Infectious Diseases

About half of Americans say they would get a COVID-19 vaccine if one is available, according to the Associated Press.

The poll, conducted by the AP-NORC Center for Public Affairs Research, also found that 31% said they weren’t sure if they’d get a vaccine, and 20% said they’d refuse to get one. The poll was conducted May 14-18 and released May 27.

A massive national and international effort is underway to develop a vaccine for the coronavirus. According to the poll, 20% of Americans believe a vaccine will be available before the end of 2020. Another 61% think it will arrive in 2021, and 17% say it will take longer.

“It’s always better to under-promise and over-deliver,” William Schaffner, MD, an infectious disease specialist at Vanderbilt University Medical Center, told the AP.

Americans over age 60 were more likely to say they’ll get a coronavirus vaccine when it’s available. Those who worry that they or someone in their household could become infected with the virus were also more likely to say they’ll get a vaccine. However, Black Americans were more likely than were Hispanic or white responders to say that they don’t plan to get a vaccine.

Among those who plan to get a vaccine, 93% said they want to protect themselves, and 88% said they want to protect their family. About 72% said “life won’t go back to normal until most people are vaccinated,” and 33% said they have a chronic health condition such as asthma or diabetes and believe it’s important to receive a vaccine.

Among those who don’t plan to get a vaccine, 70% said they’re concerned about side effects. Another 42% are worried about getting the coronavirus from the vaccine. Others say they’re not concerned about getting seriously ill from the coronavirus, they don’t think vaccines work well, the COVID-19 outbreak isn’t serious, or they don’t like needles.

The National Institutes of Health says that safety is the top priority and is creating a plan to test the vaccine in thousands of people for safety and efficacy in coming months, according to the AP.

“I would not want people to think that we’re cutting corners because that would be a big mistake,” NIH director Francis Collins, MD, told AP earlier this month. “I think this is an effort to try to achieve efficiencies but not to sacrifice rigor.”

This article first appeared on WebMD.com.

About half of Americans say they would get a COVID-19 vaccine if one is available, according to the Associated Press.

The poll, conducted by the AP-NORC Center for Public Affairs Research, also found that 31% said they weren’t sure if they’d get a vaccine, and 20% said they’d refuse to get one. The poll was conducted May 14-18 and released May 27.

A massive national and international effort is underway to develop a vaccine for the coronavirus. According to the poll, 20% of Americans believe a vaccine will be available before the end of 2020. Another 61% think it will arrive in 2021, and 17% say it will take longer.

“It’s always better to under-promise and over-deliver,” William Schaffner, MD, an infectious disease specialist at Vanderbilt University Medical Center, told the AP.

Americans over age 60 were more likely to say they’ll get a coronavirus vaccine when it’s available. Those who worry that they or someone in their household could become infected with the virus were also more likely to say they’ll get a vaccine. However, Black Americans were more likely than were Hispanic or white responders to say that they don’t plan to get a vaccine.

Among those who plan to get a vaccine, 93% said they want to protect themselves, and 88% said they want to protect their family. About 72% said “life won’t go back to normal until most people are vaccinated,” and 33% said they have a chronic health condition such as asthma or diabetes and believe it’s important to receive a vaccine.

Among those who don’t plan to get a vaccine, 70% said they’re concerned about side effects. Another 42% are worried about getting the coronavirus from the vaccine. Others say they’re not concerned about getting seriously ill from the coronavirus, they don’t think vaccines work well, the COVID-19 outbreak isn’t serious, or they don’t like needles.

The National Institutes of Health says that safety is the top priority and is creating a plan to test the vaccine in thousands of people for safety and efficacy in coming months, according to the AP.

“I would not want people to think that we’re cutting corners because that would be a big mistake,” NIH director Francis Collins, MD, told AP earlier this month. “I think this is an effort to try to achieve efficiencies but not to sacrifice rigor.”

This article first appeared on WebMD.com.

About half of Americans say they would get a COVID-19 vaccine if one is available, according to the Associated Press.

The poll, conducted by the AP-NORC Center for Public Affairs Research, also found that 31% said they weren’t sure if they’d get a vaccine, and 20% said they’d refuse to get one. The poll was conducted May 14-18 and released May 27.

A massive national and international effort is underway to develop a vaccine for the coronavirus. According to the poll, 20% of Americans believe a vaccine will be available before the end of 2020. Another 61% think it will arrive in 2021, and 17% say it will take longer.

“It’s always better to under-promise and over-deliver,” William Schaffner, MD, an infectious disease specialist at Vanderbilt University Medical Center, told the AP.

Americans over age 60 were more likely to say they’ll get a coronavirus vaccine when it’s available. Those who worry that they or someone in their household could become infected with the virus were also more likely to say they’ll get a vaccine. However, Black Americans were more likely than were Hispanic or white responders to say that they don’t plan to get a vaccine.

Among those who plan to get a vaccine, 93% said they want to protect themselves, and 88% said they want to protect their family. About 72% said “life won’t go back to normal until most people are vaccinated,” and 33% said they have a chronic health condition such as asthma or diabetes and believe it’s important to receive a vaccine.

Among those who don’t plan to get a vaccine, 70% said they’re concerned about side effects. Another 42% are worried about getting the coronavirus from the vaccine. Others say they’re not concerned about getting seriously ill from the coronavirus, they don’t think vaccines work well, the COVID-19 outbreak isn’t serious, or they don’t like needles.

The National Institutes of Health says that safety is the top priority and is creating a plan to test the vaccine in thousands of people for safety and efficacy in coming months, according to the AP.

“I would not want people to think that we’re cutting corners because that would be a big mistake,” NIH director Francis Collins, MD, told AP earlier this month. “I think this is an effort to try to achieve efficiencies but not to sacrifice rigor.”

This article first appeared on WebMD.com.

You can catch COVID-19 if an infected person coughs or sneezes and contagious droplets enter your nose or mouth. But can you become ill if the virus lands in your eyes?

Virologist Joseph Fair, PhD, an NBC News contributor, raised that concern when he became critically ill with COVID-19, the disease caused by the coronavirus. From a hospital bed in his hometown of New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection.

“My best guess,” he told the interviewer, “was that it came through the eye route.”

Asked if people should start wearing eye protection, Dr. Fair replied, “In my opinion, yes.”

While Dr. Fair is convinced that eye protection helps, other experts aren’t sure. So much remains unknown about the new coronavirus, SARS-CoV-2, that researchers are still trying to establish whether infection can actually happen through the eyes.

“I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.”

Some research has begun pointing in that direction, according to Elia Duh, MD, a researcher and professor of ophthalmology at Johns Hopkins University in Baltimore.

The clear tissue that covers the white of the eye and lines the inside of the eyelid, known as the conjunctiva, “can be infected by other viruses, such as adenoviruses associated with the common cold and the herpes simplex virus,” he said.

There’s the same chance of infection with SARS-CoV-2, said Dr. Duh. “If there are droplets that an infected individual is producing by coughing or sneezing or even speaking, then the front of the eyes are directly exposed, just like the nasal passages are exposed. In addition, people rub and touch their eyes a lot. So there’s certainly already the vulnerability.”

To study whether SARS-CoV-2 could infect the eyes, Dr. Duh and fellow researchers at Johns Hopkins looked at whether the eye’s surface cells possess key factors that make the virus more likely to enter and infect them.

In their study (BioRxiv. 2020 May 9. doi: 10.1101/2020.05.09.086165), which is now being peer-reviewed, the team examined 10 postmortem eyes and five surgical samples of conjunctiva from patients who did not have the coronavirus. They wanted to see whether the eyes’ surface cells produced the key receptor for coronavirus, the ACE2 receptor.

For SARS-CoV-2 to enter a cell, “the cell has to have ACE2 on its surface so that the coronavirus can latch onto it and gain entry into the cell,” Dr. Duh said.

Not much research existed on ACE2 and the eye’s surface cells, he said. “We were really struck that ACE2 was clearly present in the surface cells of all of the specimens.” In addition, the researchers found that the eye’s surface cells also produce TMPRSS2, an enzyme that helps the virus enter the cell.

More research is needed for a definitive answer, Dr. Duh said. But “all of this evidence together seems to suggest that there’s a good likelihood that the ocular surface cells are susceptible to infection by coronavirus.”

If that’s the case, the virus then could be transmitted through the tear ducts that connect the eyes to the nasal cavity and subsequently infect the respiratory cells, he said.

Edward E. Manche, MD, professor of ophthalmology at Stanford (Calif.) University, said that while doctors don’t know for sure, many think eye infection can happen. “I think it’s widely believed now that you can acquire it through the eye. The way the virus works, it’s most commonly transmitted through the mouth and nasal passages. We have mucosal tissues where it can get in.”

Dr. Manche said the eyes would be “the least common mode of transmission.”

Besides looking at the eyes as an entryway, researchers are exploring whether people with SARS-CoV-2 in their eyes could infect others through their tears or eye secretions.

“The virus has been detected in tears and conjunctival swab specimens from individuals with COVID-19,” Dr. Duh said. “If someone rubs their eyes and then touches someone else or touches a surface, that kind of transmission mechanism could occur.

“It again highlights how contagious the coronavirus is and how stealthy it can be in its contagiousness,” he said.

If it turns out that the coronavirus can infect the eyes, the virus could persist there as a source of contagion, Dr. Duh said. “The eyes and tears could serve as a source of infection to others for longer.” He noted a case of a COVID-infected woman with conjunctivitis who still had detectable virus in her eyes 3 weeks after her symptoms started.

Conjunctivitis, commonly called pink eye, could be a symptom of COVID-19, said Dr. Sen, who is an ophthalmologist. She recommends that people get tested for COVID-19 if they have this condition, which is marked by redness, itchiness, tearing, discharge, and a gritty sensation in the eye.

Dr. Fair, the virologist, was released from the hospital to recover at home and continued to urge eye protection. “People like to call people like me fearmongers ... but the reality is, we’re just trying to keep them safe,” he told NBC News.

The CDC hasn’t issued such advice. In an email, the agency said it “does not have specific recommendations for the public regarding eye protection. However, in health care settings, the CDC does recommend eye protection for health care workers to prevent transmission via droplets.”

Dr. Sen agrees. “For the general public, I don’t think we have enough data to suggest that they should be covering the eyes in some form,” she said.

When she goes to the grocery store, she doesn’t wear eye protection. “I am only wearing goggles when I’m seeing ophthalmology patients up close, basically because I’m 4 or 5 inches away from them.”

But fuller protection – a mask, gloves, and even eye protection, such as goggles – might help those taking care of a COVID-19 patient at home, Dr. Manche said. “If you’re caring for somebody, that’s a much higher risk because they’re shedding viral load. You lessen the chance of transmission.”

