17 reported symptoms, compared to 11 in recovered ­patients).⁹

Continue to: Fatigue

Fatigue, including postexertion malaise and impaired daily function and mobility, is the most common symptom of long COVID,^8-10,14 reported in 28% to 98%¹⁴ of patients after initial COVID-19. This fatigue is more than simply being tired: Patients describe profound exhaustion, in which fatigue is out of proportion to exertion. Fatigue and myalgia are commonly reported among patients with impaired hepatic and pulmonary function as a consequence of long COVID.¹³ Patients often report that even minor activities result in decreased attention, focus, and energy, for many hours or days afterward. Fatigue has been reported to persist from 2.5 months to as long as 6 months after initial infection or hospitalization.^9,16

Postviral fatigue has been seen in other viral outbreaks and seems to share characteristics with myalgic encephalomyelitis/­chronic fatigue syndrome, or ME/CFS, which itself has historically been stigmatized and poorly understood.¹⁷ Long COVID fatigue might be more common among women and patients who have an existing diagnosis of depression and antidepressant use,^10,11,16,18 although the mechanism of this relationship is unclear. Potential mechanisms include damage from systemic inflammation to metabolism in the frontal lobe and cerebellum¹⁹ and direct infection by SARS-CoV-2 in skeletal muscle.²⁰ Townsend and colleagues¹⁶ found no relationship between long COVID fatigue and markers of inflammation (leukocyte, neutrophil, and lymphocyte counts; the neutrophil-to-lymphocyte ratio; lactate dehydrogenase; C-reactive protein; serum interleukin-6; and soluble CD25).

Neuropsychiatric symptoms are also common in long COVID and can have a significant impact on patients’ quality of life. Studies have reported poor sleep quality or insomnia (38% to 90%), headache (17% to 91.2%), speech and language problems (48% to 50%), confusion (20%), dementia (28.6%), difficulty concentrating (1.9% to 27%), and memory loss or cognitive impairment (5.4% to 73%).^9,10,14,15 For some patients, these symptoms persisted for ≥ 6 months, making it difficult for those affected to return to work.⁹

Isolation and loneliness, a common situation for patients with COVID-19, can have long-term effects on mental health.²¹ The COVID-19 pandemic itself has had a negative effect on behavioral health, including depression (4.3% to 25% of patients), anxiety (1.9% to 46%), obsessive compulsive disorder (4.9% to 20%), and posttraumatic stress disorder (29%).²² The persistence of symptoms of long COVID has resulted in a great deal of frustration, fear, and confusion for those affected—some of whom report a loss of trust in their community health care providers to address their ongoing struggles.²³ Such loss can be accompanied by a reported increase in feelings of anxiety and changes to perceptions of self (ie, “how I used to be” in contrast to “how I am now”).²³ These neuropsychiatric symptoms, including mental health conditions, appear to be more common among older adults.⁴

Other neurologic deficits found in long COVID include olfactory disorders (9% to 27% of patients), altered taste (5% to 18%), numbness or tingling sensations (6%), blurred vision (17.1%), and tinnitus (16.%).¹⁴ Dizziness (2.6% to 6%) and lightheadedness or presyncope (7%) have also been reported, although these symptoms appear to be less common than other neurocognitive effects.¹⁴

Continue to: The mechanism of action...

The mechanism of action of damage to the nervous system in long COVID is likely multifactorial. COVID-19 can directly infect the central nervous system through a hematogenous route, which can result in direct cytolytic damage to neurons. Infection can also affect the blood–brain barrier.²⁴ Additionally, COVID-19 can invade the central nervous system through peripheral nerves, including the olfactory and vagus nerves.²⁵ Many human respiratory viruses, including SARS-CoV-2, result in an increase in pro-inflammatory and anti-inflammatory cytokines; this so-called cytokine storm is an exaggerated response to infection and can trigger neurodegenerative and psychiatric syndromes.²⁶ It is unclear whether the cytokine storm is different for people with COVID-19, compared to other respiratory viruses.

Respiratory symptoms are very common after COVID-19¹⁵: In studies, as many as 87.1% of patients continued to have shortness of breath ≥ 140 days after initial symptom onset, including breathlessness (48% to 60%), wheezing (5.3%), cough (10.5% to 46%), and congestion (32%),^14,18 any of which can persist for as long as 6 months.⁹ Among a sample of previously hospitalized COVID-19 patients in Wuhan, China, 22% to 56% displayed a pulmonary diffusion abnormality 6 months later, with those who required supplemental oxygen during initial COVID-19 having a greater risk for these abnormalities at follow-up, compared to those who did not require supplemental oxygen (odds ratio = 2.42; 95% CI, 1.15-5.08).¹¹

Cardiovascular symptoms. New-onset autonomic dysfunction has been described in multiple case reports and in some larger cohort studies of patients post COVID-19.²⁷ Many common long COVID symptoms, including fatigue and orthostatic intolerance, are commonly seen in postural orthostatic tachycardia syndrome. Emerging evidence indicates that there are likely similar underlying mechanisms and a significant amount of overlap between long COVID and postural orthostatic tachycardia syndrome.²⁷

The high rate of cardiac complications post COVID-19 highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

A study of patients within the US Department of Veterans Affairs population found that, regardless of disease severity, patients who had a positive COVID-19 test had a higher rate of cardiac disease 30 days after diagnosis,²⁸ including stroke, transient ischemic attack, dysrhythmia, inflammatory heart disease, acute coronary disease, myocardial infarction, ischemic cardiopathy, angina, heart failure, nonischemic cardiomyopathy, and cardiac arrest. Patients with COVID-19 were at increased risk for major adverse cardiovascular events (myocardial infarction, stroke, and all-cause mortality).²⁸ Demographics of the VA population (ie, most are White men) might limit the generalizability of these data, but similar findings have been found elsewhere.^5,10,15Given that, in general, chest pain is common after the acute phase of an infection and the causes of chest pain are broad, the high rate of cardiac complications post COVID-19 nevertheless highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

Other symptoms. Body aches and generalized joint pain are another common symptom group of long COVID.⁹ These include body aches (20%), joint pain (78%), and muscle aches (87.7%).^14,18

Continue to: Commonly reported...

Commonly reported gastrointestinal symptoms include diarrhea, loss of appetite, nausea, and abdominal pain.^9,15

Other symptoms reported less commonly include dermatologic conditions, such as pruritus and rash; reproductive and endocrine symptoms, including extreme thirst, irregular menstruation, and sexual dysfunction; and new or exacerbated allergic response.⁹

Does severity of initial disease play a role?

Keep in mind that long COVID is not specific to patients who were hospitalized or had severe initial infection. In fact, 75% of patients who have a diagnosis of a post–COVID-19 condition were not hospitalized for their initial infection.⁷ However, the severity of initial COVID-19 infection might contribute to the presence or severity of long COVID symptoms²—although findings in current literature are mixed. For example:

• In reporting from Wuhan, China, higher position on a disease severity scale during a hospital stay for COVID-19 was associated with:
  • greater likelihood of reporting ≥ 1 symptoms at a 6-month ­follow-up
  • increased risk for pulmonary diffusion abnormalities, fatigue, and mood disorders.¹¹
• After 2 years’ follow-up of the same cohort, 55% of patients continued to report ≥ 1 symptoms of long COVID, and those who had been hospitalized with COVID-19 continued to report reduced health-related quality of life, compared to the control group.⁸
• Similarly, patients initially hospitalized with COVID-19 were more likely to experience impairment of ≥ 2 organs—in particular, the liver and pancreas—compared to nonhospitalized patients after a median 5 months post initial infection, among a sample in the United Kingdom.¹³
• In an international cohort, patients who reported a greater number of symptoms during initial COVID-19 were more likely to experience long COVID.¹²
• Last, long COVID fatigue did not vary by severity of initial COVID-19 infection among a sample of hospitalized and nonhospitalized participants in Dublin, Ireland.¹⁶

No specific treatments yet available

There are no specific treatments for long ­COVID; overall, the emphasis is on providing supportive care and managing preexisting chronic conditions.⁵ This is where expertise in primary care, relationships with patients and the community, and psychosocial knowledge can help patients recover from ongoing ­COVID-19 symptoms.

Long COVID–associated fatigue is more than simply being tired. Patients describe profound exhaustion, in which fatigue is out of proportion to exertion.

Clinicians should continue to perform a thorough physical assessment of patients with previous or ongoing COVID-19 to identify and monitor new or recurring symptoms after hospital discharge or initial resolution of symptoms.²⁹ This approach includes developing an individualized plan for care and rehabilitation that is specific to presenting symptoms, including psychological support. We encourage family physicians to familiarize themselves with the work of Vance and colleagues,³⁰ who have created a comprehensive table^a to guide treatment and referral for the gamut of long COVID symptoms, including cardiovascular issues (eg, palpitations, edema), chronic cough, headache, pain, and insomnia.

Continue to: This new clinical entity is a formidable challenge

Long COVID is a new condition that requires comprehensive evaluation to understand the full, often long-term, effects of COVID-19. Our review of this condition substantiated that symptoms of long COVID often affect a variety of organs^13,14 and have been observed to persist for ≥ 2 years.⁸

Some studies that have examined the long-term effects of COVID-19 included only participants who were not hospitalized; others include hospitalized patients exclusively. The literature is mixed in regard to including severity of initial infection as it relates to long COVID. Available research demonstrates that it is common for people with COVID-19 to experience persistent symptoms that can significantly impact daily life and well-being.

Likely, it will be several years before we even begin to understand the full extent of COVID-19. Until research elucidates the relationship between the disease and short- and long-term health outcomes, clinicians should:

• acknowledge and address the reality of long COVID when meeting with persistently symptomatic patients,
• provide support, therapeutic listening, and referral to rehabilitation as appropriate, and
• offer information on the potential for long-term effects of COVID-19 to vaccine-hesitant patients.

^a “Systems, symptoms, and treatments for post-COVID patients,” pages 1231-1234 in the source article (www.jabfm.org/content/jabfp/34/6/1229.full.pdf).³⁰

CORRESPONDENCE
Nicole Mayo, PhD, 46 Prince Street, Rochester, NY 14607; Nicole_Mayo@URMC.Rochester.edu

Several years into the pandemic, COVID-19 continues to deeply impact our society; at the time of publication of this review, 98.8 million cases in the United States have been reported to the Centers for Disease Control and Prevention (CDC).¹ Although many people recover well from infection, there is mounting concern regarding long-term sequelae of COVID-19. These long-term symptoms have been termed long COVID, among other names.

What exactly is long COVID?

The CDC and National Institutes of Health define long COVID as new or ongoing health problems experienced ≥ 4 weeks after initial infection.² Evidence suggests that even people who have mild initial COVID-19 symptoms are at risk for long COVID.

Available data about long COVID are imperfect, however; much about the condition remains poorly understood. For example, there is little evidence regarding the effect of vaccination and viral variants on the prevalence of long ­COVID. A recent study of more than 13 million people from the US Department of Veterans Affairs database did demonstrate that vaccination against SARS-CoV-2 lowered the risk for long ­COVID by only about 15%.³

Persistent symptoms associated with long COVID often lead to disability and decreased quality of life. Furthermore, long COVID is a challenge to treat because there is a paucity of evidence to guide COVID-19 treatment beyond initial infection.

The prevalence of long COVID symptoms appears to increase with age.

Because many patients who have ongoing COVID-19 symptoms will be seen in primary care, it is important to understand how to manage and support them. In this article, we discuss current understanding of long COVID epidemiology, symptoms that can persist 4 weeks after initial infection, and potential treatment options.

Prevalence and diagnosis

The prevalence of long COVID is not well defined because many epidemiologic studies rely on self-reporting. The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.⁴ Other studies variously cite 5% to 85% of people who have had a diagnosis of COVID-19 as experiencing long COVID, although that rate more consistently appears to be 10% to 30%.⁵

Copyright Brian Stauffer

A study of adult patients in France found that self-reported symptoms of long COVID, 10 to 12 months after the first wave of the pandemic (May through November 2020), were associated with the belief of having had COVID-19 but not necessarily with having tested positive for anti-SARS-CoV-2 antibodies,⁶ which indicates prior COVID-19. This complicates research on long COVID because, first, there is no specific test to confirm a diagnosis of long COVID and, second, studies often rely on self-reporting of earlier COVID-19.

Continue to: As such, long COVID...

As such, long COVID is diagnosed primarily through a medical history and physical examination. The medical history provides a guide as to whether additional testing is warranted to evaluate for known complications of COVID-19, such as deep vein thrombosis, pulmonary embolism, myocarditis, and pulmonary fibrosis. As of October 1, 2021, a new International Classification of Disease (10th Revision) code went into effect for post ­COVID condition, unspecified (U09.9).⁷

The prevalence of long COVID symptoms appears to increase with age. Among patients whose disease was diagnosed using code U09.9, most were 36 to 64 years of age; children and adults ages 22 years or younger constituted only 10.5% of diagnoses.⁷ Long COVID symptoms might also be more prevalent among women and in people with a preexisting chronic comorbidity.^2,7

Symptoms can be numerous, severe or mild, and lasting

Initially, there was no widely accepted definition of long COVID; follow-up in early studies ranged from 21 days to 2 years after initial infection (or from discharge, for hospitalized patients).⁸ Differences in descriptions that have been used on surveys to self-report symptoms make it a challenge to clearly summarize the frequency of each aspect of long COVID.

Long COVID can be mild or debilitating; severity can fluctuate. Common symptoms include fatigue, dyspnea or other breathing difficulties, headache, and cognitive dysfunction, but as many as 203 lasting symptoms have been reported.^2,8-12 From October 1, 2021, through January 31, 2022, the most common accompanying manifestations of long COVID were difficulty breathing, cough, and fatigue.⁷ Long COVID can affect multiple organ systems,^13,14 with symptoms varying by organ system affected. Regardless of the need for hospitalization initially, having had COVID-19 significantly increases the risk for subsequent death at 30 days and at 6 months after initial infection.¹⁵

The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.

Symptoms of long COVID have been reported as long as 2 years after initial infection.⁸ When Davis and colleagues studied the onset and progression of reported symptoms of long COVID,⁹ they determined that, among patients who reported recovery from COVID-19 in < 90 days, symptoms peaked at approximately Week 2 of infection. In comparison, patients who reported not having recovered in < 90 days had (1) symptoms that peaked later (2 months) and (2) on average, more symptoms (mean, 17 reported symptoms, compared to 11 in recovered ­patients).⁹

Continue to: Fatigue

Fatigue, including postexertion malaise and impaired daily function and mobility, is the most common symptom of long COVID,^8-10,14 reported in 28% to 98%¹⁴ of patients after initial COVID-19. This fatigue is more than simply being tired: Patients describe profound exhaustion, in which fatigue is out of proportion to exertion. Fatigue and myalgia are commonly reported among patients with impaired hepatic and pulmonary function as a consequence of long COVID.¹³ Patients often report that even minor activities result in decreased attention, focus, and energy, for many hours or days afterward. Fatigue has been reported to persist from 2.5 months to as long as 6 months after initial infection or hospitalization.^9,16

Postviral fatigue has been seen in other viral outbreaks and seems to share characteristics with myalgic encephalomyelitis/­chronic fatigue syndrome, or ME/CFS, which itself has historically been stigmatized and poorly understood.¹⁷ Long COVID fatigue might be more common among women and patients who have an existing diagnosis of depression and antidepressant use,^10,11,16,18 although the mechanism of this relationship is unclear. Potential mechanisms include damage from systemic inflammation to metabolism in the frontal lobe and cerebellum¹⁹ and direct infection by SARS-CoV-2 in skeletal muscle.²⁰ Townsend and colleagues¹⁶ found no relationship between long COVID fatigue and markers of inflammation (leukocyte, neutrophil, and lymphocyte counts; the neutrophil-to-lymphocyte ratio; lactate dehydrogenase; C-reactive protein; serum interleukin-6; and soluble CD25).