For the public, Dr. Sen stresses the continued importance of hand hygiene. “In an abundance of caution, I would still encourage handwashing and not touching the eye for many reasons, not just COVID. You can transmit simple infections to your eye. We have other viruses and bacteria that are circulating in the environment and in our bodies elsewhere, so we can easily carry those to the eyes.”

Switching from contact lenses to eyeglasses could help cut down on touching the eyes, she says. Eyeglasses can also be a “mechanical barrier” to keep hands away.

Eyeglasses might block some droplets if someone nearby sneezes or coughs, Dr. Manche said, although they “aren’t sealed around the edges. They’re not like true medical goggles that are going to keep out the virus.”

Dr. Duh agrees that health care workers must don eye protection, but he said the public doesn’t need to start wearing goggles, face shields, or other eye protection. “I still think the major mode of transmission is through the nasal passages and the respiratory system,” he said.

It’s unclear whether eye protection is warranted for airplane passengers, Dr. Manche said. “It probably wouldn’t hurt, but I think the more important thing would be to take precautions: wearing a face mask, washing your hands, cleaning the seats and tray tables in front of you, and not touching things and touching your face and eyes.”

A version of this article originally appeared on WebMD.com.

You can catch COVID-19 if an infected person coughs or sneezes and contagious droplets enter your nose or mouth. But can you become ill if the virus lands in your eyes?

Virologist Joseph Fair, PhD, an NBC News contributor, raised that concern when he became critically ill with COVID-19, the disease caused by the coronavirus. From a hospital bed in his hometown of New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection.

“My best guess,” he told the interviewer, “was that it came through the eye route.”

Asked if people should start wearing eye protection, Dr. Fair replied, “In my opinion, yes.”

While Dr. Fair is convinced that eye protection helps, other experts aren’t sure. So much remains unknown about the new coronavirus, SARS-CoV-2, that researchers are still trying to establish whether infection can actually happen through the eyes.

“I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.”

Some research has begun pointing in that direction, according to Elia Duh, MD, a researcher and professor of ophthalmology at Johns Hopkins University in Baltimore.

The clear tissue that covers the white of the eye and lines the inside of the eyelid, known as the conjunctiva, “can be infected by other viruses, such as adenoviruses associated with the common cold and the herpes simplex virus,” he said.

There’s the same chance of infection with SARS-CoV-2, said Dr. Duh. “If there are droplets that an infected individual is producing by coughing or sneezing or even speaking, then the front of the eyes are directly exposed, just like the nasal passages are exposed. In addition, people rub and touch their eyes a lot. So there’s certainly already the vulnerability.”

To study whether SARS-CoV-2 could infect the eyes, Dr. Duh and fellow researchers at Johns Hopkins looked at whether the eye’s surface cells possess key factors that make the virus more likely to enter and infect them.

In their study (BioRxiv. 2020 May 9. doi: 10.1101/2020.05.09.086165), which is now being peer-reviewed, the team examined 10 postmortem eyes and five surgical samples of conjunctiva from patients who did not have the coronavirus. They wanted to see whether the eyes’ surface cells produced the key receptor for coronavirus, the ACE2 receptor.

For SARS-CoV-2 to enter a cell, “the cell has to have ACE2 on its surface so that the coronavirus can latch onto it and gain entry into the cell,” Dr. Duh said.

Not much research existed on ACE2 and the eye’s surface cells, he said. “We were really struck that ACE2 was clearly present in the surface cells of all of the specimens.” In addition, the researchers found that the eye’s surface cells also produce TMPRSS2, an enzyme that helps the virus enter the cell.

More research is needed for a definitive answer, Dr. Duh said. But “all of this evidence together seems to suggest that there’s a good likelihood that the ocular surface cells are susceptible to infection by coronavirus.”

If that’s the case, the virus then could be transmitted through the tear ducts that connect the eyes to the nasal cavity and subsequently infect the respiratory cells, he said.

Edward E. Manche, MD, professor of ophthalmology at Stanford (Calif.) University, said that while doctors don’t know for sure, many think eye infection can happen. “I think it’s widely believed now that you can acquire it through the eye. The way the virus works, it’s most commonly transmitted through the mouth and nasal passages. We have mucosal tissues where it can get in.”

Dr. Manche said the eyes would be “the least common mode of transmission.”

Besides looking at the eyes as an entryway, researchers are exploring whether people with SARS-CoV-2 in their eyes could infect others through their tears or eye secretions.

“The virus has been detected in tears and conjunctival swab specimens from individuals with COVID-19,” Dr. Duh said. “If someone rubs their eyes and then touches someone else or touches a surface, that kind of transmission mechanism could occur.

“It again highlights how contagious the coronavirus is and how stealthy it can be in its contagiousness,” he said.

If it turns out that the coronavirus can infect the eyes, the virus could persist there as a source of contagion, Dr. Duh said. “The eyes and tears could serve as a source of infection to others for longer.” He noted a case of a COVID-infected woman with conjunctivitis who still had detectable virus in her eyes 3 weeks after her symptoms started.

Conjunctivitis, commonly called pink eye, could be a symptom of COVID-19, said Dr. Sen, who is an ophthalmologist. She recommends that people get tested for COVID-19 if they have this condition, which is marked by redness, itchiness, tearing, discharge, and a gritty sensation in the eye.

Dr. Fair, the virologist, was released from the hospital to recover at home and continued to urge eye protection. “People like to call people like me fearmongers ... but the reality is, we’re just trying to keep them safe,” he told NBC News.

The CDC hasn’t issued such advice. In an email, the agency said it “does not have specific recommendations for the public regarding eye protection. However, in health care settings, the CDC does recommend eye protection for health care workers to prevent transmission via droplets.”

Dr. Sen agrees. “For the general public, I don’t think we have enough data to suggest that they should be covering the eyes in some form,” she said.

When she goes to the grocery store, she doesn’t wear eye protection. “I am only wearing goggles when I’m seeing ophthalmology patients up close, basically because I’m 4 or 5 inches away from them.”

But fuller protection – a mask, gloves, and even eye protection, such as goggles – might help those taking care of a COVID-19 patient at home, Dr. Manche said. “If you’re caring for somebody, that’s a much higher risk because they’re shedding viral load. You lessen the chance of transmission.”

For the public, Dr. Sen stresses the continued importance of hand hygiene. “In an abundance of caution, I would still encourage handwashing and not touching the eye for many reasons, not just COVID. You can transmit simple infections to your eye. We have other viruses and bacteria that are circulating in the environment and in our bodies elsewhere, so we can easily carry those to the eyes.”

Switching from contact lenses to eyeglasses could help cut down on touching the eyes, she says. Eyeglasses can also be a “mechanical barrier” to keep hands away.

Eyeglasses might block some droplets if someone nearby sneezes or coughs, Dr. Manche said, although they “aren’t sealed around the edges. They’re not like true medical goggles that are going to keep out the virus.”

Dr. Duh agrees that health care workers must don eye protection, but he said the public doesn’t need to start wearing goggles, face shields, or other eye protection. “I still think the major mode of transmission is through the nasal passages and the respiratory system,” he said.

It’s unclear whether eye protection is warranted for airplane passengers, Dr. Manche said. “It probably wouldn’t hurt, but I think the more important thing would be to take precautions: wearing a face mask, washing your hands, cleaning the seats and tray tables in front of you, and not touching things and touching your face and eyes.”

A version of this article originally appeared on WebMD.com.

You can catch COVID-19 if an infected person coughs or sneezes and contagious droplets enter your nose or mouth. But can you become ill if the virus lands in your eyes?

Virologist Joseph Fair, PhD, an NBC News contributor, raised that concern when he became critically ill with COVID-19, the disease caused by the coronavirus. From a hospital bed in his hometown of New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection.

“My best guess,” he told the interviewer, “was that it came through the eye route.”

Asked if people should start wearing eye protection, Dr. Fair replied, “In my opinion, yes.”

While Dr. Fair is convinced that eye protection helps, other experts aren’t sure. So much remains unknown about the new coronavirus, SARS-CoV-2, that researchers are still trying to establish whether infection can actually happen through the eyes.

“I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.”

Some research has begun pointing in that direction, according to Elia Duh, MD, a researcher and professor of ophthalmology at Johns Hopkins University in Baltimore.

The clear tissue that covers the white of the eye and lines the inside of the eyelid, known as the conjunctiva, “can be infected by other viruses, such as adenoviruses associated with the common cold and the herpes simplex virus,” he said.

There’s the same chance of infection with SARS-CoV-2, said Dr. Duh. “If there are droplets that an infected individual is producing by coughing or sneezing or even speaking, then the front of the eyes are directly exposed, just like the nasal passages are exposed. In addition, people rub and touch their eyes a lot. So there’s certainly already the vulnerability.”

To study whether SARS-CoV-2 could infect the eyes, Dr. Duh and fellow researchers at Johns Hopkins looked at whether the eye’s surface cells possess key factors that make the virus more likely to enter and infect them.

In their study (BioRxiv. 2020 May 9. doi: 10.1101/2020.05.09.086165), which is now being peer-reviewed, the team examined 10 postmortem eyes and five surgical samples of conjunctiva from patients who did not have the coronavirus. They wanted to see whether the eyes’ surface cells produced the key receptor for coronavirus, the ACE2 receptor.

For SARS-CoV-2 to enter a cell, “the cell has to have ACE2 on its surface so that the coronavirus can latch onto it and gain entry into the cell,” Dr. Duh said.

Not much research existed on ACE2 and the eye’s surface cells, he said. “We were really struck that ACE2 was clearly present in the surface cells of all of the specimens.” In addition, the researchers found that the eye’s surface cells also produce TMPRSS2, an enzyme that helps the virus enter the cell.

More research is needed for a definitive answer, Dr. Duh said. But “all of this evidence together seems to suggest that there’s a good likelihood that the ocular surface cells are susceptible to infection by coronavirus.”

If that’s the case, the virus then could be transmitted through the tear ducts that connect the eyes to the nasal cavity and subsequently infect the respiratory cells, he said.

Edward E. Manche, MD, professor of ophthalmology at Stanford (Calif.) University, said that while doctors don’t know for sure, many think eye infection can happen. “I think it’s widely believed now that you can acquire it through the eye. The way the virus works, it’s most commonly transmitted through the mouth and nasal passages. We have mucosal tissues where it can get in.”

Dr. Manche said the eyes would be “the least common mode of transmission.”

Besides looking at the eyes as an entryway, researchers are exploring whether people with SARS-CoV-2 in their eyes could infect others through their tears or eye secretions.