Neuropsychiatric symptoms are also common in long COVID and can have a significant impact on patients’ quality of life. Studies have reported poor sleep quality or insomnia (38% to 90%), headache (17% to 91.2%), speech and language problems (48% to 50%), confusion (20%), dementia (28.6%), difficulty concentrating (1.9% to 27%), and memory loss or cognitive impairment (5.4% to 73%).^9,10,14,15 For some patients, these symptoms persisted for ≥ 6 months, making it difficult for those affected to return to work.⁹

Isolation and loneliness, a common situation for patients with COVID-19, can have long-term effects on mental health.²¹ The COVID-19 pandemic itself has had a negative effect on behavioral health, including depression (4.3% to 25% of patients), anxiety (1.9% to 46%), obsessive compulsive disorder (4.9% to 20%), and posttraumatic stress disorder (29%).²² The persistence of symptoms of long COVID has resulted in a great deal of frustration, fear, and confusion for those affected—some of whom report a loss of trust in their community health care providers to address their ongoing struggles.²³ Such loss can be accompanied by a reported increase in feelings of anxiety and changes to perceptions of self (ie, “how I used to be” in contrast to “how I am now”).²³ These neuropsychiatric symptoms, including mental health conditions, appear to be more common among older adults.⁴

Other neurologic deficits found in long COVID include olfactory disorders (9% to 27% of patients), altered taste (5% to 18%), numbness or tingling sensations (6%), blurred vision (17.1%), and tinnitus (16.%).¹⁴ Dizziness (2.6% to 6%) and lightheadedness or presyncope (7%) have also been reported, although these symptoms appear to be less common than other neurocognitive effects.¹⁴

Continue to: The mechanism of action...

The mechanism of action of damage to the nervous system in long COVID is likely multifactorial. COVID-19 can directly infect the central nervous system through a hematogenous route, which can result in direct cytolytic damage to neurons. Infection can also affect the blood–brain barrier.²⁴ Additionally, COVID-19 can invade the central nervous system through peripheral nerves, including the olfactory and vagus nerves.²⁵ Many human respiratory viruses, including SARS-CoV-2, result in an increase in pro-inflammatory and anti-inflammatory cytokines; this so-called cytokine storm is an exaggerated response to infection and can trigger neurodegenerative and psychiatric syndromes.²⁶ It is unclear whether the cytokine storm is different for people with COVID-19, compared to other respiratory viruses.

Respiratory symptoms are very common after COVID-19¹⁵: In studies, as many as 87.1% of patients continued to have shortness of breath ≥ 140 days after initial symptom onset, including breathlessness (48% to 60%), wheezing (5.3%), cough (10.5% to 46%), and congestion (32%),^14,18 any of which can persist for as long as 6 months.⁹ Among a sample of previously hospitalized COVID-19 patients in Wuhan, China, 22% to 56% displayed a pulmonary diffusion abnormality 6 months later, with those who required supplemental oxygen during initial COVID-19 having a greater risk for these abnormalities at follow-up, compared to those who did not require supplemental oxygen (odds ratio = 2.42; 95% CI, 1.15-5.08).¹¹

Cardiovascular symptoms. New-onset autonomic dysfunction has been described in multiple case reports and in some larger cohort studies of patients post COVID-19.²⁷ Many common long COVID symptoms, including fatigue and orthostatic intolerance, are commonly seen in postural orthostatic tachycardia syndrome. Emerging evidence indicates that there are likely similar underlying mechanisms and a significant amount of overlap between long COVID and postural orthostatic tachycardia syndrome.²⁷

The high rate of cardiac complications post COVID-19 highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

A study of patients within the US Department of Veterans Affairs population found that, regardless of disease severity, patients who had a positive COVID-19 test had a higher rate of cardiac disease 30 days after diagnosis,²⁸ including stroke, transient ischemic attack, dysrhythmia, inflammatory heart disease, acute coronary disease, myocardial infarction, ischemic cardiopathy, angina, heart failure, nonischemic cardiomyopathy, and cardiac arrest. Patients with COVID-19 were at increased risk for major adverse cardiovascular events (myocardial infarction, stroke, and all-cause mortality).²⁸ Demographics of the VA population (ie, most are White men) might limit the generalizability of these data, but similar findings have been found elsewhere.^5,10,15Given that, in general, chest pain is common after the acute phase of an infection and the causes of chest pain are broad, the high rate of cardiac complications post COVID-19 nevertheless highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

Other symptoms. Body aches and generalized joint pain are another common symptom group of long COVID.⁹ These include body aches (20%), joint pain (78%), and muscle aches (87.7%).^14,18

Continue to: Commonly reported...

Commonly reported gastrointestinal symptoms include diarrhea, loss of appetite, nausea, and abdominal pain.^9,15

Other symptoms reported less commonly include dermatologic conditions, such as pruritus and rash; reproductive and endocrine symptoms, including extreme thirst, irregular menstruation, and sexual dysfunction; and new or exacerbated allergic response.⁹

Does severity of initial disease play a role?

Keep in mind that long COVID is not specific to patients who were hospitalized or had severe initial infection. In fact, 75% of patients who have a diagnosis of a post–COVID-19 condition were not hospitalized for their initial infection.⁷ However, the severity of initial COVID-19 infection might contribute to the presence or severity of long COVID symptoms²—although findings in current literature are mixed. For example:

• In reporting from Wuhan, China, higher position on a disease severity scale during a hospital stay for COVID-19 was associated with:
  • greater likelihood of reporting ≥ 1 symptoms at a 6-month ­follow-up
  • increased risk for pulmonary diffusion abnormalities, fatigue, and mood disorders.¹¹
• After 2 years’ follow-up of the same cohort, 55% of patients continued to report ≥ 1 symptoms of long COVID, and those who had been hospitalized with COVID-19 continued to report reduced health-related quality of life, compared to the control group.⁸
• Similarly, patients initially hospitalized with COVID-19 were more likely to experience impairment of ≥ 2 organs—in particular, the liver and pancreas—compared to nonhospitalized patients after a median 5 months post initial infection, among a sample in the United Kingdom.¹³
• In an international cohort, patients who reported a greater number of symptoms during initial COVID-19 were more likely to experience long COVID.¹²
• Last, long COVID fatigue did not vary by severity of initial COVID-19 infection among a sample of hospitalized and nonhospitalized participants in Dublin, Ireland.¹⁶

No specific treatments yet available

There are no specific treatments for long ­COVID; overall, the emphasis is on providing supportive care and managing preexisting chronic conditions.⁵ This is where expertise in primary care, relationships with patients and the community, and psychosocial knowledge can help patients recover from ongoing ­COVID-19 symptoms.

Long COVID–associated fatigue is more than simply being tired. Patients describe profound exhaustion, in which fatigue is out of proportion to exertion.

Clinicians should continue to perform a thorough physical assessment of patients with previous or ongoing COVID-19 to identify and monitor new or recurring symptoms after hospital discharge or initial resolution of symptoms.²⁹ This approach includes developing an individualized plan for care and rehabilitation that is specific to presenting symptoms, including psychological support. We encourage family physicians to familiarize themselves with the work of Vance and colleagues,³⁰ who have created a comprehensive table^a to guide treatment and referral for the gamut of long COVID symptoms, including cardiovascular issues (eg, palpitations, edema), chronic cough, headache, pain, and insomnia.

Continue to: This new clinical entity is a formidable challenge

Long COVID is a new condition that requires comprehensive evaluation to understand the full, often long-term, effects of COVID-19. Our review of this condition substantiated that symptoms of long COVID often affect a variety of organs^13,14 and have been observed to persist for ≥ 2 years.⁸

Some studies that have examined the long-term effects of COVID-19 included only participants who were not hospitalized; others include hospitalized patients exclusively. The literature is mixed in regard to including severity of initial infection as it relates to long COVID. Available research demonstrates that it is common for people with COVID-19 to experience persistent symptoms that can significantly impact daily life and well-being.

Likely, it will be several years before we even begin to understand the full extent of COVID-19. Until research elucidates the relationship between the disease and short- and long-term health outcomes, clinicians should:

• acknowledge and address the reality of long COVID when meeting with persistently symptomatic patients,
• provide support, therapeutic listening, and referral to rehabilitation as appropriate, and
• offer information on the potential for long-term effects of COVID-19 to vaccine-hesitant patients.

^a “Systems, symptoms, and treatments for post-COVID patients,” pages 1231-1234 in the source article (www.jabfm.org/content/jabfp/34/6/1229.full.pdf).³⁰

CORRESPONDENCE
Nicole Mayo, PhD, 46 Prince Street, Rochester, NY 14607; Nicole_Mayo@URMC.Rochester.edu

Several years into the pandemic, COVID-19 continues to deeply impact our society; at the time of publication of this review, 98.8 million cases in the United States have been reported to the Centers for Disease Control and Prevention (CDC).¹ Although many people recover well from infection, there is mounting concern regarding long-term sequelae of COVID-19. These long-term symptoms have been termed long COVID, among other names.

What exactly is long COVID?

The CDC and National Institutes of Health define long COVID as new or ongoing health problems experienced ≥ 4 weeks after initial infection.² Evidence suggests that even people who have mild initial COVID-19 symptoms are at risk for long COVID.

Available data about long COVID are imperfect, however; much about the condition remains poorly understood. For example, there is little evidence regarding the effect of vaccination and viral variants on the prevalence of long ­COVID. A recent study of more than 13 million people from the US Department of Veterans Affairs database did demonstrate that vaccination against SARS-CoV-2 lowered the risk for long ­COVID by only about 15%.³

Persistent symptoms associated with long COVID often lead to disability and decreased quality of life. Furthermore, long COVID is a challenge to treat because there is a paucity of evidence to guide COVID-19 treatment beyond initial infection.

The prevalence of long COVID symptoms appears to increase with age.

Because many patients who have ongoing COVID-19 symptoms will be seen in primary care, it is important to understand how to manage and support them. In this article, we discuss current understanding of long COVID epidemiology, symptoms that can persist 4 weeks after initial infection, and potential treatment options.

Prevalence and diagnosis

The prevalence of long COVID is not well defined because many epidemiologic studies rely on self-reporting. The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.⁴ Other studies variously cite 5% to 85% of people who have had a diagnosis of COVID-19 as experiencing long COVID, although that rate more consistently appears to be 10% to 30%.⁵

Copyright Brian Stauffer

A study of adult patients in France found that self-reported symptoms of long COVID, 10 to 12 months after the first wave of the pandemic (May through November 2020), were associated with the belief of having had COVID-19 but not necessarily with having tested positive for anti-SARS-CoV-2 antibodies,⁶ which indicates prior COVID-19. This complicates research on long COVID because, first, there is no specific test to confirm a diagnosis of long COVID and, second, studies often rely on self-reporting of earlier COVID-19.

Continue to: As such, long COVID...

As such, long COVID is diagnosed primarily through a medical history and physical examination. The medical history provides a guide as to whether additional testing is warranted to evaluate for known complications of COVID-19, such as deep vein thrombosis, pulmonary embolism, myocarditis, and pulmonary fibrosis. As of October 1, 2021, a new International Classification of Disease (10th Revision) code went into effect for post ­COVID condition, unspecified (U09.9).⁷

The prevalence of long COVID symptoms appears to increase with age. Among patients whose disease was diagnosed using code U09.9, most were 36 to 64 years of age; children and adults ages 22 years or younger constituted only 10.5% of diagnoses.⁷ Long COVID symptoms might also be more prevalent among women and in people with a preexisting chronic comorbidity.^2,7

Symptoms can be numerous, severe or mild, and lasting

Initially, there was no widely accepted definition of long COVID; follow-up in early studies ranged from 21 days to 2 years after initial infection (or from discharge, for hospitalized patients).⁸ Differences in descriptions that have been used on surveys to self-report symptoms make it a challenge to clearly summarize the frequency of each aspect of long COVID.

Long COVID can be mild or debilitating; severity can fluctuate. Common symptoms include fatigue, dyspnea or other breathing difficulties, headache, and cognitive dysfunction, but as many as 203 lasting symptoms have been reported.^2,8-12 From October 1, 2021, through January 31, 2022, the most common accompanying manifestations of long COVID were difficulty breathing, cough, and fatigue.⁷ Long COVID can affect multiple organ systems,^13,14 with symptoms varying by organ system affected. Regardless of the need for hospitalization initially, having had COVID-19 significantly increases the risk for subsequent death at 30 days and at 6 months after initial infection.¹⁵

The CDC reports that 20% to 25% of COVID-19 survivors experience a new condition that might be attributable to their initial infection.

Symptoms of long COVID have been reported as long as 2 years after initial infection.⁸ When Davis and colleagues studied the onset and progression of reported symptoms of long COVID,⁹ they determined that, among patients who reported recovery from COVID-19 in < 90 days, symptoms peaked at approximately Week 2 of infection. In comparison, patients who reported not having recovered in < 90 days had (1) symptoms that peaked later (2 months) and (2) on average, more symptoms (mean, 17 reported symptoms, compared to 11 in recovered ­patients).⁹

Continue to: Fatigue

Fatigue, including postexertion malaise and impaired daily function and mobility, is the most common symptom of long COVID,^8-10,14 reported in 28% to 98%¹⁴ of patients after initial COVID-19. This fatigue is more than simply being tired: Patients describe profound exhaustion, in which fatigue is out of proportion to exertion. Fatigue and myalgia are commonly reported among patients with impaired hepatic and pulmonary function as a consequence of long COVID.¹³ Patients often report that even minor activities result in decreased attention, focus, and energy, for many hours or days afterward. Fatigue has been reported to persist from 2.5 months to as long as 6 months after initial infection or hospitalization.^9,16

Postviral fatigue has been seen in other viral outbreaks and seems to share characteristics with myalgic encephalomyelitis/­chronic fatigue syndrome, or ME/CFS, which itself has historically been stigmatized and poorly understood.¹⁷ Long COVID fatigue might be more common among women and patients who have an existing diagnosis of depression and antidepressant use,^10,11,16,18 although the mechanism of this relationship is unclear. Potential mechanisms include damage from systemic inflammation to metabolism in the frontal lobe and cerebellum¹⁹ and direct infection by SARS-CoV-2 in skeletal muscle.²⁰ Townsend and colleagues¹⁶ found no relationship between long COVID fatigue and markers of inflammation (leukocyte, neutrophil, and lymphocyte counts; the neutrophil-to-lymphocyte ratio; lactate dehydrogenase; C-reactive protein; serum interleukin-6; and soluble CD25).

Neuropsychiatric symptoms are also common in long COVID and can have a significant impact on patients’ quality of life. Studies have reported poor sleep quality or insomnia (38% to 90%), headache (17% to 91.2%), speech and language problems (48% to 50%), confusion (20%), dementia (28.6%), difficulty concentrating (1.9% to 27%), and memory loss or cognitive impairment (5.4% to 73%).^9,10,14,15 For some patients, these symptoms persisted for ≥ 6 months, making it difficult for those affected to return to work.⁹

Isolation and loneliness, a common situation for patients with COVID-19, can have long-term effects on mental health.²¹ The COVID-19 pandemic itself has had a negative effect on behavioral health, including depression (4.3% to 25% of patients), anxiety (1.9% to 46%), obsessive compulsive disorder (4.9% to 20%), and posttraumatic stress disorder (29%).²² The persistence of symptoms of long COVID has resulted in a great deal of frustration, fear, and confusion for those affected—some of whom report a loss of trust in their community health care providers to address their ongoing struggles.²³ Such loss can be accompanied by a reported increase in feelings of anxiety and changes to perceptions of self (ie, “how I used to be” in contrast to “how I am now”).²³ These neuropsychiatric symptoms, including mental health conditions, appear to be more common among older adults.⁴

Other neurologic deficits found in long COVID include olfactory disorders (9% to 27% of patients), altered taste (5% to 18%), numbness or tingling sensations (6%), blurred vision (17.1%), and tinnitus (16.%).¹⁴ Dizziness (2.6% to 6%) and lightheadedness or presyncope (7%) have also been reported, although these symptoms appear to be less common than other neurocognitive effects.¹⁴

Continue to: The mechanism of action...