“The virus has been detected in tears and conjunctival swab specimens from individuals with COVID-19,” Dr. Duh said. “If someone rubs their eyes and then touches someone else or touches a surface, that kind of transmission mechanism could occur.

“It again highlights how contagious the coronavirus is and how stealthy it can be in its contagiousness,” he said.

If it turns out that the coronavirus can infect the eyes, the virus could persist there as a source of contagion, Dr. Duh said. “The eyes and tears could serve as a source of infection to others for longer.” He noted a case of a COVID-infected woman with conjunctivitis who still had detectable virus in her eyes 3 weeks after her symptoms started.

Conjunctivitis, commonly called pink eye, could be a symptom of COVID-19, said Dr. Sen, who is an ophthalmologist. She recommends that people get tested for COVID-19 if they have this condition, which is marked by redness, itchiness, tearing, discharge, and a gritty sensation in the eye.

Dr. Fair, the virologist, was released from the hospital to recover at home and continued to urge eye protection. “People like to call people like me fearmongers ... but the reality is, we’re just trying to keep them safe,” he told NBC News.

The CDC hasn’t issued such advice. In an email, the agency said it “does not have specific recommendations for the public regarding eye protection. However, in health care settings, the CDC does recommend eye protection for health care workers to prevent transmission via droplets.”

Dr. Sen agrees. “For the general public, I don’t think we have enough data to suggest that they should be covering the eyes in some form,” she said.

When she goes to the grocery store, she doesn’t wear eye protection. “I am only wearing goggles when I’m seeing ophthalmology patients up close, basically because I’m 4 or 5 inches away from them.”

But fuller protection – a mask, gloves, and even eye protection, such as goggles – might help those taking care of a COVID-19 patient at home, Dr. Manche said. “If you’re caring for somebody, that’s a much higher risk because they’re shedding viral load. You lessen the chance of transmission.”

For the public, Dr. Sen stresses the continued importance of hand hygiene. “In an abundance of caution, I would still encourage handwashing and not touching the eye for many reasons, not just COVID. You can transmit simple infections to your eye. We have other viruses and bacteria that are circulating in the environment and in our bodies elsewhere, so we can easily carry those to the eyes.”

Switching from contact lenses to eyeglasses could help cut down on touching the eyes, she says. Eyeglasses can also be a “mechanical barrier” to keep hands away.

Eyeglasses might block some droplets if someone nearby sneezes or coughs, Dr. Manche said, although they “aren’t sealed around the edges. They’re not like true medical goggles that are going to keep out the virus.”

Dr. Duh agrees that health care workers must don eye protection, but he said the public doesn’t need to start wearing goggles, face shields, or other eye protection. “I still think the major mode of transmission is through the nasal passages and the respiratory system,” he said.

It’s unclear whether eye protection is warranted for airplane passengers, Dr. Manche said. “It probably wouldn’t hurt, but I think the more important thing would be to take precautions: wearing a face mask, washing your hands, cleaning the seats and tray tables in front of you, and not touching things and touching your face and eyes.”

A version of this article originally appeared on WebMD.com.

Children with COVID-19 are more likely to develop severe illness and require intensive care than previously realized, data from a single-center study suggest.

Jerry Y. Chao, MD, of the department of anesthesiology, Albert Einstein College of Medicine, New York, and colleagues reported their findings in an article published online May 11 in the Journal of Pediatrics.

“Thankfully most children with COVID-19 fare well, and some do not have any symptoms at all, but this research is a sobering reminder that children are not immune to this virus and some do require a higher level of care,” senior author Shivanand S. Medar, MD, FAAP, attending physician, Cardiac Intensive Care, Children’s Hospital at Montefiore, and assistant professor of pediatrics, Albert Einstein College of Medicine, said in a Montefiore Medical Center news release.

The study included 67 patients aged 1 month to 21 years (median, 13.1 years) who were treated for COVID-19 at a tertiary care children’s hospital between March 15 and April 13. Of those, 21 (31.3%) were treated as outpatients.

“As the number of patients screened for COVID-19 was restricted during the first weeks of the outbreak because of limited testing availability, the number of mildly symptomatic patients is not known, and therefore these 21 patients are not included in the analysis,” the authors wrote.

Of the 46 hospitalized patients, 33 (72%) were admitted to a general pediatric medical ward, and 13 (28%) were admitted to the pediatric intensive care unit (PICU).

Almost one-third (14 children; 30.4%) of the admitted patients were obese, and almost one-quarter (11 children; 24.4%) had asthma, but neither factor was associated with an increased risk for PICU admission.

“We know that in adults, obesity is a risk factor for more severe disease, however, surprisingly, our study found that children admitted to the intensive care unit did not have a higher prevalence of obesity than those on the general unit,” Dr. Chao said in the news release.

Three of the PICU patients (25%) had preexisting seizure disorders, as did one (3%) patient on the general medical unit. “There was no significant difference in the usage of ibuprofen prior to hospitalization among patients admitted to medical unit compared with those admitted to the PICU,” the authors wrote.

Platelet counts were lower in patients admitted to the PICU compared with those on the general medical unit; however, C-reactive protein, procalcitonin, and pro–brain natriuretic peptide levels were all elevated in patients admitted to the PICU compared with those admitted to the general medical unit.

Patients admitted to the PICU were more likely to need high-flow nasal cannula. Ten (77%) patients in the PICU developed acute respiratory distress syndrome (ARDS), and six (46.2%) of them needed “invasive mechanical ventilation for a median of 9 days.”

The only clinical symptom significantly linked to PICU admission was shortness of breath (92.3% vs 30.3%; P < .001).

Eight (61.5%) of the 13 patients treated in the PICU were discharged to home; four (30.7%) were still hospitalized and receiving ventilatory support on day 14. One patient had metastatic cancer and died as a result of the cancer after life-sustaining therapy was withdrawn.

Those admitted to the PICU were more likely to receive treatment with remdesivir via compassionate use compared with those treated in the general medical unit. Seven (53.8%) patients in the PICU developed severe sepsis and septic shock syndromes.

The average hospital stay was 4 days longer for the children admitted to the PICU than for the children admitted to the general medical unit.

Cough (63%) and fever (60.9%) were the most frequently reported symptoms at admission. The median duration of symptoms before admission was 3 days. None of the children had traveled to an area affected by COVID-19 before becoming ill, and only 20 (43.5%) children were confirmed to have had contact with someone with COVID-19. “The lack of a known sick contact reported in our study may have implications for how healthcare providers identify and screen for potential cases,” the authors explained.

Although children are believed to experience milder SARS-CoV-2 illness, these results and those of an earlier study suggest that some pediatric patients develop illness severe enough to require PICU admission. “This subset had significantly higher markers of inflammation (CRP, pro-BNP, procalcitonin) compared with patients in the medical unit. Inflammation likely contributed to the high rate of ARDS we observed, although serum levels of IL-6 and other cytokines linked to ARDS were not determined,” the authors wrote.

A retrospective cohort study found that of 177 children and young adults treated in a single center, patients younger than 1 year and older than 15 years were more likely to become critically ill with COVID-19 (J Pediatr. 2020 May. doi: 10.1016/j.jpeds.2020.05.007).

Each of the two age groups accounted for 32% of the hospitalized patients.

The authors have disclosed no relevant financial relationships.
 

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

Children with COVID-19 are more likely to develop severe illness and require intensive care than previously realized, data from a single-center study suggest.

Jerry Y. Chao, MD, of the department of anesthesiology, Albert Einstein College of Medicine, New York, and colleagues reported their findings in an article published online May 11 in the Journal of Pediatrics.

“Thankfully most children with COVID-19 fare well, and some do not have any symptoms at all, but this research is a sobering reminder that children are not immune to this virus and some do require a higher level of care,” senior author Shivanand S. Medar, MD, FAAP, attending physician, Cardiac Intensive Care, Children’s Hospital at Montefiore, and assistant professor of pediatrics, Albert Einstein College of Medicine, said in a Montefiore Medical Center news release.

The study included 67 patients aged 1 month to 21 years (median, 13.1 years) who were treated for COVID-19 at a tertiary care children’s hospital between March 15 and April 13. Of those, 21 (31.3%) were treated as outpatients.

“As the number of patients screened for COVID-19 was restricted during the first weeks of the outbreak because of limited testing availability, the number of mildly symptomatic patients is not known, and therefore these 21 patients are not included in the analysis,” the authors wrote.

Of the 46 hospitalized patients, 33 (72%) were admitted to a general pediatric medical ward, and 13 (28%) were admitted to the pediatric intensive care unit (PICU).

Almost one-third (14 children; 30.4%) of the admitted patients were obese, and almost one-quarter (11 children; 24.4%) had asthma, but neither factor was associated with an increased risk for PICU admission.

“We know that in adults, obesity is a risk factor for more severe disease, however, surprisingly, our study found that children admitted to the intensive care unit did not have a higher prevalence of obesity than those on the general unit,” Dr. Chao said in the news release.

Three of the PICU patients (25%) had preexisting seizure disorders, as did one (3%) patient on the general medical unit. “There was no significant difference in the usage of ibuprofen prior to hospitalization among patients admitted to medical unit compared with those admitted to the PICU,” the authors wrote.

Platelet counts were lower in patients admitted to the PICU compared with those on the general medical unit; however, C-reactive protein, procalcitonin, and pro–brain natriuretic peptide levels were all elevated in patients admitted to the PICU compared with those admitted to the general medical unit.

Patients admitted to the PICU were more likely to need high-flow nasal cannula. Ten (77%) patients in the PICU developed acute respiratory distress syndrome (ARDS), and six (46.2%) of them needed “invasive mechanical ventilation for a median of 9 days.”

The only clinical symptom significantly linked to PICU admission was shortness of breath (92.3% vs 30.3%; P < .001).

Eight (61.5%) of the 13 patients treated in the PICU were discharged to home; four (30.7%) were still hospitalized and receiving ventilatory support on day 14. One patient had metastatic cancer and died as a result of the cancer after life-sustaining therapy was withdrawn.

Those admitted to the PICU were more likely to receive treatment with remdesivir via compassionate use compared with those treated in the general medical unit. Seven (53.8%) patients in the PICU developed severe sepsis and septic shock syndromes.

The average hospital stay was 4 days longer for the children admitted to the PICU than for the children admitted to the general medical unit.

Cough (63%) and fever (60.9%) were the most frequently reported symptoms at admission. The median duration of symptoms before admission was 3 days. None of the children had traveled to an area affected by COVID-19 before becoming ill, and only 20 (43.5%) children were confirmed to have had contact with someone with COVID-19. “The lack of a known sick contact reported in our study may have implications for how healthcare providers identify and screen for potential cases,” the authors explained.