The mechanism of action of damage to the nervous system in long COVID is likely multifactorial. COVID-19 can directly infect the central nervous system through a hematogenous route, which can result in direct cytolytic damage to neurons. Infection can also affect the blood–brain barrier.²⁴ Additionally, COVID-19 can invade the central nervous system through peripheral nerves, including the olfactory and vagus nerves.²⁵ Many human respiratory viruses, including SARS-CoV-2, result in an increase in pro-inflammatory and anti-inflammatory cytokines; this so-called cytokine storm is an exaggerated response to infection and can trigger neurodegenerative and psychiatric syndromes.²⁶ It is unclear whether the cytokine storm is different for people with COVID-19, compared to other respiratory viruses.

Respiratory symptoms are very common after COVID-19¹⁵: In studies, as many as 87.1% of patients continued to have shortness of breath ≥ 140 days after initial symptom onset, including breathlessness (48% to 60%), wheezing (5.3%), cough (10.5% to 46%), and congestion (32%),^14,18 any of which can persist for as long as 6 months.⁹ Among a sample of previously hospitalized COVID-19 patients in Wuhan, China, 22% to 56% displayed a pulmonary diffusion abnormality 6 months later, with those who required supplemental oxygen during initial COVID-19 having a greater risk for these abnormalities at follow-up, compared to those who did not require supplemental oxygen (odds ratio = 2.42; 95% CI, 1.15-5.08).¹¹

Cardiovascular symptoms. New-onset autonomic dysfunction has been described in multiple case reports and in some larger cohort studies of patients post COVID-19.²⁷ Many common long COVID symptoms, including fatigue and orthostatic intolerance, are commonly seen in postural orthostatic tachycardia syndrome. Emerging evidence indicates that there are likely similar underlying mechanisms and a significant amount of overlap between long COVID and postural orthostatic tachycardia syndrome.²⁷

The high rate of cardiac complications post COVID-19 highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

A study of patients within the US Department of Veterans Affairs population found that, regardless of disease severity, patients who had a positive COVID-19 test had a higher rate of cardiac disease 30 days after diagnosis,²⁸ including stroke, transient ischemic attack, dysrhythmia, inflammatory heart disease, acute coronary disease, myocardial infarction, ischemic cardiopathy, angina, heart failure, nonischemic cardiomyopathy, and cardiac arrest. Patients with COVID-19 were at increased risk for major adverse cardiovascular events (myocardial infarction, stroke, and all-cause mortality).²⁸ Demographics of the VA population (ie, most are White men) might limit the generalizability of these data, but similar findings have been found elsewhere.^5,10,15Given that, in general, chest pain is common after the acute phase of an infection and the causes of chest pain are broad, the high rate of cardiac complications post COVID-19 nevertheless highlights the importance of a thorough evaluation and work-up of chest pain in patients who have had COVID-19.

Other symptoms. Body aches and generalized joint pain are another common symptom group of long COVID.⁹ These include body aches (20%), joint pain (78%), and muscle aches (87.7%).^14,18

Continue to: Commonly reported...

Commonly reported gastrointestinal symptoms include diarrhea, loss of appetite, nausea, and abdominal pain.^9,15

Other symptoms reported less commonly include dermatologic conditions, such as pruritus and rash; reproductive and endocrine symptoms, including extreme thirst, irregular menstruation, and sexual dysfunction; and new or exacerbated allergic response.⁹

Does severity of initial disease play a role?

Keep in mind that long COVID is not specific to patients who were hospitalized or had severe initial infection. In fact, 75% of patients who have a diagnosis of a post–COVID-19 condition were not hospitalized for their initial infection.⁷ However, the severity of initial COVID-19 infection might contribute to the presence or severity of long COVID symptoms²—although findings in current literature are mixed. For example:

• In reporting from Wuhan, China, higher position on a disease severity scale during a hospital stay for COVID-19 was associated with:
  • greater likelihood of reporting ≥ 1 symptoms at a 6-month ­follow-up
  • increased risk for pulmonary diffusion abnormalities, fatigue, and mood disorders.¹¹
• After 2 years’ follow-up of the same cohort, 55% of patients continued to report ≥ 1 symptoms of long COVID, and those who had been hospitalized with COVID-19 continued to report reduced health-related quality of life, compared to the control group.⁸
• Similarly, patients initially hospitalized with COVID-19 were more likely to experience impairment of ≥ 2 organs—in particular, the liver and pancreas—compared to nonhospitalized patients after a median 5 months post initial infection, among a sample in the United Kingdom.¹³
• In an international cohort, patients who reported a greater number of symptoms during initial COVID-19 were more likely to experience long COVID.¹²
• Last, long COVID fatigue did not vary by severity of initial COVID-19 infection among a sample of hospitalized and nonhospitalized participants in Dublin, Ireland.¹⁶

No specific treatments yet available

There are no specific treatments for long ­COVID; overall, the emphasis is on providing supportive care and managing preexisting chronic conditions.⁵ This is where expertise in primary care, relationships with patients and the community, and psychosocial knowledge can help patients recover from ongoing ­COVID-19 symptoms.

Long COVID–associated fatigue is more than simply being tired. Patients describe profound exhaustion, in which fatigue is out of proportion to exertion.

Clinicians should continue to perform a thorough physical assessment of patients with previous or ongoing COVID-19 to identify and monitor new or recurring symptoms after hospital discharge or initial resolution of symptoms.²⁹ This approach includes developing an individualized plan for care and rehabilitation that is specific to presenting symptoms, including psychological support. We encourage family physicians to familiarize themselves with the work of Vance and colleagues,³⁰ who have created a comprehensive table^a to guide treatment and referral for the gamut of long COVID symptoms, including cardiovascular issues (eg, palpitations, edema), chronic cough, headache, pain, and insomnia.

Continue to: This new clinical entity is a formidable challenge

Long COVID is a new condition that requires comprehensive evaluation to understand the full, often long-term, effects of COVID-19. Our review of this condition substantiated that symptoms of long COVID often affect a variety of organs^13,14 and have been observed to persist for ≥ 2 years.⁸

Some studies that have examined the long-term effects of COVID-19 included only participants who were not hospitalized; others include hospitalized patients exclusively. The literature is mixed in regard to including severity of initial infection as it relates to long COVID. Available research demonstrates that it is common for people with COVID-19 to experience persistent symptoms that can significantly impact daily life and well-being.

Likely, it will be several years before we even begin to understand the full extent of COVID-19. Until research elucidates the relationship between the disease and short- and long-term health outcomes, clinicians should:

• acknowledge and address the reality of long COVID when meeting with persistently symptomatic patients,
• provide support, therapeutic listening, and referral to rehabilitation as appropriate, and
• offer information on the potential for long-term effects of COVID-19 to vaccine-hesitant patients.

^a “Systems, symptoms, and treatments for post-COVID patients,” pages 1231-1234 in the source article (www.jabfm.org/content/jabfp/34/6/1229.full.pdf).³⁰

CORRESPONDENCE
Nicole Mayo, PhD, 46 Prince Street, Rochester, NY 14607; Nicole_Mayo@URMC.Rochester.edu

Multidrug-resistant gram-negative infections (MDRGNIs) are an emerging and deadly threat worldwide. Some of these infections are now resistant to nearly all antibiotics, and very few treatment options exist. Some of the remaining antibiotics for these MDRGNIs can cause acute kidney injury and have other toxic effects and can worsen antibiotic resistance. When deciding which drugs to use, clinicians need to juggle the possible lethality of the infection with the dangers of its treatment.

Samuel Windham, MD, and Marin H. Kollef, MD, authors of a recent article in Current Opinion in Infectious Diseases, express this urgency. They offer recommendations based on current guidelines and recently published research for treating MDRGNIs with some of the newer antibiotics.

Dr. Kollef, professor of pulmonary and critical care medicine at Washington University in St. Louis, said in an email, “Our recommendations differ in that they offer an approach that is based on disease severity, local resistance prevalence in MDRGNIs, and patient risk factors for infection with MDRGNIs. For patients with severe infection and risk factors for infection with MDRGNIs, we suggest empiric coverage for MDRGNIs until susceptibility data are available or based on rapid molecular testing. Selection of antibiotic therapy would be based on which MDRGNIs predominate locally.”

In their article, the authors discuss how to best utilize the newer antibiotics of ceftazidime-avibactam (CZA), cefiderocol, ceftolozane-tazobactam (C/T), meropenem-vaborbactam (MVB), imipenem-relebactam (I-R), aztreonam-avibactam (ATM-AVI), eravacycline, and plazomicin.
 

The scope of the problem

Bacterial infections are deadly and are becoming less treatable. The Centers for Disease Control and Prevention reported in 2022 that the COVID-19 pandemic has reversed years of decreases in health care–associated infections. Much of the increase has been caused by multidrug-resistant organisms.

In November 2022, authors of an article published in The Lancet estimated worldwide deaths from 33 bacterial genera across 11 infectious syndromes. They found that these infections were the second leading cause of death worldwide in 2019 (ischemic heart disease was the first). Furthermore, they discovered that 54.9% of these deaths were attributable to just five pathogens – Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Three of those five bacterial species – E. coli, K. pneumoniae, and P. aeruginosa – are gram-negative and are highly prone to drug resistance.

The CDC classified each of those three pathogens as an “urgent threat” in its 2019 Antibiotic Resistance Threats in the United States report. Of particular concern are gram-negative infections that have become resistant to carbapenems, a heavy-hitting class of antibiotics.

Regarding organisms that cause MDRGNIs, the major groups of concern are those that produce compounds that destroy antibiotics such as extended-spectrum beta-lactamases, AmpC beta-lactamases, and the carbapenemases known as serine-beta-lactamases (OXA, KPC, and CTX-M) and metallo-beta-lactamases (NDM, VIM, and IMP). Carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumanii also produce carbapenemases, rendering them invulnerable to carbapenem antibiotics.

Traditionally, a common alternative used for carbapenem-resistant infections has been colistin, an older and very toxic antibiotic. The authors cite recent research demonstrating that CZA yields significantly better outcomes with regard to patient mortality and acute kidney injury than colistin and that CZA plus aztreonam can even decrease mortality and length of hospital stay for patients who have bloodstream infections with metallo-beta-lactamase-producing Enterobacterales, which are some of the hardest infections to treat.

“CZA has been demonstrated to have excellent activity against MDR Pseudomonas aeruginosa and KPC Enterobacterales. It should be the preferred agent for use, compared with colistin, for the treatment of carbapenem-resistant gram-negative bacteria susceptible to CZA. Moreover, CZA combined with aztreonam has been shown to be an effective treatment for metallo-beta-lactamase MDRGNIs,” Dr. Kollef said.
 

Four key recommendations for treating MDRGNIs

The authors base their recommendations, in addition to the recent studies they cite concerning CZA, upon two major guidelines on the treatment of MDRGNIs: the European Society of Clinical Microbiology and Infectious Diseases’ Guidelines for the Treatment of Infections Caused by Multidrug-Resistant Gram-Negative Bacilli, and the Infectious Diseases Society of America’s (IDSA’s) Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections (multiple documents, found here and here).

Dr. Windham and Dr. Kollef present a table showing the spectrum of activity of the newer antibiotics, as well as an algorithm for decision-making. They summarize their treatment recommendations, which are based upon the bacterial infection cultures or on historical risk (previous infection or colonization history). They encourage empiric treatment if there is an increased risk of death or the presence of shock. By pathogen, they recommend the following:

• For carbapenem-resistant Enterobacterales, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, imipenem-cilastatin-relabactam, or meropenem-vaborbactam. 
• For carbapenem-resistant Pseudomonas aeruginosa, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, imipenem-cilastatin-relabactam, or ceftolozane-tazobactam. 
• For carbapenem-resistant Acinetobacter baumanii, clinicians should treat patients with a cefiderocol backbone with or without the addition of plazomicin, eravacycline, or other older antibacterials. 
• For metallo-beta-lactamase-producing organisms, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, aztreonam, imipenem-cilastatin-relabactam, aztreonam, or aztreonam-avibactam. The authors acknowledge that evidence is limited on treating these infections.

“In general, ceftazidime-avibactam works pretty well in patients with MDRGNIs, and there is no evidence that any of the other new agents is conclusively better in treatment responses. CZA and ceftolozane-tazobactam were the first of the new antibiotics active against highly MDRGN to get approved, and they have been most widely used,” Cornelius “Neil” J. Clancy, MD, chief of the Infectious Diseases Section at the VA Pittsburgh Health Care System, explained. Dr. Clancy was not involved in the Windham-Kollef review article.

“As such, it is not surprising that resistance has emerged and that it has been reported more commonly than for some other agents. The issue of resistance will be considered again as IDSA puts together their update,” Dr. Clancy said.

“The IDSA guidelines are regularly updated. The next updated iteration will be online in early 2023,” said Dr. Clancy, who is also affiliated with IDSA. “Clinical and resistance data that have appeared since the last update in 2022 will be considered as the guidance is put together.”

In general, Dr. Kollef also recommends using a facility’s antibiogram. “They are useful in determining which MDRGN’s predominate locally,” he said.

Dr. Kollef is a consultant for Pfizer, Merck, and Shionogi. Dr. Clancy has received research funding from Merck and from the National Institutes of Health.

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

Multidrug-resistant gram-negative infections (MDRGNIs) are an emerging and deadly threat worldwide. Some of these infections are now resistant to nearly all antibiotics, and very few treatment options exist. Some of the remaining antibiotics for these MDRGNIs can cause acute kidney injury and have other toxic effects and can worsen antibiotic resistance. When deciding which drugs to use, clinicians need to juggle the possible lethality of the infection with the dangers of its treatment.

Samuel Windham, MD, and Marin H. Kollef, MD, authors of a recent article in Current Opinion in Infectious Diseases, express this urgency. They offer recommendations based on current guidelines and recently published research for treating MDRGNIs with some of the newer antibiotics.

Dr. Kollef, professor of pulmonary and critical care medicine at Washington University in St. Louis, said in an email, “Our recommendations differ in that they offer an approach that is based on disease severity, local resistance prevalence in MDRGNIs, and patient risk factors for infection with MDRGNIs. For patients with severe infection and risk factors for infection with MDRGNIs, we suggest empiric coverage for MDRGNIs until susceptibility data are available or based on rapid molecular testing. Selection of antibiotic therapy would be based on which MDRGNIs predominate locally.”

In their article, the authors discuss how to best utilize the newer antibiotics of ceftazidime-avibactam (CZA), cefiderocol, ceftolozane-tazobactam (C/T), meropenem-vaborbactam (MVB), imipenem-relebactam (I-R), aztreonam-avibactam (ATM-AVI), eravacycline, and plazomicin.
 

The scope of the problem

Bacterial infections are deadly and are becoming less treatable. The Centers for Disease Control and Prevention reported in 2022 that the COVID-19 pandemic has reversed years of decreases in health care–associated infections. Much of the increase has been caused by multidrug-resistant organisms.

In November 2022, authors of an article published in The Lancet estimated worldwide deaths from 33 bacterial genera across 11 infectious syndromes. They found that these infections were the second leading cause of death worldwide in 2019 (ischemic heart disease was the first). Furthermore, they discovered that 54.9% of these deaths were attributable to just five pathogens – Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Three of those five bacterial species – E. coli, K. pneumoniae, and P. aeruginosa – are gram-negative and are highly prone to drug resistance.

The CDC classified each of those three pathogens as an “urgent threat” in its 2019 Antibiotic Resistance Threats in the United States report. Of particular concern are gram-negative infections that have become resistant to carbapenems, a heavy-hitting class of antibiotics.

Regarding organisms that cause MDRGNIs, the major groups of concern are those that produce compounds that destroy antibiotics such as extended-spectrum beta-lactamases, AmpC beta-lactamases, and the carbapenemases known as serine-beta-lactamases (OXA, KPC, and CTX-M) and metallo-beta-lactamases (NDM, VIM, and IMP). Carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumanii also produce carbapenemases, rendering them invulnerable to carbapenem antibiotics.

Traditionally, a common alternative used for carbapenem-resistant infections has been colistin, an older and very toxic antibiotic. The authors cite recent research demonstrating that CZA yields significantly better outcomes with regard to patient mortality and acute kidney injury than colistin and that CZA plus aztreonam can even decrease mortality and length of hospital stay for patients who have bloodstream infections with metallo-beta-lactamase-producing Enterobacterales, which are some of the hardest infections to treat.

“CZA has been demonstrated to have excellent activity against MDR Pseudomonas aeruginosa and KPC Enterobacterales. It should be the preferred agent for use, compared with colistin, for the treatment of carbapenem-resistant gram-negative bacteria susceptible to CZA. Moreover, CZA combined with aztreonam has been shown to be an effective treatment for metallo-beta-lactamase MDRGNIs,” Dr. Kollef said.
 

Four key recommendations for treating MDRGNIs

The authors base their recommendations, in addition to the recent studies they cite concerning CZA, upon two major guidelines on the treatment of MDRGNIs: the European Society of Clinical Microbiology and Infectious Diseases’ Guidelines for the Treatment of Infections Caused by Multidrug-Resistant Gram-Negative Bacilli, and the Infectious Diseases Society of America’s (IDSA’s) Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections (multiple documents, found here and here).

Dr. Windham and Dr. Kollef present a table showing the spectrum of activity of the newer antibiotics, as well as an algorithm for decision-making. They summarize their treatment recommendations, which are based upon the bacterial infection cultures or on historical risk (previous infection or colonization history). They encourage empiric treatment if there is an increased risk of death or the presence of shock. By pathogen, they recommend the following:

• For carbapenem-resistant Enterobacterales, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, imipenem-cilastatin-relabactam, or meropenem-vaborbactam. 
• For carbapenem-resistant Pseudomonas aeruginosa, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, imipenem-cilastatin-relabactam, or ceftolozane-tazobactam. 
• For carbapenem-resistant Acinetobacter baumanii, clinicians should treat patients with a cefiderocol backbone with or without the addition of plazomicin, eravacycline, or other older antibacterials. 
• For metallo-beta-lactamase-producing organisms, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, aztreonam, imipenem-cilastatin-relabactam, aztreonam, or aztreonam-avibactam. The authors acknowledge that evidence is limited on treating these infections.

“In general, ceftazidime-avibactam works pretty well in patients with MDRGNIs, and there is no evidence that any of the other new agents is conclusively better in treatment responses. CZA and ceftolozane-tazobactam were the first of the new antibiotics active against highly MDRGN to get approved, and they have been most widely used,” Cornelius “Neil” J. Clancy, MD, chief of the Infectious Diseases Section at the VA Pittsburgh Health Care System, explained. Dr. Clancy was not involved in the Windham-Kollef review article.

“As such, it is not surprising that resistance has emerged and that it has been reported more commonly than for some other agents. The issue of resistance will be considered again as IDSA puts together their update,” Dr. Clancy said.

“The IDSA guidelines are regularly updated. The next updated iteration will be online in early 2023,” said Dr. Clancy, who is also affiliated with IDSA. “Clinical and resistance data that have appeared since the last update in 2022 will be considered as the guidance is put together.”

In general, Dr. Kollef also recommends using a facility’s antibiogram. “They are useful in determining which MDRGN’s predominate locally,” he said.

Dr. Kollef is a consultant for Pfizer, Merck, and Shionogi. Dr. Clancy has received research funding from Merck and from the National Institutes of Health.

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

Multidrug-resistant gram-negative infections (MDRGNIs) are an emerging and deadly threat worldwide. Some of these infections are now resistant to nearly all antibiotics, and very few treatment options exist. Some of the remaining antibiotics for these MDRGNIs can cause acute kidney injury and have other toxic effects and can worsen antibiotic resistance. When deciding which drugs to use, clinicians need to juggle the possible lethality of the infection with the dangers of its treatment.

Samuel Windham, MD, and Marin H. Kollef, MD, authors of a recent article in Current Opinion in Infectious Diseases, express this urgency. They offer recommendations based on current guidelines and recently published research for treating MDRGNIs with some of the newer antibiotics.

Dr. Kollef, professor of pulmonary and critical care medicine at Washington University in St. Louis, said in an email, “Our recommendations differ in that they offer an approach that is based on disease severity, local resistance prevalence in MDRGNIs, and patient risk factors for infection with MDRGNIs. For patients with severe infection and risk factors for infection with MDRGNIs, we suggest empiric coverage for MDRGNIs until susceptibility data are available or based on rapid molecular testing. Selection of antibiotic therapy would be based on which MDRGNIs predominate locally.”

In their article, the authors discuss how to best utilize the newer antibiotics of ceftazidime-avibactam (CZA), cefiderocol, ceftolozane-tazobactam (C/T), meropenem-vaborbactam (MVB), imipenem-relebactam (I-R), aztreonam-avibactam (ATM-AVI), eravacycline, and plazomicin.
 

The scope of the problem

Bacterial infections are deadly and are becoming less treatable. The Centers for Disease Control and Prevention reported in 2022 that the COVID-19 pandemic has reversed years of decreases in health care–associated infections. Much of the increase has been caused by multidrug-resistant organisms.

In November 2022, authors of an article published in The Lancet estimated worldwide deaths from 33 bacterial genera across 11 infectious syndromes. They found that these infections were the second leading cause of death worldwide in 2019 (ischemic heart disease was the first). Furthermore, they discovered that 54.9% of these deaths were attributable to just five pathogens – Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Three of those five bacterial species – E. coli, K. pneumoniae, and P. aeruginosa – are gram-negative and are highly prone to drug resistance.

The CDC classified each of those three pathogens as an “urgent threat” in its 2019 Antibiotic Resistance Threats in the United States report. Of particular concern are gram-negative infections that have become resistant to carbapenems, a heavy-hitting class of antibiotics.

Regarding organisms that cause MDRGNIs, the major groups of concern are those that produce compounds that destroy antibiotics such as extended-spectrum beta-lactamases, AmpC beta-lactamases, and the carbapenemases known as serine-beta-lactamases (OXA, KPC, and CTX-M) and metallo-beta-lactamases (NDM, VIM, and IMP). Carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumanii also produce carbapenemases, rendering them invulnerable to carbapenem antibiotics.

Traditionally, a common alternative used for carbapenem-resistant infections has been colistin, an older and very toxic antibiotic. The authors cite recent research demonstrating that CZA yields significantly better outcomes with regard to patient mortality and acute kidney injury than colistin and that CZA plus aztreonam can even decrease mortality and length of hospital stay for patients who have bloodstream infections with metallo-beta-lactamase-producing Enterobacterales, which are some of the hardest infections to treat.

“CZA has been demonstrated to have excellent activity against MDR Pseudomonas aeruginosa and KPC Enterobacterales. It should be the preferred agent for use, compared with colistin, for the treatment of carbapenem-resistant gram-negative bacteria susceptible to CZA. Moreover, CZA combined with aztreonam has been shown to be an effective treatment for metallo-beta-lactamase MDRGNIs,” Dr. Kollef said.
 

Four key recommendations for treating MDRGNIs

The authors base their recommendations, in addition to the recent studies they cite concerning CZA, upon two major guidelines on the treatment of MDRGNIs: the European Society of Clinical Microbiology and Infectious Diseases’ Guidelines for the Treatment of Infections Caused by Multidrug-Resistant Gram-Negative Bacilli, and the Infectious Diseases Society of America’s (IDSA’s) Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections (multiple documents, found here and here).

Dr. Windham and Dr. Kollef present a table showing the spectrum of activity of the newer antibiotics, as well as an algorithm for decision-making. They summarize their treatment recommendations, which are based upon the bacterial infection cultures or on historical risk (previous infection or colonization history). They encourage empiric treatment if there is an increased risk of death or the presence of shock. By pathogen, they recommend the following:

• For carbapenem-resistant Enterobacterales, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, imipenem-cilastatin-relabactam, or meropenem-vaborbactam. 
• For carbapenem-resistant Pseudomonas aeruginosa, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, imipenem-cilastatin-relabactam, or ceftolozane-tazobactam. 
• For carbapenem-resistant Acinetobacter baumanii, clinicians should treat patients with a cefiderocol backbone with or without the addition of plazomicin, eravacycline, or other older antibacterials. 
• For metallo-beta-lactamase-producing organisms, clinicians should treat patients with cefiderocol, ceftazidime-avibactam, aztreonam, imipenem-cilastatin-relabactam, aztreonam, or aztreonam-avibactam. The authors acknowledge that evidence is limited on treating these infections.

“In general, ceftazidime-avibactam works pretty well in patients with MDRGNIs, and there is no evidence that any of the other new agents is conclusively better in treatment responses. CZA and ceftolozane-tazobactam were the first of the new antibiotics active against highly MDRGN to get approved, and they have been most widely used,” Cornelius “Neil” J. Clancy, MD, chief of the Infectious Diseases Section at the VA Pittsburgh Health Care System, explained. Dr. Clancy was not involved in the Windham-Kollef review article.

“As such, it is not surprising that resistance has emerged and that it has been reported more commonly than for some other agents. The issue of resistance will be considered again as IDSA puts together their update,” Dr. Clancy said.

“The IDSA guidelines are regularly updated. The next updated iteration will be online in early 2023,” said Dr. Clancy, who is also affiliated with IDSA. “Clinical and resistance data that have appeared since the last update in 2022 will be considered as the guidance is put together.”

In general, Dr. Kollef also recommends using a facility’s antibiogram. “They are useful in determining which MDRGN’s predominate locally,” he said.

Dr. Kollef is a consultant for Pfizer, Merck, and Shionogi. Dr. Clancy has received research funding from Merck and from the National Institutes of Health.

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

COVID-19 has lifted the lid on the risks of secondary pulmonary fungal infections in patients with severe respiratory viral illness – even previously immunocompetent individuals – and highlighted the importance of vigilant investigation to achieve early diagnoses, leading experts say.

Kathryn Kon/Science Photo Library/Getty Images

Most fungi are not under surveillance in the United States, leaving experts without a national picture of the true burden of infection through the pandemic. However, a collection of published case series, cohort studies, and reviews from Europe, the United States, and throughout the world – mainly pre-Omicron – show that fungal disease has affected a significant portion of critically ill patients with COVID-19, with concerning excess mortality, these experts say.

COVID-associated pulmonary aspergillosis (CAPA) has been the predominant fungal coinfection in the United States and internationally. But COVID-associated mucormycosis (CAM) – the infection that surged in India in early 2021 – has also affected some patients in the United States, published data show. So have Pneumocystitis pneumonia, cryptococcosis, histoplasmosis, and Candida infections (which mainly affect the bloodstream and abdomen), say the experts who were interviewed.

“We had predicted [a rise in] aspergillosis, but we saw more than we thought we’d see. Most fungal infections became more common with COVID-19,” said George Thompson, MD, professor of clinical medicine at the University of California, Davis, and cochair of the University of Alabama–based Mycoses Study Group Education Committee, a group of experts in medical mycology. Pneumocystitis, for instance, “has historically been associated with AIDS or different types of leukemia or lymphoma, and is not an infection we’ve typically seen in our otherwise healthy ICU patients,” he noted. “But we did see more of it [with COVID-19].”

More recently, with fewer patients during the Omicron phase in intensive care units with acute respiratory failure, the profile of fungal disease secondary to COVID-19 has changed. Increasing proportions of patients have traditional risk factors for aspergillosis, such as hematologic malignancies and longer-term, pre-COVID use of systemic corticosteroids – a change that makes the contribution of the viral illness harder to distinguish.

Moving forward, the lessons of the COVID era – the fungal risks to patients with serious viral infections and the persistence needed to diagnose aspergillosis and other pulmonary fungal infections using bronchoscopy and imperfect noninvasive tests – should be taken to heart, experts say.

“Fungal diseases are not rare. They’re just not diagnosed because no one thinks to look for them,” said Dr. Thompson, a contributor to a recently released World Health Organization report naming a “fungal priority pathogens” list.

“We’re going to continue to see [secondary fungal infections] with other respiratory viruses,” he said. And overall, given environmental and other changes, “we’re going to see more and more fungal disease in the patients we take care of.”


 

CAPA not a surprise

CAPA is “not an unfamiliar story” in the world of fungal disease, given a history of influenza-associated pulmonary aspergillosis (IAPA), said Kieren A. Marr, MD, MBA, adjunct professor of medicine and past director of the transplant and oncology infectious diseases program at Johns Hopkins University, Baltimore, who has long researched invasive fungal disease.

European researchers, she said, have led the way in describing a high incidence of IAPA in patients admitted to ICUs with influenza. In a retrospective multicenter cohort study reported in 2018 by the Dutch-Belgian Mycosis Study group, for instance, almost 20% of 432 influenza patients admitted to the ICU, including patients who were otherwise healthy and not immunocompromised, had the diagnosis a median of 3 days after ICU admission. (Across other cohort studies, rates of IAPA have ranged from 7% to 30%.)

Mortality was significant: 51% of patients with influenza and invasive pulmonary aspergillosis died within 90 days, compared with 28% of patients with influenza and no invasive pulmonary aspergillosis.

Reports from Europe early in the pandemic indicated that CAPA was a similarly serious problem, prompting establishment at Johns Hopkins University of an aggressive screening program utilizing biomarker-based testing of blood and bronchoalveolar lavage (BAL) fluid. Of 396 mechanically ventilated COVID-19 patients admitted to Johns Hopkins University hospitals between March and August 2020, 39 met the institution’s criteria for CAPA, Dr. Marr and her colleagues reported this year in what might be the largest U.S. cohort study of CAPA published to date.

“We now know definitively that people with severe influenza and with severe COVID also have high risks for both invasive and airway disease caused by airborne fungi, most commonly aspergilliosis,” Dr. Marr said.

More recent unpublished analyses of patients from the start of the pandemic to June 2021 show persistent risk, said Nitipong Permpalung, MD, MPH, assistant professor in transplant and oncology infectious diseases at Johns Hopkins University and lead author of the cohort study. Among 832 patients with COVID-19 who were mechanically ventilated in Johns Hopkins University hospitals, 11.8% had CAPA, he said. (Also, 3.2% had invasive candidiasis, and 1.1% had other invasive fungal infections.)

Other sources said in interviews that these CAPA prevalence rates generally mirror reports from Europe, though some investigators in Europe have reported CAPA rates more toward 15%.

(The Mycoses Study Group recently collected data from its consortium of U.S. medical centers on the prevalence of CAPA, with funding support from the CDC, but at press time the data had not yet been released. Dr. Thompson said he suspected the prevalence will be lower than earlier papers have suggested, “but still will reflect a significant burden of disease.”)