Although children are believed to experience milder SARS-CoV-2 illness, these results and those of an earlier study suggest that some pediatric patients develop illness severe enough to require PICU admission. “This subset had significantly higher markers of inflammation (CRP, pro-BNP, procalcitonin) compared with patients in the medical unit. Inflammation likely contributed to the high rate of ARDS we observed, although serum levels of IL-6 and other cytokines linked to ARDS were not determined,” the authors wrote.

A retrospective cohort study found that of 177 children and young adults treated in a single center, patients younger than 1 year and older than 15 years were more likely to become critically ill with COVID-19 (J Pediatr. 2020 May. doi: 10.1016/j.jpeds.2020.05.007).

Each of the two age groups accounted for 32% of the hospitalized patients.

The authors have disclosed no relevant financial relationships.
 

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

Children with COVID-19 are more likely to develop severe illness and require intensive care than previously realized, data from a single-center study suggest.

Jerry Y. Chao, MD, of the department of anesthesiology, Albert Einstein College of Medicine, New York, and colleagues reported their findings in an article published online May 11 in the Journal of Pediatrics.

“Thankfully most children with COVID-19 fare well, and some do not have any symptoms at all, but this research is a sobering reminder that children are not immune to this virus and some do require a higher level of care,” senior author Shivanand S. Medar, MD, FAAP, attending physician, Cardiac Intensive Care, Children’s Hospital at Montefiore, and assistant professor of pediatrics, Albert Einstein College of Medicine, said in a Montefiore Medical Center news release.

The study included 67 patients aged 1 month to 21 years (median, 13.1 years) who were treated for COVID-19 at a tertiary care children’s hospital between March 15 and April 13. Of those, 21 (31.3%) were treated as outpatients.

“As the number of patients screened for COVID-19 was restricted during the first weeks of the outbreak because of limited testing availability, the number of mildly symptomatic patients is not known, and therefore these 21 patients are not included in the analysis,” the authors wrote.

Of the 46 hospitalized patients, 33 (72%) were admitted to a general pediatric medical ward, and 13 (28%) were admitted to the pediatric intensive care unit (PICU).

Almost one-third (14 children; 30.4%) of the admitted patients were obese, and almost one-quarter (11 children; 24.4%) had asthma, but neither factor was associated with an increased risk for PICU admission.

“We know that in adults, obesity is a risk factor for more severe disease, however, surprisingly, our study found that children admitted to the intensive care unit did not have a higher prevalence of obesity than those on the general unit,” Dr. Chao said in the news release.

Three of the PICU patients (25%) had preexisting seizure disorders, as did one (3%) patient on the general medical unit. “There was no significant difference in the usage of ibuprofen prior to hospitalization among patients admitted to medical unit compared with those admitted to the PICU,” the authors wrote.

Platelet counts were lower in patients admitted to the PICU compared with those on the general medical unit; however, C-reactive protein, procalcitonin, and pro–brain natriuretic peptide levels were all elevated in patients admitted to the PICU compared with those admitted to the general medical unit.

Patients admitted to the PICU were more likely to need high-flow nasal cannula. Ten (77%) patients in the PICU developed acute respiratory distress syndrome (ARDS), and six (46.2%) of them needed “invasive mechanical ventilation for a median of 9 days.”

The only clinical symptom significantly linked to PICU admission was shortness of breath (92.3% vs 30.3%; P < .001).

Eight (61.5%) of the 13 patients treated in the PICU were discharged to home; four (30.7%) were still hospitalized and receiving ventilatory support on day 14. One patient had metastatic cancer and died as a result of the cancer after life-sustaining therapy was withdrawn.

Those admitted to the PICU were more likely to receive treatment with remdesivir via compassionate use compared with those treated in the general medical unit. Seven (53.8%) patients in the PICU developed severe sepsis and septic shock syndromes.

The average hospital stay was 4 days longer for the children admitted to the PICU than for the children admitted to the general medical unit.

Cough (63%) and fever (60.9%) were the most frequently reported symptoms at admission. The median duration of symptoms before admission was 3 days. None of the children had traveled to an area affected by COVID-19 before becoming ill, and only 20 (43.5%) children were confirmed to have had contact with someone with COVID-19. “The lack of a known sick contact reported in our study may have implications for how healthcare providers identify and screen for potential cases,” the authors explained.

Although children are believed to experience milder SARS-CoV-2 illness, these results and those of an earlier study suggest that some pediatric patients develop illness severe enough to require PICU admission. “This subset had significantly higher markers of inflammation (CRP, pro-BNP, procalcitonin) compared with patients in the medical unit. Inflammation likely contributed to the high rate of ARDS we observed, although serum levels of IL-6 and other cytokines linked to ARDS were not determined,” the authors wrote.

A retrospective cohort study found that of 177 children and young adults treated in a single center, patients younger than 1 year and older than 15 years were more likely to become critically ill with COVID-19 (J Pediatr. 2020 May. doi: 10.1016/j.jpeds.2020.05.007).

Each of the two age groups accounted for 32% of the hospitalized patients.

The authors have disclosed no relevant financial relationships.
 

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

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

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

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

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

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

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

From Western Michigan University, Homer Stryker MD School of Medicine, Kalamazoo, MI (Dr. Vaillant and Dr. Kavanaugh), Ferris State University, Grand Rapids, MI (Dr. Mersfelder), and Bronson Methodist Hospital, Kalamazoo, MI (Dr. Maynard).

Abstract

• Background: Procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin. The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied, and use of this biomarker has been shown to decrease antibiotic usage in clinical trials. We sought to evaluate the impact of a pharmacist-driven initiative regarding discontinuation of antibiotics utilizing procalcitonin levels at a community teaching hospital.
• Methods: We retrospectively gathered baseline data on adult patients admitted to a community teaching hospital who were 18 years of age and older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during admission. We then prospectively identified an intervention group of similar patients using a web-based, real-time clinical surveillance system. When a low procalcitonin level was identified in the intervention group, the participating clinical pharmacists screened for antibiotic use and the indication(s), determined whether the antibiotic could be discontinued based on the low procalcitonin level and the absence of another indication for antibiotics, and, when appropriate, contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. The total antibiotic treatment duration was compared between the baseline and intervention groups.
• Results: A total of 172 patients were included in this study (86 in each group). The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and the intervention (3.34 ± 2.8 days) groups (P = 0.1083). Other patient demographics did not influence antibiotic duration.
• Conclusion: Our study did not demonstrate a difference in total antibiotic treatment duration with the utilization of procalcitonin and an oral communication intervention made by a clinical pharmacist at a community-based teaching hospital. Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis and treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program to reduce antibiotic use and effectively use laboratory values.

Keywords: antibiotic use; bacterial infection; biomarkers; procalcitonin.

Procalcitonin is the precursor of the hormone calcitonin, which is normally produced in the parafollicular cells of the thyroid gland under physiological conditions.¹ However, procalcitonin is also released in response to a proinflammatory stimulus, especially that of bacterial origin.¹ The source of the procalcitonin surge seen during proinflammatory states is not the parafollicular cells of the thyroid, but rather the neuroendocrine cells of the lung and intestine.¹ Stimulants of procalcitonin in these scenarios include bacterial endotoxin, tumor necrosis factor, and interleukin-6.^1,2 Due to these observations, procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin.³

The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied.^4,5 Various randomized controlled trials have shown that antibiotic stewardship guided by procalcitonin levels resulted in lower rates of antibiotic initiation and shorter duration of antibiotic use.^4-6 Similar results were obtained in prospective studies evaluating its role in patients with chronic obstructive pulmonary disease and sepsis.^7,8 Based on these data, protocol-driven procalcitonin-guided antibiotic stewardship appears beneficial.

Many of these studies employed rigorous protocols. Studies of procalcitonin use in a so-called real-world setting, in which the provider can order and use procalcitonin levels without the use of protocols, are limited. The objective of our study was to evaluate the impact of a pharmacist-driven initiative on discontinuing antibiotics, if indicated, utilizing single procalcitonin measurement results of < 0.25 mcg/L at a community teaching hospital.

Methods

Our study utilized a 2-phase approach. The first phase was a retrospective chart review to establish baseline data regarding adult inpatients with a low procalcitonin level; these patients were randomly selected over a 1-year period (2017). Patients were included if they were 18 years of age or older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during their admission. Patients admitted to the intensive care unit were excluded. In the second phase, we prospectively identified similar patients admitted between January and March 2018 using a web-based, real-time clinical surveillance system. When patients with low procalcitonin levels were identified, 2 participating clinical pharmacists screened for antibiotic use and indication. If it was determined that the antibiotic could be discontinued as a result of the low procalcitonin level and no additional indication for antibiotics was present, the pharmacist contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. Data collected before and after the intervention included total antibiotic treatment duration, white blood cell count, maximum temperature, age, and procalcitonin level.

A sample size of 86 was calculated to provide an alpha of 0.05 and a power of 0.8. A nonparametric Wilcoxon 2-sample test was used to test for a difference in duration of antibiotic treatment between the baseline and intervention groups. A nonparametric test was used due to right-skewed data. All patients were included in the group analysis, regardless of antibiotic use, as the procalcitonin level may have been used in the decision to initiate antibiotics, and this is more representative of a real-world application of the test. This allowed for detection of a significant decrease of 2 days in antibiotic duration post intervention, with a 10% margin to compensate for potential missing data. Data from 86 patients obtained prior to the pharmacist intervention acted as a control comparison group. Statistical analysis was performed using SAS 9.4.

Results

A total of 172 patients were included in this study: 86 patients prior to the intervention, and 86 after implementation. Baseline demographics, laboratory values, vitals, and principal diagnoses for both groups are shown in Table 1 and Table 2. The most common indications for procalcitonin measurement were pneumonia (45.9%), chronic obstructive pulmonary disease (15.7%), and sepsis (14.5%). The remaining diagnoses were encephalopathy, fever and leukocytosis, skin and soft tissue infection, urinary tract infection or pyelonephritis, bone and joint infection, meningitis, intra-abdominal infection, and asthma exacerbation.

Antibiotic therapy was initiated in 68% of the patients overall, 59% in the baseline group and 76% in the intervention group. The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and intervention (3.34 ± 2.8 days) groups (P = 0.1083). Furthermore, antibiotic treatment duration did not vary significantly with patient age, white blood cell count, maximum temperature, or procalcitonin level in either group. Although there was no difference in total antibiotic treatment duration, a post-hoc analysis revealed a 0.6-day decrease in the interval between the date of procalcitonin measurement and the stop date of antibiotics in the intervention group. The average time from admission to obtaining a procalcitonin level was 3 days in the baseline group and 2 days in the intervention group.