Patients in the published Johns Hopkins University study who had CAPA were more likely than those with COVID-19 but no CAPA to have underlying pulmonary disease, liver disease, coagulopathy, solid tumors, multiple myeloma, and COVID-19–directed corticosteroids. And they had uniformly worse outcomes with regards to severity of illness and length of intubation.

How much of CAPA is driven by the SARS-CoV-2 virus itself and how much is a consequence of COVID-19 treatments is a topic of active discussion and research. Martin Hoenigl, MD, of the University of Graz, Austria, a leading researcher in medical mycology, said research shows corticosteroids and anti–IL-6 treatments, such as tocilizumab, used to treat COVID-19–driven acute respiratory failure clearly have contributed to CAPA. But he contends that “a number of other mechanisms” are involved as well.

“The immunologic mechanisms are definitely different in these patients with viral illness than in other ICU patients [who develop aspergilliosis]. It’s not just the corticosteroids. The more we learn, we see the virus plays a role as well, suppressing the interferon pathway,” for example, said Dr. Hoenigl, associate professor in the division of infectious diseases and the European Confederation of Medical Mycology (ECMM) Center of Excellence at the university. The earliest reports of CAPA came “when ICUs weren’t using dexamethasone or tocilizumab,” he noted.

In a paper published recently in Lancet Respiratory Medicine that Dr. Hoenigl and others point to, Belgian researchers reported a “three-level breach” in innate antifungal immunity in both IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytose and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils.

The researchers ran a host of genetic and protein analyses on lung samples (most collected via BAL) of 169 patients with influenza or COVID-19, with and without aspergillosis. They found that patients with CAPA had significantly lower neutrophil cell fractions than patients with COVID-19 only, and patients with IAPA or CAPA had reduced type II IFN signaling and increased concentrations of fibrosis-associated growth factors in the lower respiratory tracts (Lancet Respir Med. 2022 Aug 24).

Tom Chiller, MD, MPH, chief of the Center for Disease Control and Prevention’s Mycotic Disease Branch, said he’s watching such research with interest. For now, he said, it’s important to also consider that “data on COVID show that almost all patients going into the ICUs with pneumonia and COVID are getting broad-spectrum antibiotics” in addition to corticosteroids.

By wiping out good bacteria, the antibiotics could be “creating a perfect niche for fungi to grow,” he said.


 

Diagnostic challenges

Aspergillus that has invaded the lung tissue in patients with COVID-19 appears to grow there for some time – around 8-10 days, much longer than in IAPA – before becoming angioinvasive, said Dr. Hoenigl. Such a pathophysiology “implicates that we should try to diagnose it while it’s in the lung tissue, using the BAL fluid, and not yet in the blood,” he said.

Some multicenter studies, including one from Europe on Aspergillus test profiles in critically ill COVID-19 patients, have shown mortality rates of close to 90% in patients with CAPA who have positive serum biomarkers, despite appropriate antifungal therapy. “If diagnosed while confined to the lung, however, mortality rates are more like 40%-50% with antifungal therapy,” Dr. Hoenigl said. (Cohort studies published thus far have fairly consistently reported mortality rates in patients with CAPA greater than 40%, he said.)

Bronchoscopy isn’t always pragmatic or possible, however, and is variably used. Some patients with severe COVID-19 may be too unstable for any invasive procedure, said Dr. Permpalung.

Dr. Permpalung looks for CAPA using serum (1-3) beta-D-glucan (BDG, a generic fungal test not specific to Aspergillus), serum galactomannan (GM, specific for Aspergillus), and respiratory cultures (sputum or endotracheal aspirate if intubated) as initial screening tests in the ICU. If there are concerns for CAPA – based on these tests and/or the clinical picture – “a thoughtful risk-benefit discussion is required to determine if patients would benefit from a bronchoscopy or if we should just start them on empiric antifungal therapy.”

Unfortunately, the sensitivity of serum GM is relatively low in CAPA – lower than with classic invasive aspergillosis in the nonviral setting, sources said. BDG, on the other hand, can be falsely positive in the setting of antimicrobials and within the ICU. And the utility of imaging for CAPA is limited. Both the clinical picture and radiological findings of CAPA have resembled those of severe COVID – with the caveat of cavitary lung lesions visible on imaging.

“Cavities or nodules are a highly suspicious finding that could indicate possible fungal infection,” said pulmonologist Amir A. Zeki, MD, MAS, professor of medicine at the University of California, Davis, and codirector of the UC Davis Asthma Network Clinic, who has cared for patients with CAPA.

Cavitation has been described in only a proportion of patients with CAPA, however. So in patients not doing well, “your suspicion has to be raised if you’re not seeing cavities,” he said.

Early in the pandemic, when patients worsened or failed to progress on mechanical ventilation, clinicians at the University of California, Davis, quickly learned not to pin blame too quickly on COVID-19 alone. This remains good advice today, Dr. Zeki said.

“If you have a patient who’s not doing well on a ventilator, not getting better [over weeks], has to be reintubated, has infiltrates or lung nodules that are evolving, or certainly, if they have a cavity, you have to suspect fungal infection,” said Dr. Zeki, who also practices at the Veterans Affairs Medical Center in San Diego. “Think about it for those patients who just aren’t moving forward and are continuing to struggle. Have a high index of suspicion, and consult with your infectious disease colleagues.”

Empiric treatment is warranted in some cases if a patient is doing poorly and suspicion for fungal infection is high based on clinical, radiographic, and/or laboratory evidence, he said.

The CDC’s Dr. Chiller said that screening and diagnostic algorithms currently vary from institution to institution, and that diagnostic challenges likely dissuade clinicians from thinking about fungi. “Clinicians often don’t want to deal with fungi – they’re difficult to diagnose, the treatments are limited and can be toxic. But fungi get pushed back until it’s too late,” he said.

“Fungal diagnostics is an area we all need a lot more help with,” and new diagnostics are in the pipeline, he said. In the meantime, he said, “there are tools out there, and we just need to use them more, and improve how they’re used.”

While reported CAPA thus far has typically occurred in the setting of ICU care and mechanical ventilation, it’s not always the case, Dr. Permpalung said. Lung and other solid organ transplant (SOT) recipients with COVID-19 are developing CAPA and other invasive secondary invasive fungal infections despite not being intubated, he said.

Of 276 SOT recipients with COVID-19 who required inpatient treatment at Johns Hopkins University hospitals from the beginning of the pandemic to March 2022, 23 patients developed invasive fungal infections (13 CAPA). Only a fraction – 38 of the 276 – had been intubated, he said.
 

Mucormycosis resistance

After CAPA, candidiasis and COVID-19-associated mucormycosis (CAM) – most frequently, rhino-orbital-cerebral disease or pulmonary disease – have been the leading reported fungal coinfections in COVID-19, said Dr. Hoenigl, who described the incidence, timeline, risk factors, and pathogenesis of these infections in a review published this year in Nature Microbiology. .

In India, where there has long been high exposure to Mucorales spores and a greater burden of invasive fungal disease, the rate of mucormycosis doubled in 2021, with rhino-orbital-cerebral disease reported almost exclusively, he said. Pulmonary disease has occurred almost exclusively in the ICU setting and has been present in about 50% of cases outside of India, including Europe and the United States.

A preprint meta-analysis of CAM cases posted by the Lancet in July 2022, in which investigators analyzed individual data of 556 reported cases of COVID-19–associated CAM, shows diabetes and history of corticosteroid use present in most patients, and an overall mortality rate of 44.4%, most of which stems from cases of pulmonary or disseminated disease. Thirteen of the 556 reported cases were from the United States.

An important take-away from the analysis, Dr. Hoenigl said, is that Aspergillus coinfection was seen in 7% of patients and was associated with higher mortality. “It’s important to consider that coinfections [of Aspergillus and Mucorales] can exist,” Dr. Hoenigl said, noting that like CAPA, pulmonary CAM is likely underdiagnosed and underreported.

As with CAPA, the clinical and radiological features of pulmonary CAM largely overlap with those associated with COVID-19, and bronchoscopy plays a central role in definitive diagnosis. In the United States, a Mucorales PCR test for blood and BAL fluid is commercially available and used at some centers, Dr. Hoenigl said.

“Mucormycosis is always difficult to treat ... a lot of the treatments don’t work particularly well,” said Dr. Thompson. “With aspergillosis, we have better treatment options.”

Dr. Thompson worries, however, about treatment resistance becoming widespread. Resistance to azole antifungal agents “is already pretty widespread in northern Europe, particularly in the Netherlands and part of the U.K.” because of injudicious use of antifungals in agriculture, he said. “We’ve started to see a few cases [of azole-resistant aspergillosis in the United States] and know it will be more widespread soon.”

Treatment resistance is a focus of the new WHO fungal priority pathogens list – the first such report from the organization. Of the 19 fungi on the list, 4 were ranked as critical: Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans. Like Dr. Thompson, Dr. Hoenigl contributed to the WHO report.

Dr. Hoenigl reported grant/research support from Astellas, Merck, F2G, Gilread, Pfizer, and Scynexis. Dr. Marr disclosed employment and equity in Pearl Diagnostics and Sfunga Therapeutics. Dr. Thompson, Dr. Permpalung, and Dr. Zeki reported that they have no relevant financial disclosures.
 

COVID-19 has lifted the lid on the risks of secondary pulmonary fungal infections in patients with severe respiratory viral illness – even previously immunocompetent individuals – and highlighted the importance of vigilant investigation to achieve early diagnoses, leading experts say.

Kathryn Kon/Science Photo Library/Getty Images

Most fungi are not under surveillance in the United States, leaving experts without a national picture of the true burden of infection through the pandemic. However, a collection of published case series, cohort studies, and reviews from Europe, the United States, and throughout the world – mainly pre-Omicron – show that fungal disease has affected a significant portion of critically ill patients with COVID-19, with concerning excess mortality, these experts say.

COVID-associated pulmonary aspergillosis (CAPA) has been the predominant fungal coinfection in the United States and internationally. But COVID-associated mucormycosis (CAM) – the infection that surged in India in early 2021 – has also affected some patients in the United States, published data show. So have Pneumocystitis pneumonia, cryptococcosis, histoplasmosis, and Candida infections (which mainly affect the bloodstream and abdomen), say the experts who were interviewed.

“We had predicted [a rise in] aspergillosis, but we saw more than we thought we’d see. Most fungal infections became more common with COVID-19,” said George Thompson, MD, professor of clinical medicine at the University of California, Davis, and cochair of the University of Alabama–based Mycoses Study Group Education Committee, a group of experts in medical mycology. Pneumocystitis, for instance, “has historically been associated with AIDS or different types of leukemia or lymphoma, and is not an infection we’ve typically seen in our otherwise healthy ICU patients,” he noted. “But we did see more of it [with COVID-19].”

More recently, with fewer patients during the Omicron phase in intensive care units with acute respiratory failure, the profile of fungal disease secondary to COVID-19 has changed. Increasing proportions of patients have traditional risk factors for aspergillosis, such as hematologic malignancies and longer-term, pre-COVID use of systemic corticosteroids – a change that makes the contribution of the viral illness harder to distinguish.

Moving forward, the lessons of the COVID era – the fungal risks to patients with serious viral infections and the persistence needed to diagnose aspergillosis and other pulmonary fungal infections using bronchoscopy and imperfect noninvasive tests – should be taken to heart, experts say.

“Fungal diseases are not rare. They’re just not diagnosed because no one thinks to look for them,” said Dr. Thompson, a contributor to a recently released World Health Organization report naming a “fungal priority pathogens” list.

“We’re going to continue to see [secondary fungal infections] with other respiratory viruses,” he said. And overall, given environmental and other changes, “we’re going to see more and more fungal disease in the patients we take care of.”


 

CAPA not a surprise

CAPA is “not an unfamiliar story” in the world of fungal disease, given a history of influenza-associated pulmonary aspergillosis (IAPA), said Kieren A. Marr, MD, MBA, adjunct professor of medicine and past director of the transplant and oncology infectious diseases program at Johns Hopkins University, Baltimore, who has long researched invasive fungal disease.

European researchers, she said, have led the way in describing a high incidence of IAPA in patients admitted to ICUs with influenza. In a retrospective multicenter cohort study reported in 2018 by the Dutch-Belgian Mycosis Study group, for instance, almost 20% of 432 influenza patients admitted to the ICU, including patients who were otherwise healthy and not immunocompromised, had the diagnosis a median of 3 days after ICU admission. (Across other cohort studies, rates of IAPA have ranged from 7% to 30%.)

Mortality was significant: 51% of patients with influenza and invasive pulmonary aspergillosis died within 90 days, compared with 28% of patients with influenza and no invasive pulmonary aspergillosis.

Reports from Europe early in the pandemic indicated that CAPA was a similarly serious problem, prompting establishment at Johns Hopkins University of an aggressive screening program utilizing biomarker-based testing of blood and bronchoalveolar lavage (BAL) fluid. Of 396 mechanically ventilated COVID-19 patients admitted to Johns Hopkins University hospitals between March and August 2020, 39 met the institution’s criteria for CAPA, Dr. Marr and her colleagues reported this year in what might be the largest U.S. cohort study of CAPA published to date.

“We now know definitively that people with severe influenza and with severe COVID also have high risks for both invasive and airway disease caused by airborne fungi, most commonly aspergilliosis,” Dr. Marr said.

More recent unpublished analyses of patients from the start of the pandemic to June 2021 show persistent risk, said Nitipong Permpalung, MD, MPH, assistant professor in transplant and oncology infectious diseases at Johns Hopkins University and lead author of the cohort study. Among 832 patients with COVID-19 who were mechanically ventilated in Johns Hopkins University hospitals, 11.8% had CAPA, he said. (Also, 3.2% had invasive candidiasis, and 1.1% had other invasive fungal infections.)

Other sources said in interviews that these CAPA prevalence rates generally mirror reports from Europe, though some investigators in Europe have reported CAPA rates more toward 15%.

(The Mycoses Study Group recently collected data from its consortium of U.S. medical centers on the prevalence of CAPA, with funding support from the CDC, but at press time the data had not yet been released. Dr. Thompson said he suspected the prevalence will be lower than earlier papers have suggested, “but still will reflect a significant burden of disease.”)

Patients in the published Johns Hopkins University study who had CAPA were more likely than those with COVID-19 but no CAPA to have underlying pulmonary disease, liver disease, coagulopathy, solid tumors, multiple myeloma, and COVID-19–directed corticosteroids. And they had uniformly worse outcomes with regards to severity of illness and length of intubation.

How much of CAPA is driven by the SARS-CoV-2 virus itself and how much is a consequence of COVID-19 treatments is a topic of active discussion and research. Martin Hoenigl, MD, of the University of Graz, Austria, a leading researcher in medical mycology, said research shows corticosteroids and anti–IL-6 treatments, such as tocilizumab, used to treat COVID-19–driven acute respiratory failure clearly have contributed to CAPA. But he contends that “a number of other mechanisms” are involved as well.

“The immunologic mechanisms are definitely different in these patients with viral illness than in other ICU patients [who develop aspergilliosis]. It’s not just the corticosteroids. The more we learn, we see the virus plays a role as well, suppressing the interferon pathway,” for example, said Dr. Hoenigl, associate professor in the division of infectious diseases and the European Confederation of Medical Mycology (ECMM) Center of Excellence at the university. The earliest reports of CAPA came “when ICUs weren’t using dexamethasone or tocilizumab,” he noted.

In a paper published recently in Lancet Respiratory Medicine that Dr. Hoenigl and others point to, Belgian researchers reported a “three-level breach” in innate antifungal immunity in both IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytose and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils.

The researchers ran a host of genetic and protein analyses on lung samples (most collected via BAL) of 169 patients with influenza or COVID-19, with and without aspergillosis. They found that patients with CAPA had significantly lower neutrophil cell fractions than patients with COVID-19 only, and patients with IAPA or CAPA had reduced type II IFN signaling and increased concentrations of fibrosis-associated growth factors in the lower respiratory tracts (Lancet Respir Med. 2022 Aug 24).

Tom Chiller, MD, MPH, chief of the Center for Disease Control and Prevention’s Mycotic Disease Branch, said he’s watching such research with interest. For now, he said, it’s important to also consider that “data on COVID show that almost all patients going into the ICUs with pneumonia and COVID are getting broad-spectrum antibiotics” in addition to corticosteroids.

By wiping out good bacteria, the antibiotics could be “creating a perfect niche for fungi to grow,” he said.


 

Diagnostic challenges

Aspergillus that has invaded the lung tissue in patients with COVID-19 appears to grow there for some time – around 8-10 days, much longer than in IAPA – before becoming angioinvasive, said Dr. Hoenigl. Such a pathophysiology “implicates that we should try to diagnose it while it’s in the lung tissue, using the BAL fluid, and not yet in the blood,” he said.

Some multicenter studies, including one from Europe on Aspergillus test profiles in critically ill COVID-19 patients, have shown mortality rates of close to 90% in patients with CAPA who have positive serum biomarkers, despite appropriate antifungal therapy. “If diagnosed while confined to the lung, however, mortality rates are more like 40%-50% with antifungal therapy,” Dr. Hoenigl said. (Cohort studies published thus far have fairly consistently reported mortality rates in patients with CAPA greater than 40%, he said.)

Bronchoscopy isn’t always pragmatic or possible, however, and is variably used. Some patients with severe COVID-19 may be too unstable for any invasive procedure, said Dr. Permpalung.

Dr. Permpalung looks for CAPA using serum (1-3) beta-D-glucan (BDG, a generic fungal test not specific to Aspergillus), serum galactomannan (GM, specific for Aspergillus), and respiratory cultures (sputum or endotracheal aspirate if intubated) as initial screening tests in the ICU. If there are concerns for CAPA – based on these tests and/or the clinical picture – “a thoughtful risk-benefit discussion is required to determine if patients would benefit from a bronchoscopy or if we should just start them on empiric antifungal therapy.”

Unfortunately, the sensitivity of serum GM is relatively low in CAPA – lower than with classic invasive aspergillosis in the nonviral setting, sources said. BDG, on the other hand, can be falsely positive in the setting of antimicrobials and within the ICU. And the utility of imaging for CAPA is limited. Both the clinical picture and radiological findings of CAPA have resembled those of severe COVID – with the caveat of cavitary lung lesions visible on imaging.

“Cavities or nodules are a highly suspicious finding that could indicate possible fungal infection,” said pulmonologist Amir A. Zeki, MD, MAS, professor of medicine at the University of California, Davis, and codirector of the UC Davis Asthma Network Clinic, who has cared for patients with CAPA.

Cavitation has been described in only a proportion of patients with CAPA, however. So in patients not doing well, “your suspicion has to be raised if you’re not seeing cavities,” he said.

Early in the pandemic, when patients worsened or failed to progress on mechanical ventilation, clinicians at the University of California, Davis, quickly learned not to pin blame too quickly on COVID-19 alone. This remains good advice today, Dr. Zeki said.

“If you have a patient who’s not doing well on a ventilator, not getting better [over weeks], has to be reintubated, has infiltrates or lung nodules that are evolving, or certainly, if they have a cavity, you have to suspect fungal infection,” said Dr. Zeki, who also practices at the Veterans Affairs Medical Center in San Diego. “Think about it for those patients who just aren’t moving forward and are continuing to struggle. Have a high index of suspicion, and consult with your infectious disease colleagues.”

Empiric treatment is warranted in some cases if a patient is doing poorly and suspicion for fungal infection is high based on clinical, radiographic, and/or laboratory evidence, he said.

The CDC’s Dr. Chiller said that screening and diagnostic algorithms currently vary from institution to institution, and that diagnostic challenges likely dissuade clinicians from thinking about fungi. “Clinicians often don’t want to deal with fungi – they’re difficult to diagnose, the treatments are limited and can be toxic. But fungi get pushed back until it’s too late,” he said.

“Fungal diagnostics is an area we all need a lot more help with,” and new diagnostics are in the pipeline, he said. In the meantime, he said, “there are tools out there, and we just need to use them more, and improve how they’re used.”

While reported CAPA thus far has typically occurred in the setting of ICU care and mechanical ventilation, it’s not always the case, Dr. Permpalung said. Lung and other solid organ transplant (SOT) recipients with COVID-19 are developing CAPA and other invasive secondary invasive fungal infections despite not being intubated, he said.

Of 276 SOT recipients with COVID-19 who required inpatient treatment at Johns Hopkins University hospitals from the beginning of the pandemic to March 2022, 23 patients developed invasive fungal infections (13 CAPA). Only a fraction – 38 of the 276 – had been intubated, he said.
 

Mucormycosis resistance

After CAPA, candidiasis and COVID-19-associated mucormycosis (CAM) – most frequently, rhino-orbital-cerebral disease or pulmonary disease – have been the leading reported fungal coinfections in COVID-19, said Dr. Hoenigl, who described the incidence, timeline, risk factors, and pathogenesis of these infections in a review published this year in Nature Microbiology. .

In India, where there has long been high exposure to Mucorales spores and a greater burden of invasive fungal disease, the rate of mucormycosis doubled in 2021, with rhino-orbital-cerebral disease reported almost exclusively, he said. Pulmonary disease has occurred almost exclusively in the ICU setting and has been present in about 50% of cases outside of India, including Europe and the United States.

A preprint meta-analysis of CAM cases posted by the Lancet in July 2022, in which investigators analyzed individual data of 556 reported cases of COVID-19–associated CAM, shows diabetes and history of corticosteroid use present in most patients, and an overall mortality rate of 44.4%, most of which stems from cases of pulmonary or disseminated disease. Thirteen of the 556 reported cases were from the United States.

An important take-away from the analysis, Dr. Hoenigl said, is that Aspergillus coinfection was seen in 7% of patients and was associated with higher mortality. “It’s important to consider that coinfections [of Aspergillus and Mucorales] can exist,” Dr. Hoenigl said, noting that like CAPA, pulmonary CAM is likely underdiagnosed and underreported.

As with CAPA, the clinical and radiological features of pulmonary CAM largely overlap with those associated with COVID-19, and bronchoscopy plays a central role in definitive diagnosis. In the United States, a Mucorales PCR test for blood and BAL fluid is commercially available and used at some centers, Dr. Hoenigl said.

“Mucormycosis is always difficult to treat ... a lot of the treatments don’t work particularly well,” said Dr. Thompson. “With aspergillosis, we have better treatment options.”

Dr. Thompson worries, however, about treatment resistance becoming widespread. Resistance to azole antifungal agents “is already pretty widespread in northern Europe, particularly in the Netherlands and part of the U.K.” because of injudicious use of antifungals in agriculture, he said. “We’ve started to see a few cases [of azole-resistant aspergillosis in the United States] and know it will be more widespread soon.”

Treatment resistance is a focus of the new WHO fungal priority pathogens list – the first such report from the organization. Of the 19 fungi on the list, 4 were ranked as critical: Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans. Like Dr. Thompson, Dr. Hoenigl contributed to the WHO report.

Dr. Hoenigl reported grant/research support from Astellas, Merck, F2G, Gilread, Pfizer, and Scynexis. Dr. Marr disclosed employment and equity in Pearl Diagnostics and Sfunga Therapeutics. Dr. Thompson, Dr. Permpalung, and Dr. Zeki reported that they have no relevant financial disclosures.
 

COVID-19 has lifted the lid on the risks of secondary pulmonary fungal infections in patients with severe respiratory viral illness – even previously immunocompetent individuals – and highlighted the importance of vigilant investigation to achieve early diagnoses, leading experts say.

Kathryn Kon/Science Photo Library/Getty Images

Most fungi are not under surveillance in the United States, leaving experts without a national picture of the true burden of infection through the pandemic. However, a collection of published case series, cohort studies, and reviews from Europe, the United States, and throughout the world – mainly pre-Omicron – show that fungal disease has affected a significant portion of critically ill patients with COVID-19, with concerning excess mortality, these experts say.

COVID-associated pulmonary aspergillosis (CAPA) has been the predominant fungal coinfection in the United States and internationally. But COVID-associated mucormycosis (CAM) – the infection that surged in India in early 2021 – has also affected some patients in the United States, published data show. So have Pneumocystitis pneumonia, cryptococcosis, histoplasmosis, and Candida infections (which mainly affect the bloodstream and abdomen), say the experts who were interviewed.

“We had predicted [a rise in] aspergillosis, but we saw more than we thought we’d see. Most fungal infections became more common with COVID-19,” said George Thompson, MD, professor of clinical medicine at the University of California, Davis, and cochair of the University of Alabama–based Mycoses Study Group Education Committee, a group of experts in medical mycology. Pneumocystitis, for instance, “has historically been associated with AIDS or different types of leukemia or lymphoma, and is not an infection we’ve typically seen in our otherwise healthy ICU patients,” he noted. “But we did see more of it [with COVID-19].”

More recently, with fewer patients during the Omicron phase in intensive care units with acute respiratory failure, the profile of fungal disease secondary to COVID-19 has changed. Increasing proportions of patients have traditional risk factors for aspergillosis, such as hematologic malignancies and longer-term, pre-COVID use of systemic corticosteroids – a change that makes the contribution of the viral illness harder to distinguish.

Moving forward, the lessons of the COVID era – the fungal risks to patients with serious viral infections and the persistence needed to diagnose aspergillosis and other pulmonary fungal infections using bronchoscopy and imperfect noninvasive tests – should be taken to heart, experts say.

“Fungal diseases are not rare. They’re just not diagnosed because no one thinks to look for them,” said Dr. Thompson, a contributor to a recently released World Health Organization report naming a “fungal priority pathogens” list.

“We’re going to continue to see [secondary fungal infections] with other respiratory viruses,” he said. And overall, given environmental and other changes, “we’re going to see more and more fungal disease in the patients we take care of.”


 

CAPA not a surprise

CAPA is “not an unfamiliar story” in the world of fungal disease, given a history of influenza-associated pulmonary aspergillosis (IAPA), said Kieren A. Marr, MD, MBA, adjunct professor of medicine and past director of the transplant and oncology infectious diseases program at Johns Hopkins University, Baltimore, who has long researched invasive fungal disease.

European researchers, she said, have led the way in describing a high incidence of IAPA in patients admitted to ICUs with influenza. In a retrospective multicenter cohort study reported in 2018 by the Dutch-Belgian Mycosis Study group, for instance, almost 20% of 432 influenza patients admitted to the ICU, including patients who were otherwise healthy and not immunocompromised, had the diagnosis a median of 3 days after ICU admission. (Across other cohort studies, rates of IAPA have ranged from 7% to 30%.)

Mortality was significant: 51% of patients with influenza and invasive pulmonary aspergillosis died within 90 days, compared with 28% of patients with influenza and no invasive pulmonary aspergillosis.

Reports from Europe early in the pandemic indicated that CAPA was a similarly serious problem, prompting establishment at Johns Hopkins University of an aggressive screening program utilizing biomarker-based testing of blood and bronchoalveolar lavage (BAL) fluid. Of 396 mechanically ventilated COVID-19 patients admitted to Johns Hopkins University hospitals between March and August 2020, 39 met the institution’s criteria for CAPA, Dr. Marr and her colleagues reported this year in what might be the largest U.S. cohort study of CAPA published to date.

“We now know definitively that people with severe influenza and with severe COVID also have high risks for both invasive and airway disease caused by airborne fungi, most commonly aspergilliosis,” Dr. Marr said.

More recent unpublished analyses of patients from the start of the pandemic to June 2021 show persistent risk, said Nitipong Permpalung, MD, MPH, assistant professor in transplant and oncology infectious diseases at Johns Hopkins University and lead author of the cohort study. Among 832 patients with COVID-19 who were mechanically ventilated in Johns Hopkins University hospitals, 11.8% had CAPA, he said. (Also, 3.2% had invasive candidiasis, and 1.1% had other invasive fungal infections.)

Other sources said in interviews that these CAPA prevalence rates generally mirror reports from Europe, though some investigators in Europe have reported CAPA rates more toward 15%.

(The Mycoses Study Group recently collected data from its consortium of U.S. medical centers on the prevalence of CAPA, with funding support from the CDC, but at press time the data had not yet been released. Dr. Thompson said he suspected the prevalence will be lower than earlier papers have suggested, “but still will reflect a significant burden of disease.”)

Patients in the published Johns Hopkins University study who had CAPA were more likely than those with COVID-19 but no CAPA to have underlying pulmonary disease, liver disease, coagulopathy, solid tumors, multiple myeloma, and COVID-19–directed corticosteroids. And they had uniformly worse outcomes with regards to severity of illness and length of intubation.

How much of CAPA is driven by the SARS-CoV-2 virus itself and how much is a consequence of COVID-19 treatments is a topic of active discussion and research. Martin Hoenigl, MD, of the University of Graz, Austria, a leading researcher in medical mycology, said research shows corticosteroids and anti–IL-6 treatments, such as tocilizumab, used to treat COVID-19–driven acute respiratory failure clearly have contributed to CAPA. But he contends that “a number of other mechanisms” are involved as well.

“The immunologic mechanisms are definitely different in these patients with viral illness than in other ICU patients [who develop aspergilliosis]. It’s not just the corticosteroids. The more we learn, we see the virus plays a role as well, suppressing the interferon pathway,” for example, said Dr. Hoenigl, associate professor in the division of infectious diseases and the European Confederation of Medical Mycology (ECMM) Center of Excellence at the university. The earliest reports of CAPA came “when ICUs weren’t using dexamethasone or tocilizumab,” he noted.

In a paper published recently in Lancet Respiratory Medicine that Dr. Hoenigl and others point to, Belgian researchers reported a “three-level breach” in innate antifungal immunity in both IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytose and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils.

The researchers ran a host of genetic and protein analyses on lung samples (most collected via BAL) of 169 patients with influenza or COVID-19, with and without aspergillosis. They found that patients with CAPA had significantly lower neutrophil cell fractions than patients with COVID-19 only, and patients with IAPA or CAPA had reduced type II IFN signaling and increased concentrations of fibrosis-associated growth factors in the lower respiratory tracts (Lancet Respir Med. 2022 Aug 24).

Tom Chiller, MD, MPH, chief of the Center for Disease Control and Prevention’s Mycotic Disease Branch, said he’s watching such research with interest. For now, he said, it’s important to also consider that “data on COVID show that almost all patients going into the ICUs with pneumonia and COVID are getting broad-spectrum antibiotics” in addition to corticosteroids.

By wiping out good bacteria, the antibiotics could be “creating a perfect niche for fungi to grow,” he said.


 

Diagnostic challenges

Aspergillus that has invaded the lung tissue in patients with COVID-19 appears to grow there for some time – around 8-10 days, much longer than in IAPA – before becoming angioinvasive, said Dr. Hoenigl. Such a pathophysiology “implicates that we should try to diagnose it while it’s in the lung tissue, using the BAL fluid, and not yet in the blood,” he said.

Some multicenter studies, including one from Europe on Aspergillus test profiles in critically ill COVID-19 patients, have shown mortality rates of close to 90% in patients with CAPA who have positive serum biomarkers, despite appropriate antifungal therapy. “If diagnosed while confined to the lung, however, mortality rates are more like 40%-50% with antifungal therapy,” Dr. Hoenigl said. (Cohort studies published thus far have fairly consistently reported mortality rates in patients with CAPA greater than 40%, he said.)