Discussion

Our study did not demonstrate a difference in total antibiotic treatment duration with procalcitonin measurement and an oral communication intervention made by a clinical pharmacist at a community teaching hospital with a well-established antimicrobial stewardship program. This may be due to several factors. First, the providers did not receive ongoing education regarding the appropriate use or interpretation of procalcitonin. The procalcitonin result in the electronic health record references the risk for progression to severe sepsis and/or septic shock, but does not indicate how to use procalcitonin as an aid in antibiotic decision-making. However, a recent study in patients with lower respiratory tract infections treated by providers who had been educated on the use of procalcitonin failed to find a reduction in total antibiotic use.⁹ Second, our study included hospital-wide use of procalcitonin, and was not limited to infections for which procalcitonin use has the strongest evidence (eg, upper respiratory tract infections, pneumonia, sepsis). Thus, providers may have been less likely to use protocolized guidelines. Last, we did not limit the data on antibiotic duration to patients with a procalcitonin level obtained within a defined time frame from antibiotic initiation or time of admission, and some patients had procalcitonin levels measured several days into their hospital stay. While this is likely to have skewed the data in favor of longer antibiotic treatment courses, it also represents a more realistic way in which this laboratory test is being used. Our post-hoc finding of earlier discontinuation of antibiotics after procalcitonin measurement suggests that our intervention may have influenced the decision to discontinue antibiotics. Such an effect may be augmented if procalcitonin is measured earlier in a hospital admission.

Previous studies have also failed to show that the use of procalcitonin decreased duration of antibiotics.^9,10 In the aforementioned study regarding real-world outcomes in patients with lower respiratory tract infections, antibiotic duration was not reduced, despite provider education.⁹ A large observational study that evaluated real-world outcomes in intensive care unit patients did not find decreased antibiotic use or improved outcomes with procalcitonin use.¹⁰ With these large studies evaluating the 2 most common infectious diseases for which procalcitonin has previously been found to have clinical benefit, it is important for institutions to re-evaluate how procalcitonin is being utilized by providers. Furthermore, institutions should explore ways to optimize procalcitonin use and decrease unnecessary health care costs. Notably, the current community-acquired pneumonia guidelines recommend against routine use of procalcitonin.¹¹

Conclusion

Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis or treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program that includes an algorithmic protocol to promote appropriate laboratory testing and reduce total antibiotic use. In addition to improved communication with providers, other interventions need to be investigated to effectively use this biomarker or limit its use.

Acknowledgment: The authors thank the Western Michigan University Department of Epidemiology and Biostatistics for their assistance in preparing this article.

Corresponding author: James Vaillant, MD, Western Michigan University, Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, 49008; [email protected].

Financial disclosures: None.

From Western Michigan University, Homer Stryker MD School of Medicine, Kalamazoo, MI (Dr. Vaillant and Dr. Kavanaugh), Ferris State University, Grand Rapids, MI (Dr. Mersfelder), and Bronson Methodist Hospital, Kalamazoo, MI (Dr. Maynard).

Abstract

• Background: Procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin. The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied, and use of this biomarker has been shown to decrease antibiotic usage in clinical trials. We sought to evaluate the impact of a pharmacist-driven initiative regarding discontinuation of antibiotics utilizing procalcitonin levels at a community teaching hospital.
• Methods: We retrospectively gathered baseline data on adult patients admitted to a community teaching hospital who were 18 years of age and older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during admission. We then prospectively identified an intervention group of similar patients using a web-based, real-time clinical surveillance system. When a low procalcitonin level was identified in the intervention group, the participating clinical pharmacists screened for antibiotic use and the indication(s), determined whether the antibiotic could be discontinued based on the low procalcitonin level and the absence of another indication for antibiotics, and, when appropriate, contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. The total antibiotic treatment duration was compared between the baseline and intervention groups.
• Results: A total of 172 patients were included in this study (86 in each group). The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and the intervention (3.34 ± 2.8 days) groups (P = 0.1083). Other patient demographics did not influence antibiotic duration.
• Conclusion: Our study did not demonstrate a difference in total antibiotic treatment duration with the utilization of procalcitonin and an oral communication intervention made by a clinical pharmacist at a community-based teaching hospital. Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis and treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program to reduce antibiotic use and effectively use laboratory values.

Keywords: antibiotic use; bacterial infection; biomarkers; procalcitonin.

Procalcitonin is the precursor of the hormone calcitonin, which is normally produced in the parafollicular cells of the thyroid gland under physiological conditions.¹ However, procalcitonin is also released in response to a proinflammatory stimulus, especially that of bacterial origin.¹ The source of the procalcitonin surge seen during proinflammatory states is not the parafollicular cells of the thyroid, but rather the neuroendocrine cells of the lung and intestine.¹ Stimulants of procalcitonin in these scenarios include bacterial endotoxin, tumor necrosis factor, and interleukin-6.^1,2 Due to these observations, procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin.³

The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied.^4,5 Various randomized controlled trials have shown that antibiotic stewardship guided by procalcitonin levels resulted in lower rates of antibiotic initiation and shorter duration of antibiotic use.^4-6 Similar results were obtained in prospective studies evaluating its role in patients with chronic obstructive pulmonary disease and sepsis.^7,8 Based on these data, protocol-driven procalcitonin-guided antibiotic stewardship appears beneficial.

Many of these studies employed rigorous protocols. Studies of procalcitonin use in a so-called real-world setting, in which the provider can order and use procalcitonin levels without the use of protocols, are limited. The objective of our study was to evaluate the impact of a pharmacist-driven initiative on discontinuing antibiotics, if indicated, utilizing single procalcitonin measurement results of < 0.25 mcg/L at a community teaching hospital.

Methods

Our study utilized a 2-phase approach. The first phase was a retrospective chart review to establish baseline data regarding adult inpatients with a low procalcitonin level; these patients were randomly selected over a 1-year period (2017). Patients were included if they were 18 years of age or older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during their admission. Patients admitted to the intensive care unit were excluded. In the second phase, we prospectively identified similar patients admitted between January and March 2018 using a web-based, real-time clinical surveillance system. When patients with low procalcitonin levels were identified, 2 participating clinical pharmacists screened for antibiotic use and indication. If it was determined that the antibiotic could be discontinued as a result of the low procalcitonin level and no additional indication for antibiotics was present, the pharmacist contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. Data collected before and after the intervention included total antibiotic treatment duration, white blood cell count, maximum temperature, age, and procalcitonin level.

A sample size of 86 was calculated to provide an alpha of 0.05 and a power of 0.8. A nonparametric Wilcoxon 2-sample test was used to test for a difference in duration of antibiotic treatment between the baseline and intervention groups. A nonparametric test was used due to right-skewed data. All patients were included in the group analysis, regardless of antibiotic use, as the procalcitonin level may have been used in the decision to initiate antibiotics, and this is more representative of a real-world application of the test. This allowed for detection of a significant decrease of 2 days in antibiotic duration post intervention, with a 10% margin to compensate for potential missing data. Data from 86 patients obtained prior to the pharmacist intervention acted as a control comparison group. Statistical analysis was performed using SAS 9.4.

Results

A total of 172 patients were included in this study: 86 patients prior to the intervention, and 86 after implementation. Baseline demographics, laboratory values, vitals, and principal diagnoses for both groups are shown in Table 1 and Table 2. The most common indications for procalcitonin measurement were pneumonia (45.9%), chronic obstructive pulmonary disease (15.7%), and sepsis (14.5%). The remaining diagnoses were encephalopathy, fever and leukocytosis, skin and soft tissue infection, urinary tract infection or pyelonephritis, bone and joint infection, meningitis, intra-abdominal infection, and asthma exacerbation.

Antibiotic therapy was initiated in 68% of the patients overall, 59% in the baseline group and 76% in the intervention group. The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and intervention (3.34 ± 2.8 days) groups (P = 0.1083). Furthermore, antibiotic treatment duration did not vary significantly with patient age, white blood cell count, maximum temperature, or procalcitonin level in either group. Although there was no difference in total antibiotic treatment duration, a post-hoc analysis revealed a 0.6-day decrease in the interval between the date of procalcitonin measurement and the stop date of antibiotics in the intervention group. The average time from admission to obtaining a procalcitonin level was 3 days in the baseline group and 2 days in the intervention group.

Discussion

Our study did not demonstrate a difference in total antibiotic treatment duration with procalcitonin measurement and an oral communication intervention made by a clinical pharmacist at a community teaching hospital with a well-established antimicrobial stewardship program. This may be due to several factors. First, the providers did not receive ongoing education regarding the appropriate use or interpretation of procalcitonin. The procalcitonin result in the electronic health record references the risk for progression to severe sepsis and/or septic shock, but does not indicate how to use procalcitonin as an aid in antibiotic decision-making. However, a recent study in patients with lower respiratory tract infections treated by providers who had been educated on the use of procalcitonin failed to find a reduction in total antibiotic use.⁹ Second, our study included hospital-wide use of procalcitonin, and was not limited to infections for which procalcitonin use has the strongest evidence (eg, upper respiratory tract infections, pneumonia, sepsis). Thus, providers may have been less likely to use protocolized guidelines. Last, we did not limit the data on antibiotic duration to patients with a procalcitonin level obtained within a defined time frame from antibiotic initiation or time of admission, and some patients had procalcitonin levels measured several days into their hospital stay. While this is likely to have skewed the data in favor of longer antibiotic treatment courses, it also represents a more realistic way in which this laboratory test is being used. Our post-hoc finding of earlier discontinuation of antibiotics after procalcitonin measurement suggests that our intervention may have influenced the decision to discontinue antibiotics. Such an effect may be augmented if procalcitonin is measured earlier in a hospital admission.

Previous studies have also failed to show that the use of procalcitonin decreased duration of antibiotics.^9,10 In the aforementioned study regarding real-world outcomes in patients with lower respiratory tract infections, antibiotic duration was not reduced, despite provider education.⁹ A large observational study that evaluated real-world outcomes in intensive care unit patients did not find decreased antibiotic use or improved outcomes with procalcitonin use.¹⁰ With these large studies evaluating the 2 most common infectious diseases for which procalcitonin has previously been found to have clinical benefit, it is important for institutions to re-evaluate how procalcitonin is being utilized by providers. Furthermore, institutions should explore ways to optimize procalcitonin use and decrease unnecessary health care costs. Notably, the current community-acquired pneumonia guidelines recommend against routine use of procalcitonin.¹¹

Conclusion

Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis or treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program that includes an algorithmic protocol to promote appropriate laboratory testing and reduce total antibiotic use. In addition to improved communication with providers, other interventions need to be investigated to effectively use this biomarker or limit its use.