Bronchoscopy isn’t always pragmatic or possible, however, and is variably used. Some patients with severe COVID-19 may be too unstable for any invasive procedure, said Dr. Permpalung.

Dr. Permpalung looks for CAPA using serum (1-3) beta-D-glucan (BDG, a generic fungal test not specific to Aspergillus), serum galactomannan (GM, specific for Aspergillus), and respiratory cultures (sputum or endotracheal aspirate if intubated) as initial screening tests in the ICU. If there are concerns for CAPA – based on these tests and/or the clinical picture – “a thoughtful risk-benefit discussion is required to determine if patients would benefit from a bronchoscopy or if we should just start them on empiric antifungal therapy.”

Unfortunately, the sensitivity of serum GM is relatively low in CAPA – lower than with classic invasive aspergillosis in the nonviral setting, sources said. BDG, on the other hand, can be falsely positive in the setting of antimicrobials and within the ICU. And the utility of imaging for CAPA is limited. Both the clinical picture and radiological findings of CAPA have resembled those of severe COVID – with the caveat of cavitary lung lesions visible on imaging.

“Cavities or nodules are a highly suspicious finding that could indicate possible fungal infection,” said pulmonologist Amir A. Zeki, MD, MAS, professor of medicine at the University of California, Davis, and codirector of the UC Davis Asthma Network Clinic, who has cared for patients with CAPA.

Cavitation has been described in only a proportion of patients with CAPA, however. So in patients not doing well, “your suspicion has to be raised if you’re not seeing cavities,” he said.

Early in the pandemic, when patients worsened or failed to progress on mechanical ventilation, clinicians at the University of California, Davis, quickly learned not to pin blame too quickly on COVID-19 alone. This remains good advice today, Dr. Zeki said.

“If you have a patient who’s not doing well on a ventilator, not getting better [over weeks], has to be reintubated, has infiltrates or lung nodules that are evolving, or certainly, if they have a cavity, you have to suspect fungal infection,” said Dr. Zeki, who also practices at the Veterans Affairs Medical Center in San Diego. “Think about it for those patients who just aren’t moving forward and are continuing to struggle. Have a high index of suspicion, and consult with your infectious disease colleagues.”

Empiric treatment is warranted in some cases if a patient is doing poorly and suspicion for fungal infection is high based on clinical, radiographic, and/or laboratory evidence, he said.

The CDC’s Dr. Chiller said that screening and diagnostic algorithms currently vary from institution to institution, and that diagnostic challenges likely dissuade clinicians from thinking about fungi. “Clinicians often don’t want to deal with fungi – they’re difficult to diagnose, the treatments are limited and can be toxic. But fungi get pushed back until it’s too late,” he said.

“Fungal diagnostics is an area we all need a lot more help with,” and new diagnostics are in the pipeline, he said. In the meantime, he said, “there are tools out there, and we just need to use them more, and improve how they’re used.”

While reported CAPA thus far has typically occurred in the setting of ICU care and mechanical ventilation, it’s not always the case, Dr. Permpalung said. Lung and other solid organ transplant (SOT) recipients with COVID-19 are developing CAPA and other invasive secondary invasive fungal infections despite not being intubated, he said.

Of 276 SOT recipients with COVID-19 who required inpatient treatment at Johns Hopkins University hospitals from the beginning of the pandemic to March 2022, 23 patients developed invasive fungal infections (13 CAPA). Only a fraction – 38 of the 276 – had been intubated, he said.
 

Mucormycosis resistance

After CAPA, candidiasis and COVID-19-associated mucormycosis (CAM) – most frequently, rhino-orbital-cerebral disease or pulmonary disease – have been the leading reported fungal coinfections in COVID-19, said Dr. Hoenigl, who described the incidence, timeline, risk factors, and pathogenesis of these infections in a review published this year in Nature Microbiology. .

In India, where there has long been high exposure to Mucorales spores and a greater burden of invasive fungal disease, the rate of mucormycosis doubled in 2021, with rhino-orbital-cerebral disease reported almost exclusively, he said. Pulmonary disease has occurred almost exclusively in the ICU setting and has been present in about 50% of cases outside of India, including Europe and the United States.

A preprint meta-analysis of CAM cases posted by the Lancet in July 2022, in which investigators analyzed individual data of 556 reported cases of COVID-19–associated CAM, shows diabetes and history of corticosteroid use present in most patients, and an overall mortality rate of 44.4%, most of which stems from cases of pulmonary or disseminated disease. Thirteen of the 556 reported cases were from the United States.

An important take-away from the analysis, Dr. Hoenigl said, is that Aspergillus coinfection was seen in 7% of patients and was associated with higher mortality. “It’s important to consider that coinfections [of Aspergillus and Mucorales] can exist,” Dr. Hoenigl said, noting that like CAPA, pulmonary CAM is likely underdiagnosed and underreported.

As with CAPA, the clinical and radiological features of pulmonary CAM largely overlap with those associated with COVID-19, and bronchoscopy plays a central role in definitive diagnosis. In the United States, a Mucorales PCR test for blood and BAL fluid is commercially available and used at some centers, Dr. Hoenigl said.

“Mucormycosis is always difficult to treat ... a lot of the treatments don’t work particularly well,” said Dr. Thompson. “With aspergillosis, we have better treatment options.”

Dr. Thompson worries, however, about treatment resistance becoming widespread. Resistance to azole antifungal agents “is already pretty widespread in northern Europe, particularly in the Netherlands and part of the U.K.” because of injudicious use of antifungals in agriculture, he said. “We’ve started to see a few cases [of azole-resistant aspergillosis in the United States] and know it will be more widespread soon.”

Treatment resistance is a focus of the new WHO fungal priority pathogens list – the first such report from the organization. Of the 19 fungi on the list, 4 were ranked as critical: Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans. Like Dr. Thompson, Dr. Hoenigl contributed to the WHO report.

Dr. Hoenigl reported grant/research support from Astellas, Merck, F2G, Gilread, Pfizer, and Scynexis. Dr. Marr disclosed employment and equity in Pearl Diagnostics and Sfunga Therapeutics. Dr. Thompson, Dr. Permpalung, and Dr. Zeki reported that they have no relevant financial disclosures.
 

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

As soon as the pandemic started, the search was on for a medication that could stave off infection, or at least the worst consequences of infection.

One that would be cheap to make, safe, easy to distribute, and, ideally, was already available. The search had a quest-like quality, like something from a fairy tale. Society, poisoned by COVID, would find the antidote out there, somewhere, if we looked hard enough.

You know the story. There were some pretty dramatic failures: hydroxychloroquine, ivermectin. There were some successes, like dexamethasone.

I’m not here today to tell you that the antidote has been found – no, it takes large randomized trials to figure that out. But I do want to tell you about a paper that, unlike so many that came before, lays out the argument for a potential COVID preventive so thoroughly and so rigorously, that it has convinced me that this little drug, ursodeoxycholic acid (UDCA) – you may know it as Actigall, used for an uncommon form of liver disease – may actually be useful to prevent COVID infection.

How do you make a case that an existing drug – UDCA, in this case – might be useful to prevent or treat COVID? In contrast to prior basic-science studies, like the original ivermectin study, which essentially took a bunch of cells and virus in a tube filled with varying concentrations of the antiparasitic agent, the authors of this paper appearing in Nature give us multiple, complementary lines of evidence. Let me walk you through it.

All good science starts with a biologically plausible hypothesis. In this case, the authors recognized that SARS-CoV-2, in all its variants, requires the presence of the ACE2 receptor on the surface of cells to bind.

Courtesy Innovative Genomics

Courtesy Nature

Courtesy Nature

Courtesy Nature

Courtesy Nature

Courtesy Dr. F. Perry Wilson

courtesy Nature

Courtesy Nature

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. He disclosed no relevant financial relationships.

A version of this video transcript first appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

As soon as the pandemic started, the search was on for a medication that could stave off infection, or at least the worst consequences of infection.

One that would be cheap to make, safe, easy to distribute, and, ideally, was already available. The search had a quest-like quality, like something from a fairy tale. Society, poisoned by COVID, would find the antidote out there, somewhere, if we looked hard enough.

You know the story. There were some pretty dramatic failures: hydroxychloroquine, ivermectin. There were some successes, like dexamethasone.

I’m not here today to tell you that the antidote has been found – no, it takes large randomized trials to figure that out. But I do want to tell you about a paper that, unlike so many that came before, lays out the argument for a potential COVID preventive so thoroughly and so rigorously, that it has convinced me that this little drug, ursodeoxycholic acid (UDCA) – you may know it as Actigall, used for an uncommon form of liver disease – may actually be useful to prevent COVID infection.

How do you make a case that an existing drug – UDCA, in this case – might be useful to prevent or treat COVID? In contrast to prior basic-science studies, like the original ivermectin study, which essentially took a bunch of cells and virus in a tube filled with varying concentrations of the antiparasitic agent, the authors of this paper appearing in Nature give us multiple, complementary lines of evidence. Let me walk you through it.

All good science starts with a biologically plausible hypothesis. In this case, the authors recognized that SARS-CoV-2, in all its variants, requires the presence of the ACE2 receptor on the surface of cells to bind.

Courtesy Innovative Genomics

Courtesy Nature

Courtesy Nature

Courtesy Nature

Courtesy Nature

Courtesy Dr. F. Perry Wilson

courtesy Nature

Courtesy Nature

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. He disclosed no relevant financial relationships.

A version of this video transcript first appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

As soon as the pandemic started, the search was on for a medication that could stave off infection, or at least the worst consequences of infection.

One that would be cheap to make, safe, easy to distribute, and, ideally, was already available. The search had a quest-like quality, like something from a fairy tale. Society, poisoned by COVID, would find the antidote out there, somewhere, if we looked hard enough.

You know the story. There were some pretty dramatic failures: hydroxychloroquine, ivermectin. There were some successes, like dexamethasone.

I’m not here today to tell you that the antidote has been found – no, it takes large randomized trials to figure that out. But I do want to tell you about a paper that, unlike so many that came before, lays out the argument for a potential COVID preventive so thoroughly and so rigorously, that it has convinced me that this little drug, ursodeoxycholic acid (UDCA) – you may know it as Actigall, used for an uncommon form of liver disease – may actually be useful to prevent COVID infection.

How do you make a case that an existing drug – UDCA, in this case – might be useful to prevent or treat COVID? In contrast to prior basic-science studies, like the original ivermectin study, which essentially took a bunch of cells and virus in a tube filled with varying concentrations of the antiparasitic agent, the authors of this paper appearing in Nature give us multiple, complementary lines of evidence. Let me walk you through it.

All good science starts with a biologically plausible hypothesis. In this case, the authors recognized that SARS-CoV-2, in all its variants, requires the presence of the ACE2 receptor on the surface of cells to bind.

Courtesy Innovative Genomics

Courtesy Nature

Courtesy Nature

Courtesy Nature

Courtesy Nature

Courtesy Dr. F. Perry Wilson

courtesy Nature

Courtesy Nature

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. He disclosed no relevant financial relationships.

A version of this video transcript first appeared on Medscape.com.

Nearly 6 million Americans have taken Paxlovid for free, courtesy of the federal government. The Pfizer pill has helped prevent many people infected with COVID-19 from being hospitalized or dying, and it may even reduce the risk of developing long COVID. But the government plans to stop footing the bill within months, and millions of people who are at the highest risk of severe illness and are least able to afford the drug – the uninsured and seniors – may have to pay the full price.

And that means fewer people will get the potentially lifesaving treatments, experts said.

“I think the numbers will go way down,” said Jill Rosenthal, director of public health policy at the Center for American Progress, a left-leaning think tank. A bill for several hundred dollars or more would lead many people to decide the medication isn’t worth the price, she said.

In response to the unprecedented public health crisis caused by COVID, the federal government spent billions of dollars on developing new vaccines and treatments, to swift success: Less than a year after the pandemic was declared, medical workers got their first vaccines. But as many people have refused the shots and stopped wearing masks, the virus still rages and mutates. In 2022 alone, 250,000 Americans have died from COVID, more than from strokes or diabetes.

But soon the Department of Health & Human Services will stop supplying COVID treatments, and pharmacies will purchase and bill for them the same way they do for antibiotic pills or asthma inhalers. Paxlovid is expected to hit the private market in mid-2023, according to HHS plans shared in an October meeting with state health officials and clinicians. Merck’s Lagevrio, a less-effective COVID treatment pill, and AstraZeneca’s Evusheld, a preventive therapy for the immunocompromised, are on track to be commercialized sooner, sometime in the winter.

The U.S. government has so far purchased 20 million courses of Paxlovid, priced at about $530 each, a discount for buying in bulk that Pfizer CEO Albert Bourla called “really very attractive” to the federal government in a July earnings call. The drug will cost far more on the private market, although in a statement to Kaiser Health News, Pfizer declined to share the planned price. The government will also stop paying for the company’s COVID vaccine next year – those shots will quadruple in price, from the discount rate the government pays of $30 to about $120.

Mr. Bourla told investors in November that he expects the move will make Paxlovid and its COVID vaccine “a multibillion-dollars franchise.”

Nearly 9 in 10 people dying from the virus now are 65 or older. Yet federal law restricts Medicare Part D – the prescription drug program that covers nearly 50 million seniors – from covering the COVID treatment pills. The medications are meant for those most at risk of serious illness, including seniors.

Paxlovid and the other treatments are currently available under an emergency use authorization from the FDA, a fast-track review used in extraordinary situations. Although Pfizer applied for full approval in June, the process can take anywhere from several months to years. And Medicare Part D can’t cover any medications without that full stamp of approval.

Paying out-of-pocket would be “a substantial barrier” for seniors on Medicare – the very people who would benefit most from the drug, wrote federal health experts.

“From a public health perspective, and even from a health care capacity and cost perspective, it would just defy reason to not continue to make these drugs readily available,” said Dr. Larry Madoff, medical director of Massachusetts’s Bureau of Infectious Disease and Laboratory Sciences. He’s hopeful that the federal health agency will find a way to set aside unused doses for seniors and people without insurance.

In mid-November, the White House requested that Congress approve an additional $2.5 billion for COVID therapeutics and vaccines to make sure people can afford the medications when they’re no longer free. But there’s little hope it will be approved – the Senate voted that same day to end the public health emergency and denied similar requests in recent months.

Many Americans have already faced hurdles just getting a prescription for COVID treatment. Although the federal government doesn’t track who’s gotten the drug, a Centers for Disease Control and Prevention study using data from 30 medical centers found that Black and Hispanic patients with COVID were much less likely to receive Paxlovid than White patients. (Hispanic people can be of any race or combination of races.) And when the government is no longer picking up the tab, experts predict that these gaps by race, income, and geography will widen.

People in Northeastern states used the drug far more often than those in the rest of the country, according to a KHN analysis of Paxlovid use in September and October. But it wasn’t because people in the region were getting sick from COVID at much higher rates – instead, many of those states offered better access to health care to begin with and created special programs to get Paxlovid to their residents.

About 10 mostly Democratic states and several large counties in the Northeast and elsewhere created free “test-to-treat” programs that allow their residents to get an immediate doctor visit and prescription for treatment after testing positive for COVID. In Massachusetts, more than 20,000 residents have used the state’s video and phone hotline, which is available 7 days a week in 13 languages. Massachusetts, which has the highest insurance rate in the country and relatively low travel times to pharmacies, had the second-highest Paxlovid usage rate among states this fall.

States with higher COVID death rates, like Florida and Kentucky, where residents must travel farther for health care and are more likely to be uninsured, used the drug less often. Without no-cost test-to-treat options, residents have struggled to get prescriptions even though the drug itself is still free.