Acknowledgment: The authors thank the Western Michigan University Department of Epidemiology and Biostatistics for their assistance in preparing this article.

Corresponding author: James Vaillant, MD, Western Michigan University, Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, 49008; [email protected].

Financial disclosures: None.

From Western Michigan University, Homer Stryker MD School of Medicine, Kalamazoo, MI (Dr. Vaillant and Dr. Kavanaugh), Ferris State University, Grand Rapids, MI (Dr. Mersfelder), and Bronson Methodist Hospital, Kalamazoo, MI (Dr. Maynard).

Abstract

• Background: Procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin. The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied, and use of this biomarker has been shown to decrease antibiotic usage in clinical trials. We sought to evaluate the impact of a pharmacist-driven initiative regarding discontinuation of antibiotics utilizing procalcitonin levels at a community teaching hospital.
• Methods: We retrospectively gathered baseline data on adult patients admitted to a community teaching hospital who were 18 years of age and older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during admission. We then prospectively identified an intervention group of similar patients using a web-based, real-time clinical surveillance system. When a low procalcitonin level was identified in the intervention group, the participating clinical pharmacists screened for antibiotic use and the indication(s), determined whether the antibiotic could be discontinued based on the low procalcitonin level and the absence of another indication for antibiotics, and, when appropriate, contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. The total antibiotic treatment duration was compared between the baseline and intervention groups.
• Results: A total of 172 patients were included in this study (86 in each group). The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and the intervention (3.34 ± 2.8 days) groups (P = 0.1083). Other patient demographics did not influence antibiotic duration.
• Conclusion: Our study did not demonstrate a difference in total antibiotic treatment duration with the utilization of procalcitonin and an oral communication intervention made by a clinical pharmacist at a community-based teaching hospital. Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis and treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program to reduce antibiotic use and effectively use laboratory values.

Keywords: antibiotic use; bacterial infection; biomarkers; procalcitonin.

Procalcitonin is the precursor of the hormone calcitonin, which is normally produced in the parafollicular cells of the thyroid gland under physiological conditions.¹ However, procalcitonin is also released in response to a proinflammatory stimulus, especially that of bacterial origin.¹ The source of the procalcitonin surge seen during proinflammatory states is not the parafollicular cells of the thyroid, but rather the neuroendocrine cells of the lung and intestine.¹ Stimulants of procalcitonin in these scenarios include bacterial endotoxin, tumor necrosis factor, and interleukin-6.^1,2 Due to these observations, procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin.³

The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied.^4,5 Various randomized controlled trials have shown that antibiotic stewardship guided by procalcitonin levels resulted in lower rates of antibiotic initiation and shorter duration of antibiotic use.^4-6 Similar results were obtained in prospective studies evaluating its role in patients with chronic obstructive pulmonary disease and sepsis.^7,8 Based on these data, protocol-driven procalcitonin-guided antibiotic stewardship appears beneficial.

Many of these studies employed rigorous protocols. Studies of procalcitonin use in a so-called real-world setting, in which the provider can order and use procalcitonin levels without the use of protocols, are limited. The objective of our study was to evaluate the impact of a pharmacist-driven initiative on discontinuing antibiotics, if indicated, utilizing single procalcitonin measurement results of < 0.25 mcg/L at a community teaching hospital.

Methods

Our study utilized a 2-phase approach. The first phase was a retrospective chart review to establish baseline data regarding adult inpatients with a low procalcitonin level; these patients were randomly selected over a 1-year period (2017). Patients were included if they were 18 years of age or older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during their admission. Patients admitted to the intensive care unit were excluded. In the second phase, we prospectively identified similar patients admitted between January and March 2018 using a web-based, real-time clinical surveillance system. When patients with low procalcitonin levels were identified, 2 participating clinical pharmacists screened for antibiotic use and indication. If it was determined that the antibiotic could be discontinued as a result of the low procalcitonin level and no additional indication for antibiotics was present, the pharmacist contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. Data collected before and after the intervention included total antibiotic treatment duration, white blood cell count, maximum temperature, age, and procalcitonin level.

A sample size of 86 was calculated to provide an alpha of 0.05 and a power of 0.8. A nonparametric Wilcoxon 2-sample test was used to test for a difference in duration of antibiotic treatment between the baseline and intervention groups. A nonparametric test was used due to right-skewed data. All patients were included in the group analysis, regardless of antibiotic use, as the procalcitonin level may have been used in the decision to initiate antibiotics, and this is more representative of a real-world application of the test. This allowed for detection of a significant decrease of 2 days in antibiotic duration post intervention, with a 10% margin to compensate for potential missing data. Data from 86 patients obtained prior to the pharmacist intervention acted as a control comparison group. Statistical analysis was performed using SAS 9.4.

Results

A total of 172 patients were included in this study: 86 patients prior to the intervention, and 86 after implementation. Baseline demographics, laboratory values, vitals, and principal diagnoses for both groups are shown in Table 1 and Table 2. The most common indications for procalcitonin measurement were pneumonia (45.9%), chronic obstructive pulmonary disease (15.7%), and sepsis (14.5%). The remaining diagnoses were encephalopathy, fever and leukocytosis, skin and soft tissue infection, urinary tract infection or pyelonephritis, bone and joint infection, meningitis, intra-abdominal infection, and asthma exacerbation.

Antibiotic therapy was initiated in 68% of the patients overall, 59% in the baseline group and 76% in the intervention group. The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and intervention (3.34 ± 2.8 days) groups (P = 0.1083). Furthermore, antibiotic treatment duration did not vary significantly with patient age, white blood cell count, maximum temperature, or procalcitonin level in either group. Although there was no difference in total antibiotic treatment duration, a post-hoc analysis revealed a 0.6-day decrease in the interval between the date of procalcitonin measurement and the stop date of antibiotics in the intervention group. The average time from admission to obtaining a procalcitonin level was 3 days in the baseline group and 2 days in the intervention group.

Discussion

Our study did not demonstrate a difference in total antibiotic treatment duration with procalcitonin measurement and an oral communication intervention made by a clinical pharmacist at a community teaching hospital with a well-established antimicrobial stewardship program. This may be due to several factors. First, the providers did not receive ongoing education regarding the appropriate use or interpretation of procalcitonin. The procalcitonin result in the electronic health record references the risk for progression to severe sepsis and/or septic shock, but does not indicate how to use procalcitonin as an aid in antibiotic decision-making. However, a recent study in patients with lower respiratory tract infections treated by providers who had been educated on the use of procalcitonin failed to find a reduction in total antibiotic use.⁹ Second, our study included hospital-wide use of procalcitonin, and was not limited to infections for which procalcitonin use has the strongest evidence (eg, upper respiratory tract infections, pneumonia, sepsis). Thus, providers may have been less likely to use protocolized guidelines. Last, we did not limit the data on antibiotic duration to patients with a procalcitonin level obtained within a defined time frame from antibiotic initiation or time of admission, and some patients had procalcitonin levels measured several days into their hospital stay. While this is likely to have skewed the data in favor of longer antibiotic treatment courses, it also represents a more realistic way in which this laboratory test is being used. Our post-hoc finding of earlier discontinuation of antibiotics after procalcitonin measurement suggests that our intervention may have influenced the decision to discontinue antibiotics. Such an effect may be augmented if procalcitonin is measured earlier in a hospital admission.

Previous studies have also failed to show that the use of procalcitonin decreased duration of antibiotics.^9,10 In the aforementioned study regarding real-world outcomes in patients with lower respiratory tract infections, antibiotic duration was not reduced, despite provider education.⁹ A large observational study that evaluated real-world outcomes in intensive care unit patients did not find decreased antibiotic use or improved outcomes with procalcitonin use.¹⁰ With these large studies evaluating the 2 most common infectious diseases for which procalcitonin has previously been found to have clinical benefit, it is important for institutions to re-evaluate how procalcitonin is being utilized by providers. Furthermore, institutions should explore ways to optimize procalcitonin use and decrease unnecessary health care costs. Notably, the current community-acquired pneumonia guidelines recommend against routine use of procalcitonin.¹¹

Conclusion

Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis or treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program that includes an algorithmic protocol to promote appropriate laboratory testing and reduce total antibiotic use. In addition to improved communication with providers, other interventions need to be investigated to effectively use this biomarker or limit its use.

Acknowledgment: The authors thank the Western Michigan University Department of Epidemiology and Biostatistics for their assistance in preparing this article.

Corresponding author: James Vaillant, MD, Western Michigan University, Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, 49008; [email protected].

Financial disclosures: None.

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

[email protected]

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

[email protected]

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

[email protected]

Patients with hematological malignancies are at high risk of invasive Staphylococcus pneumoniae. Multiple myeloma (MM) patients, in particular, have been found to have one of the highest incidences of invasive pneumococcal disease. However, researchers found that a full three-dose vaccination regimen by 13-valent pneumococcal conjugate (PCV13) vaccine was protective in MM patients when provided between treatment courses, according to a study reported in Vaccine.

The researchers performed a prospective study of 18 adult patients who were vaccinated with PCV13, compared with 18 control-matched patients from 2017 to 2020. The three-dose vaccination regimen was provided between treatment courses with novel target agents (bortezomib, lenalidomide, ixazomib) with a minimum of a 1-month interval. They used the incidence of pneumonias during the one-year observation period as the primary outcome.

Totally there were 12 cases (33.3%) of clinically and radiologically confirmed pneumonias in the entire study group (n = 36), with a distribution between the vaccinated and nonvaccinated groups of 3 (16.7%) and 9 (50%). respectively (P = .037).

The absolute risk reduction seen with vaccination was 33.3%, and the number needed to treat with PCV13 vaccination in MM patients receiving novel agents was 3.0; (95% confidence interval 1.61-22.1). In addition, there were no adverse effects seen from vaccination, according to the authors.

“Despite the expected decrease in immunological response to vaccination during the chemotherapy, we have shown the clinical effectiveness of a PCV13 vaccination schedule based on 3 doses given with a minimum 1 month interval between the courses of novel agents,” the investigators concluded.

The authors reported that they had no relevant disclosures.
 

[email protected]

SOURCE: Stoma I et al. Vaccine. 2020 May 14; doi.org/10.1016/j.vaccine.2020.05.024.

Patients with hematological malignancies are at high risk of invasive Staphylococcus pneumoniae. Multiple myeloma (MM) patients, in particular, have been found to have one of the highest incidences of invasive pneumococcal disease. However, researchers found that a full three-dose vaccination regimen by 13-valent pneumococcal conjugate (PCV13) vaccine was protective in MM patients when provided between treatment courses, according to a study reported in Vaccine.

The researchers performed a prospective study of 18 adult patients who were vaccinated with PCV13, compared with 18 control-matched patients from 2017 to 2020. The three-dose vaccination regimen was provided between treatment courses with novel target agents (bortezomib, lenalidomide, ixazomib) with a minimum of a 1-month interval. They used the incidence of pneumonias during the one-year observation period as the primary outcome.

Totally there were 12 cases (33.3%) of clinically and radiologically confirmed pneumonias in the entire study group (n = 36), with a distribution between the vaccinated and nonvaccinated groups of 3 (16.7%) and 9 (50%). respectively (P = .037).

The absolute risk reduction seen with vaccination was 33.3%, and the number needed to treat with PCV13 vaccination in MM patients receiving novel agents was 3.0; (95% confidence interval 1.61-22.1). In addition, there were no adverse effects seen from vaccination, according to the authors.

“Despite the expected decrease in immunological response to vaccination during the chemotherapy, we have shown the clinical effectiveness of a PCV13 vaccination schedule based on 3 doses given with a minimum 1 month interval between the courses of novel agents,” the investigators concluded.

The authors reported that they had no relevant disclosures.
 

[email protected]

SOURCE: Stoma I et al. Vaccine. 2020 May 14; doi.org/10.1016/j.vaccine.2020.05.024.

Patients with hematological malignancies are at high risk of invasive Staphylococcus pneumoniae. Multiple myeloma (MM) patients, in particular, have been found to have one of the highest incidences of invasive pneumococcal disease. However, researchers found that a full three-dose vaccination regimen by 13-valent pneumococcal conjugate (PCV13) vaccine was protective in MM patients when provided between treatment courses, according to a study reported in Vaccine.

The researchers performed a prospective study of 18 adult patients who were vaccinated with PCV13, compared with 18 control-matched patients from 2017 to 2020. The three-dose vaccination regimen was provided between treatment courses with novel target agents (bortezomib, lenalidomide, ixazomib) with a minimum of a 1-month interval. They used the incidence of pneumonias during the one-year observation period as the primary outcome.

Totally there were 12 cases (33.3%) of clinically and radiologically confirmed pneumonias in the entire study group (n = 36), with a distribution between the vaccinated and nonvaccinated groups of 3 (16.7%) and 9 (50%). respectively (P = .037).

The absolute risk reduction seen with vaccination was 33.3%, and the number needed to treat with PCV13 vaccination in MM patients receiving novel agents was 3.0; (95% confidence interval 1.61-22.1). In addition, there were no adverse effects seen from vaccination, according to the authors.

“Despite the expected decrease in immunological response to vaccination during the chemotherapy, we have shown the clinical effectiveness of a PCV13 vaccination schedule based on 3 doses given with a minimum 1 month interval between the courses of novel agents,” the investigators concluded.

The authors reported that they had no relevant disclosures.
 

[email protected]

SOURCE: Stoma I et al. Vaccine. 2020 May 14; doi.org/10.1016/j.vaccine.2020.05.024.

From the University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL.

Abstract

• Objective: To review current reports on atypical manifestations of coronavirus disease 2019 (COVID-19).
• Methods: Review of the literature.
• Results: Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect human cells that express the angiotensin-converting enzyme 2 receptor, which would allow for a broad spectrum of illnesses affecting the renal, cardiac, and gastrointestinal organ systems. Neurologic, cutaneous, and musculoskeletal manifestations have also been reported. The potential for SARS-CoV-2 to induce a hypercoagulable state provides another avenue for the virus to indirectly damage various organ systems, as evidenced by reports of cerebrovascular disease, myocardial injury, and a chilblain-like rash in patients with COVID-19.
• Conclusion: Because the signs and symptoms of COVID-19 may occur with varying frequency across populations, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Keywords: coronavirus; severe acute respiratory syndrome coronavirus-2; SARS-CoV-2; pandemic.

Coronavirus disease 2019 (COVID-19), the syndrome caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported in Wuhan, China, in early December 2019.¹ Since then, the virus has spread quickly around the world, with the World Health Organization (WHO) declaring the coronavirus outbreak a global pandemic on March 11, 2020. As of May 21, 2020, more than 5,000,000 cases of COVID-19 have been confirmed, and more than 328,000 deaths related to COVID-19 have been reported globally.² These numbers are expected to increase, due to the reproduction number (R0) of SARS-CoV-2. R0 represents the number of new infections generated by an infectious person in a totally naïve population.³ The WHO estimates that the R0 of SARS-CoV-2 is 1.95, with other estimates ranging from 1.4 to 6.49.³ To control the pathogen, the R0 needs to be brought under a value of 1.

A fundamental tool in lowering the R0 is prompt testing and isolation of those who display signs and symptoms of infection. SARS-CoV-2 is still a novel pathogen about which we know relatively little. The common symptoms of COVID-19 are now well known—including fever, fatigue, anorexia, cough, and shortness of breath—but atypical manifestations of this viral continue to be reported and described. To help clinicians across specialties and settings identify patients with possible infection, we have summarized findings from current reports on COVID-19 manifestations involving the renal, cardiac, gastrointestinal (GI), and other organ systems.

Renal

During the 2003 SARS-CoV-1 outbreak, acute kidney injury (AKI) was an uncommon complication of the infection, but early reports suggest that AKI may occur more commonly with COVID-19.⁴ In a study of 193 patients with laboratory-confirmed COVID-19 treated in 3 Chinese hospitals, 59% presented with proteinuria, 44% with hematuria, 14% with increased blood urea nitrogen, and 10% with increased levels of serum creatinine.⁴ These markers, indicative of AKI, may be associated with increased mortality. Among this cohort, those with AKI had a mortality risk 5.3 times higher than those who did not have AKI.⁴ The pathophysiology of renal disease in COVID-19 may be related to dehydration or inflammatory mediators, causing decreased renal perfusion and cytokine storm, but evidence also suggests that SARS-CoV-2 is able to directly infect kidney cells.⁵ The virus infects cells by using angiotensin-converting enzyme 2 (ACE2) on the cell membrane as a cell entry receptor; ACE2 is expressed on the kidney, heart, and GI cells, and this may allow SARS-CoV-2 to directly infect and damage these organs. Other potential mechanisms of renal injury include overproduction of proinflammatory cytokines and administration of nephrotoxic drugs. No matter the mechanism, however, increased serum creatinine and blood urea nitrogen correlate with an increased likelihood of requiring intensive care unit (ICU) admission.⁶ Therefore, clinicians should carefully monitor renal function in patients with COVID-19.

Cardiac

In a report of 138 Chinese patients hospitalized for COVID-19, 36 required ICU admission: 44.4% of these had arrhythmias and 22.2% had developed acute cardiac injury.⁶ In addition, the cardiac cell injury biomarker troponin I was more likely to be elevated in ICU patients.⁶ A study of 21 patients admitted to the ICU in Washington State found elevated levels of brain natriuretic peptide.⁷ These biomarkers reflect the presence of myocardial stress, but do not necessarily indicate direct myocardial infection. Case reports of fulminant myocarditis in those with COVID-19 have begun to surface, however.^8,9 An examination of 68 deaths in persons with COVID-19 concluded that 7% were caused by myocarditis with circulatory failure.¹⁰

The pathophysiology of myocardial injury in COVID-19 is likely multifactorial. This includes increased inflammatory mediators, hypoxemia, and metabolic changes that can directly damage myocardial tissue. These factors can also exacerbate comorbid conditions, such as coronary artery disease, leading to ischemia and dysfunction of preexisting electrical conduction abnormalities. However, pathologic evidence of myocarditis and the presence of the ACE2 receptor, which may be a mediator of cardiac function, on cardiac muscle cells suggest that SARS-CoV-2 is capable of directly infecting and damaging myocardial cells. Other proposed mechanisms include infection-mediated downregulation of ACE2, causing cardiac dysfunction, or thrombus formation.¹¹ Although respiratory failure is the most common source of advanced illness in COVID-19 patients, myocarditis and arrhythmias can be life-threatening manifestations of the disease.

Gastrointestinal

As noted, ACE2 is expressed in the GI tract. In 73 patients hospitalized for COVID-19, 53.4% tested positive for SARS-CoV-2 RNA in stool, and 23.4% continued to have RNA-positive stool samples even after their respiratory samples tested negative.¹² These findings suggest the potential for SARS-CoV-2 to spread through fecal-oral transmission in those who are asymptomatic, pre-symptomatic, or symptomatic. This mode of transmission has yet to be determined conclusively, and more research is needed. However, GI symptoms have been reported in persons with COVID-19. Among 138 hospitalized patients, 10.1% had complaints of diarrhea and nausea and 3.6% reported vomiting.⁶ Those who reported nausea and diarrhea noted that they developed these symptoms 1 to 2 days before they developed fever.⁶ Also, among a cohort of 1099 Chinese patients with COVID-19, 3.8% complained of diarrhea.¹³ Although diarrhea does not occur in a majority of patients, GI complaints, such as nausea, vomiting, or diarrhea, should raise clinical suspicion for COVID-19, and in known areas of active transmission, testing of patients with GI symptoms is likely warranted.

Ocular

Ocular manifestations of COVID-19 are now being described, and should be taken into consideration when examining a patient. In a study of 38 patients with COVID-19 from Hubei province, China, 31.6% had ocular findings consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, and increased ocular secretions.¹⁴ SARS-CoV-2 was detected in conjunctival and nasopharyngeal samples in 2 patients from this cohort. Conjunctival congestion was reported in a cohort of 1099 patients with COVID-19 treated at multiple centers throughout China, but at a much lower incidence, approximately 0.8%.¹³ Because SARS-CoV-2 can cause conjunctival disease and has been detected in samples from the external surface of the eye, it appears the virus is transmissible from tears or contact with the eye itself.