“If you look at access to medications for people who are uninsured, I think that there’s no question that will widen those disparities,” Ms. Rosenthal said.

People who get insurance through their jobs could face high copays at the register, too, just as they do for insulin and other expensive or brand-name drugs.

Most private insurance companies will end up covering COVID therapeutics to some extent, said Sabrina Corlette, a research professor at Georgetown University’s Center on Health Insurance Reforms. After all, the pills are cheaper than a hospital stay. But for most people who get insurance through their jobs, there are “really no rules at all,” she said. Some insurers could take months to add the drugs to their plans or decide not to pay for them.

And the additional cost means many people will go without the medication. “We know from lots of research that when people face cost sharing for these drugs that they need to take, they will often forgo or cut back,” Ms. Corlette said.

One group doesn’t need to worry about sticker shock. Medicaid, the public insurance program for low-income adults and children, will cover the treatments in full until at least early 2024.

HHS officials could set aside any leftover taxpayer-funded medication for people who can’t afford to pay the full cost, but they haven’t shared any concrete plans to do so. The government purchased 20 million courses of Paxlovid and 3 million of Lagevrio. Fewer than a third have been used, and usage has fallen in recent months, according to KHN’s analysis of the data from HHS.

Sixty percent of the government’s supply of Evusheld is also still available, although the COVID prevention therapy is less effective against new strains of the virus. The health department in one state, New Mexico, has recommended against using it.

HHS did not make officials available for an interview or answer written questions about the commercialization plans.

The government created a potential workaround when they moved bebtelovimab, another COVID treatment, to the private market this summer. It now retails for $2,100 per patient. The agency set aside the remaining 60,000 government-purchased doses that hospitals could use to treat uninsured patients in a convoluted dose-replacement process. But it’s hard to tell how well that setup would work for Paxlovid: Bebtelovimab was already much less popular, and the FDA halted its use on Nov. 30 because it’s less effective against current strains of the virus.

Federal officials and insurance companies would have good reason to make sure patients can continue to afford COVID drugs: They’re far cheaper than if patients land in the emergency room.

“The medications are so worthwhile,” said Dr. Madoff, the Massachusetts health official. “They’re not expensive in the grand scheme of health care costs.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Nearly 6 million Americans have taken Paxlovid for free, courtesy of the federal government. The Pfizer pill has helped prevent many people infected with COVID-19 from being hospitalized or dying, and it may even reduce the risk of developing long COVID. But the government plans to stop footing the bill within months, and millions of people who are at the highest risk of severe illness and are least able to afford the drug – the uninsured and seniors – may have to pay the full price.

And that means fewer people will get the potentially lifesaving treatments, experts said.

“I think the numbers will go way down,” said Jill Rosenthal, director of public health policy at the Center for American Progress, a left-leaning think tank. A bill for several hundred dollars or more would lead many people to decide the medication isn’t worth the price, she said.

In response to the unprecedented public health crisis caused by COVID, the federal government spent billions of dollars on developing new vaccines and treatments, to swift success: Less than a year after the pandemic was declared, medical workers got their first vaccines. But as many people have refused the shots and stopped wearing masks, the virus still rages and mutates. In 2022 alone, 250,000 Americans have died from COVID, more than from strokes or diabetes.

But soon the Department of Health & Human Services will stop supplying COVID treatments, and pharmacies will purchase and bill for them the same way they do for antibiotic pills or asthma inhalers. Paxlovid is expected to hit the private market in mid-2023, according to HHS plans shared in an October meeting with state health officials and clinicians. Merck’s Lagevrio, a less-effective COVID treatment pill, and AstraZeneca’s Evusheld, a preventive therapy for the immunocompromised, are on track to be commercialized sooner, sometime in the winter.

The U.S. government has so far purchased 20 million courses of Paxlovid, priced at about $530 each, a discount for buying in bulk that Pfizer CEO Albert Bourla called “really very attractive” to the federal government in a July earnings call. The drug will cost far more on the private market, although in a statement to Kaiser Health News, Pfizer declined to share the planned price. The government will also stop paying for the company’s COVID vaccine next year – those shots will quadruple in price, from the discount rate the government pays of $30 to about $120.

Mr. Bourla told investors in November that he expects the move will make Paxlovid and its COVID vaccine “a multibillion-dollars franchise.”

Nearly 9 in 10 people dying from the virus now are 65 or older. Yet federal law restricts Medicare Part D – the prescription drug program that covers nearly 50 million seniors – from covering the COVID treatment pills. The medications are meant for those most at risk of serious illness, including seniors.

Paxlovid and the other treatments are currently available under an emergency use authorization from the FDA, a fast-track review used in extraordinary situations. Although Pfizer applied for full approval in June, the process can take anywhere from several months to years. And Medicare Part D can’t cover any medications without that full stamp of approval.

Paying out-of-pocket would be “a substantial barrier” for seniors on Medicare – the very people who would benefit most from the drug, wrote federal health experts.

“From a public health perspective, and even from a health care capacity and cost perspective, it would just defy reason to not continue to make these drugs readily available,” said Dr. Larry Madoff, medical director of Massachusetts’s Bureau of Infectious Disease and Laboratory Sciences. He’s hopeful that the federal health agency will find a way to set aside unused doses for seniors and people without insurance.

In mid-November, the White House requested that Congress approve an additional $2.5 billion for COVID therapeutics and vaccines to make sure people can afford the medications when they’re no longer free. But there’s little hope it will be approved – the Senate voted that same day to end the public health emergency and denied similar requests in recent months.

Many Americans have already faced hurdles just getting a prescription for COVID treatment. Although the federal government doesn’t track who’s gotten the drug, a Centers for Disease Control and Prevention study using data from 30 medical centers found that Black and Hispanic patients with COVID were much less likely to receive Paxlovid than White patients. (Hispanic people can be of any race or combination of races.) And when the government is no longer picking up the tab, experts predict that these gaps by race, income, and geography will widen.

People in Northeastern states used the drug far more often than those in the rest of the country, according to a KHN analysis of Paxlovid use in September and October. But it wasn’t because people in the region were getting sick from COVID at much higher rates – instead, many of those states offered better access to health care to begin with and created special programs to get Paxlovid to their residents.

About 10 mostly Democratic states and several large counties in the Northeast and elsewhere created free “test-to-treat” programs that allow their residents to get an immediate doctor visit and prescription for treatment after testing positive for COVID. In Massachusetts, more than 20,000 residents have used the state’s video and phone hotline, which is available 7 days a week in 13 languages. Massachusetts, which has the highest insurance rate in the country and relatively low travel times to pharmacies, had the second-highest Paxlovid usage rate among states this fall.

States with higher COVID death rates, like Florida and Kentucky, where residents must travel farther for health care and are more likely to be uninsured, used the drug less often. Without no-cost test-to-treat options, residents have struggled to get prescriptions even though the drug itself is still free.

“If you look at access to medications for people who are uninsured, I think that there’s no question that will widen those disparities,” Ms. Rosenthal said.

People who get insurance through their jobs could face high copays at the register, too, just as they do for insulin and other expensive or brand-name drugs.

Most private insurance companies will end up covering COVID therapeutics to some extent, said Sabrina Corlette, a research professor at Georgetown University’s Center on Health Insurance Reforms. After all, the pills are cheaper than a hospital stay. But for most people who get insurance through their jobs, there are “really no rules at all,” she said. Some insurers could take months to add the drugs to their plans or decide not to pay for them.

And the additional cost means many people will go without the medication. “We know from lots of research that when people face cost sharing for these drugs that they need to take, they will often forgo or cut back,” Ms. Corlette said.

One group doesn’t need to worry about sticker shock. Medicaid, the public insurance program for low-income adults and children, will cover the treatments in full until at least early 2024.

HHS officials could set aside any leftover taxpayer-funded medication for people who can’t afford to pay the full cost, but they haven’t shared any concrete plans to do so. The government purchased 20 million courses of Paxlovid and 3 million of Lagevrio. Fewer than a third have been used, and usage has fallen in recent months, according to KHN’s analysis of the data from HHS.

Sixty percent of the government’s supply of Evusheld is also still available, although the COVID prevention therapy is less effective against new strains of the virus. The health department in one state, New Mexico, has recommended against using it.

HHS did not make officials available for an interview or answer written questions about the commercialization plans.

The government created a potential workaround when they moved bebtelovimab, another COVID treatment, to the private market this summer. It now retails for $2,100 per patient. The agency set aside the remaining 60,000 government-purchased doses that hospitals could use to treat uninsured patients in a convoluted dose-replacement process. But it’s hard to tell how well that setup would work for Paxlovid: Bebtelovimab was already much less popular, and the FDA halted its use on Nov. 30 because it’s less effective against current strains of the virus.

Federal officials and insurance companies would have good reason to make sure patients can continue to afford COVID drugs: They’re far cheaper than if patients land in the emergency room.

“The medications are so worthwhile,” said Dr. Madoff, the Massachusetts health official. “They’re not expensive in the grand scheme of health care costs.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Nearly 6 million Americans have taken Paxlovid for free, courtesy of the federal government. The Pfizer pill has helped prevent many people infected with COVID-19 from being hospitalized or dying, and it may even reduce the risk of developing long COVID. But the government plans to stop footing the bill within months, and millions of people who are at the highest risk of severe illness and are least able to afford the drug – the uninsured and seniors – may have to pay the full price.

And that means fewer people will get the potentially lifesaving treatments, experts said.

“I think the numbers will go way down,” said Jill Rosenthal, director of public health policy at the Center for American Progress, a left-leaning think tank. A bill for several hundred dollars or more would lead many people to decide the medication isn’t worth the price, she said.

In response to the unprecedented public health crisis caused by COVID, the federal government spent billions of dollars on developing new vaccines and treatments, to swift success: Less than a year after the pandemic was declared, medical workers got their first vaccines. But as many people have refused the shots and stopped wearing masks, the virus still rages and mutates. In 2022 alone, 250,000 Americans have died from COVID, more than from strokes or diabetes.

But soon the Department of Health & Human Services will stop supplying COVID treatments, and pharmacies will purchase and bill for them the same way they do for antibiotic pills or asthma inhalers. Paxlovid is expected to hit the private market in mid-2023, according to HHS plans shared in an October meeting with state health officials and clinicians. Merck’s Lagevrio, a less-effective COVID treatment pill, and AstraZeneca’s Evusheld, a preventive therapy for the immunocompromised, are on track to be commercialized sooner, sometime in the winter.

The U.S. government has so far purchased 20 million courses of Paxlovid, priced at about $530 each, a discount for buying in bulk that Pfizer CEO Albert Bourla called “really very attractive” to the federal government in a July earnings call. The drug will cost far more on the private market, although in a statement to Kaiser Health News, Pfizer declined to share the planned price. The government will also stop paying for the company’s COVID vaccine next year – those shots will quadruple in price, from the discount rate the government pays of $30 to about $120.

Mr. Bourla told investors in November that he expects the move will make Paxlovid and its COVID vaccine “a multibillion-dollars franchise.”

Nearly 9 in 10 people dying from the virus now are 65 or older. Yet federal law restricts Medicare Part D – the prescription drug program that covers nearly 50 million seniors – from covering the COVID treatment pills. The medications are meant for those most at risk of serious illness, including seniors.

Paxlovid and the other treatments are currently available under an emergency use authorization from the FDA, a fast-track review used in extraordinary situations. Although Pfizer applied for full approval in June, the process can take anywhere from several months to years. And Medicare Part D can’t cover any medications without that full stamp of approval.

Paying out-of-pocket would be “a substantial barrier” for seniors on Medicare – the very people who would benefit most from the drug, wrote federal health experts.

“From a public health perspective, and even from a health care capacity and cost perspective, it would just defy reason to not continue to make these drugs readily available,” said Dr. Larry Madoff, medical director of Massachusetts’s Bureau of Infectious Disease and Laboratory Sciences. He’s hopeful that the federal health agency will find a way to set aside unused doses for seniors and people without insurance.

In mid-November, the White House requested that Congress approve an additional $2.5 billion for COVID therapeutics and vaccines to make sure people can afford the medications when they’re no longer free. But there’s little hope it will be approved – the Senate voted that same day to end the public health emergency and denied similar requests in recent months.

Many Americans have already faced hurdles just getting a prescription for COVID treatment. Although the federal government doesn’t track who’s gotten the drug, a Centers for Disease Control and Prevention study using data from 30 medical centers found that Black and Hispanic patients with COVID were much less likely to receive Paxlovid than White patients. (Hispanic people can be of any race or combination of races.) And when the government is no longer picking up the tab, experts predict that these gaps by race, income, and geography will widen.

People in Northeastern states used the drug far more often than those in the rest of the country, according to a KHN analysis of Paxlovid use in September and October. But it wasn’t because people in the region were getting sick from COVID at much higher rates – instead, many of those states offered better access to health care to begin with and created special programs to get Paxlovid to their residents.

About 10 mostly Democratic states and several large counties in the Northeast and elsewhere created free “test-to-treat” programs that allow their residents to get an immediate doctor visit and prescription for treatment after testing positive for COVID. In Massachusetts, more than 20,000 residents have used the state’s video and phone hotline, which is available 7 days a week in 13 languages. Massachusetts, which has the highest insurance rate in the country and relatively low travel times to pharmacies, had the second-highest Paxlovid usage rate among states this fall.

States with higher COVID death rates, like Florida and Kentucky, where residents must travel farther for health care and are more likely to be uninsured, used the drug less often. Without no-cost test-to-treat options, residents have struggled to get prescriptions even though the drug itself is still free.

“If you look at access to medications for people who are uninsured, I think that there’s no question that will widen those disparities,” Ms. Rosenthal said.

People who get insurance through their jobs could face high copays at the register, too, just as they do for insulin and other expensive or brand-name drugs.

Most private insurance companies will end up covering COVID therapeutics to some extent, said Sabrina Corlette, a research professor at Georgetown University’s Center on Health Insurance Reforms. After all, the pills are cheaper than a hospital stay. But for most people who get insurance through their jobs, there are “really no rules at all,” she said. Some insurers could take months to add the drugs to their plans or decide not to pay for them.

And the additional cost means many people will go without the medication. “We know from lots of research that when people face cost sharing for these drugs that they need to take, they will often forgo or cut back,” Ms. Corlette said.

One group doesn’t need to worry about sticker shock. Medicaid, the public insurance program for low-income adults and children, will cover the treatments in full until at least early 2024.

HHS officials could set aside any leftover taxpayer-funded medication for people who can’t afford to pay the full cost, but they haven’t shared any concrete plans to do so. The government purchased 20 million courses of Paxlovid and 3 million of Lagevrio. Fewer than a third have been used, and usage has fallen in recent months, according to KHN’s analysis of the data from HHS.

Sixty percent of the government’s supply of Evusheld is also still available, although the COVID prevention therapy is less effective against new strains of the virus. The health department in one state, New Mexico, has recommended against using it.

HHS did not make officials available for an interview or answer written questions about the commercialization plans.

The government created a potential workaround when they moved bebtelovimab, another COVID treatment, to the private market this summer. It now retails for $2,100 per patient. The agency set aside the remaining 60,000 government-purchased doses that hospitals could use to treat uninsured patients in a convoluted dose-replacement process. But it’s hard to tell how well that setup would work for Paxlovid: Bebtelovimab was already much less popular, and the FDA halted its use on Nov. 30 because it’s less effective against current strains of the virus.

Federal officials and insurance companies would have good reason to make sure patients can continue to afford COVID drugs: They’re far cheaper than if patients land in the emergency room.

“The medications are so worthwhile,” said Dr. Madoff, the Massachusetts health official. “They’re not expensive in the grand scheme of health care costs.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.