Neurologic

Common reported neurologic symptoms include dizziness, headache, impaired consciousness, ataxia, and cerebrovascular events. In a cohort of 214 patients from Wuhan, China, 36.4% had some form of neurological insult.¹⁵ These symptoms were more common in those with severe illness (P = 0.02).¹⁵ Two interesting neurologic symptoms that have been described are anosmia (loss of smell) and ageusia (loss of taste), which are being found primarily in tandem. It is still unclear how many people with COVID-19 are experiencing these symptoms, but a report from Italy estimates 19.4% of 320 patients examined had chemosensory dysfunction.¹⁶ The aforementioned report from Wuhan, China, found that 5.1% had anosmia and 5.6% had ageusia.¹⁵ The presence of anosmia/ageusia in some patients suggests that SARS-CoV-2 may enter the central nervous system (CNS) through a retrograde neuronal route.¹⁵ In addition, a case report from Japan described a 24-year-old man who presented with meningitis/encephalitis and had SARS-CoV-2 RNA present in his cerebrospinal fluid, showing that SARS-CoV-2 can penetrate into the CNS.¹⁷

SARS-CoV-2 may also have an association with Guillain–Barré syndrome, as this condition was reported in 5 patients from 3 hospitals in Northern Italy.¹⁸ The symptoms of Guillain–Barré syndrome presented 5 to 10 days after the typical COVID-19 symptoms, and evolved over 36 hours to 4 days afterwards. Four of the 5 patients experienced flaccid tetraparesis or tetraplegia, and 3 required mechanical ventilation.¹⁸

Another possible cause of neurologic injury in COVID-19 is damage to endothelial cells in cerebral blood vessels, causing thrombus formation and possibly increasing the risk of acute ischemic stroke.^15,19 Supporting this mechanism of injury, significantly lower platelet counts were noted in patients with CNS symptoms (P = 0.005).¹⁵ Other hematological impacts of COVID-19 have been reported, particularly hypercoagulability, as evidenced by elevated D-dimer levels.^13,20 This hypercoagulable state is linked to overproduction of proinflammatory cytokines (cytokine storm), leading to dysregulation of coagulation pathways and reduced concentrations of anticoagulants, such as protein C, antithrombin III, and tissue factor pathway inhibitor.²¹

Cutaneous

Cutaneous findings emerging in persons with COVID-19 demonstrate features of small-vessel and capillary occlusion, including erythematous skin eruptions and petechial rash. One report from Italy noted that 20.4% of patients with COVID-19 (n = 88) had a cutaneous finding, with a cutaneous manifestation developing in 8 at the onset of illness and in 10 following hospital admission.²² Fourteen patients had an erythematous rash, primarily on the trunk, with 3 patients having a diffuse urticarial appearing rash, and 1 patient developing vesicles.²² The severity of illness did not appear to correlate with the cutaneous manifestation, and the lesions healed within a few days.

One case report described a patient from Bangkok who was thought to be suffering from dengue fever, but was found to have SARS-CoV-2 infection. He initially presented with skin rash and petechiae, and later developed respiratory disease.²³

Other dermatologic findings of COVID-19 resemble chilblains disease, colloquially referred to as “COVID toes.” Two women, 27 and 35 years old, presented to a dermatology clinic in Qatar with a chief complaint of skin rash, described as red-purple papules on the dorsal aspects of the fingers bilaterally.²² Both patients had an unremarkable medical and drug history, but recent travel to the United Kingdom dictated SARS-CoV-2 screening, which was positive.²⁴ An Italian case report describes a 23-year-old man who tested positive for SARS-CoV-2 and had violaceous plaques on an erythematous background on his feet, without any lesions on his hands.²⁵ Since chilblains is less common in the warmer months and these events correspond with the COVID-19 pandemic, SARS-CoV-2 infection is the suspected etiology. The pathophysiology of these lesions is unclear, and more research is needed. As more data become available, we may see cutaneous manifestations in patients with COVID-19 similar to those commonly reported with other viral infectious processes.

Musculoskeletal

Of 138 patients hospitalized in Wuhan, China, for COVID-19, 34.8% presented with myalgia; the presence of myalgia does not appear to be correlated with an increased likelihood of ICU admission.⁶ Myalgia or arthralgia was also reported in 14.9% among the cohort of 1099 COVID-19 patients in China.¹³ These musculoskeletal symptoms are described among large muscle groups found in the extremities, trunk, and back, and should raise suspicion in patients who present with other signs and symptoms concerning for COVID-19.

Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect a human cells that express the ACE2 receptor, which would allow for a broad spectrum of illnesses. The potential for SARS-CoV-2 to induce a hypercoagulable state allows it to indirectly damage various organ systems,²⁰ leading to cerebrovascular disease, myocardial injury, and a chilblain-like rash. Clinicians must be aware of these unique features, as early recognition of persons who present with COVID-19 will allow for prompt testing, institution of infection control and isolation practices, and treatment, as needed, among those infected. Also, this is a pandemic involving a novel virus affecting different populations throughout the world, and these signs and symptoms may occur with varying frequency across populations. Therefore, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Corresponding author: Norman L. Beatty, MD, [email protected].

Financial disclosures: None.

From the University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL.

Abstract

• Objective: To review current reports on atypical manifestations of coronavirus disease 2019 (COVID-19).
• Methods: Review of the literature.
• Results: Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect human cells that express the angiotensin-converting enzyme 2 receptor, which would allow for a broad spectrum of illnesses affecting the renal, cardiac, and gastrointestinal organ systems. Neurologic, cutaneous, and musculoskeletal manifestations have also been reported. The potential for SARS-CoV-2 to induce a hypercoagulable state provides another avenue for the virus to indirectly damage various organ systems, as evidenced by reports of cerebrovascular disease, myocardial injury, and a chilblain-like rash in patients with COVID-19.
• Conclusion: Because the signs and symptoms of COVID-19 may occur with varying frequency across populations, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Keywords: coronavirus; severe acute respiratory syndrome coronavirus-2; SARS-CoV-2; pandemic.

Coronavirus disease 2019 (COVID-19), the syndrome caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported in Wuhan, China, in early December 2019.¹ Since then, the virus has spread quickly around the world, with the World Health Organization (WHO) declaring the coronavirus outbreak a global pandemic on March 11, 2020. As of May 21, 2020, more than 5,000,000 cases of COVID-19 have been confirmed, and more than 328,000 deaths related to COVID-19 have been reported globally.² These numbers are expected to increase, due to the reproduction number (R0) of SARS-CoV-2. R0 represents the number of new infections generated by an infectious person in a totally naïve population.³ The WHO estimates that the R0 of SARS-CoV-2 is 1.95, with other estimates ranging from 1.4 to 6.49.³ To control the pathogen, the R0 needs to be brought under a value of 1.

A fundamental tool in lowering the R0 is prompt testing and isolation of those who display signs and symptoms of infection. SARS-CoV-2 is still a novel pathogen about which we know relatively little. The common symptoms of COVID-19 are now well known—including fever, fatigue, anorexia, cough, and shortness of breath—but atypical manifestations of this viral continue to be reported and described. To help clinicians across specialties and settings identify patients with possible infection, we have summarized findings from current reports on COVID-19 manifestations involving the renal, cardiac, gastrointestinal (GI), and other organ systems.

Renal

During the 2003 SARS-CoV-1 outbreak, acute kidney injury (AKI) was an uncommon complication of the infection, but early reports suggest that AKI may occur more commonly with COVID-19.⁴ In a study of 193 patients with laboratory-confirmed COVID-19 treated in 3 Chinese hospitals, 59% presented with proteinuria, 44% with hematuria, 14% with increased blood urea nitrogen, and 10% with increased levels of serum creatinine.⁴ These markers, indicative of AKI, may be associated with increased mortality. Among this cohort, those with AKI had a mortality risk 5.3 times higher than those who did not have AKI.⁴ The pathophysiology of renal disease in COVID-19 may be related to dehydration or inflammatory mediators, causing decreased renal perfusion and cytokine storm, but evidence also suggests that SARS-CoV-2 is able to directly infect kidney cells.⁵ The virus infects cells by using angiotensin-converting enzyme 2 (ACE2) on the cell membrane as a cell entry receptor; ACE2 is expressed on the kidney, heart, and GI cells, and this may allow SARS-CoV-2 to directly infect and damage these organs. Other potential mechanisms of renal injury include overproduction of proinflammatory cytokines and administration of nephrotoxic drugs. No matter the mechanism, however, increased serum creatinine and blood urea nitrogen correlate with an increased likelihood of requiring intensive care unit (ICU) admission.⁶ Therefore, clinicians should carefully monitor renal function in patients with COVID-19.

Cardiac

In a report of 138 Chinese patients hospitalized for COVID-19, 36 required ICU admission: 44.4% of these had arrhythmias and 22.2% had developed acute cardiac injury.⁶ In addition, the cardiac cell injury biomarker troponin I was more likely to be elevated in ICU patients.⁶ A study of 21 patients admitted to the ICU in Washington State found elevated levels of brain natriuretic peptide.⁷ These biomarkers reflect the presence of myocardial stress, but do not necessarily indicate direct myocardial infection. Case reports of fulminant myocarditis in those with COVID-19 have begun to surface, however.^8,9 An examination of 68 deaths in persons with COVID-19 concluded that 7% were caused by myocarditis with circulatory failure.¹⁰

The pathophysiology of myocardial injury in COVID-19 is likely multifactorial. This includes increased inflammatory mediators, hypoxemia, and metabolic changes that can directly damage myocardial tissue. These factors can also exacerbate comorbid conditions, such as coronary artery disease, leading to ischemia and dysfunction of preexisting electrical conduction abnormalities. However, pathologic evidence of myocarditis and the presence of the ACE2 receptor, which may be a mediator of cardiac function, on cardiac muscle cells suggest that SARS-CoV-2 is capable of directly infecting and damaging myocardial cells. Other proposed mechanisms include infection-mediated downregulation of ACE2, causing cardiac dysfunction, or thrombus formation.¹¹ Although respiratory failure is the most common source of advanced illness in COVID-19 patients, myocarditis and arrhythmias can be life-threatening manifestations of the disease.

Gastrointestinal

As noted, ACE2 is expressed in the GI tract. In 73 patients hospitalized for COVID-19, 53.4% tested positive for SARS-CoV-2 RNA in stool, and 23.4% continued to have RNA-positive stool samples even after their respiratory samples tested negative.¹² These findings suggest the potential for SARS-CoV-2 to spread through fecal-oral transmission in those who are asymptomatic, pre-symptomatic, or symptomatic. This mode of transmission has yet to be determined conclusively, and more research is needed. However, GI symptoms have been reported in persons with COVID-19. Among 138 hospitalized patients, 10.1% had complaints of diarrhea and nausea and 3.6% reported vomiting.⁶ Those who reported nausea and diarrhea noted that they developed these symptoms 1 to 2 days before they developed fever.⁶ Also, among a cohort of 1099 Chinese patients with COVID-19, 3.8% complained of diarrhea.¹³ Although diarrhea does not occur in a majority of patients, GI complaints, such as nausea, vomiting, or diarrhea, should raise clinical suspicion for COVID-19, and in known areas of active transmission, testing of patients with GI symptoms is likely warranted.

Ocular

Ocular manifestations of COVID-19 are now being described, and should be taken into consideration when examining a patient. In a study of 38 patients with COVID-19 from Hubei province, China, 31.6% had ocular findings consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, and increased ocular secretions.¹⁴ SARS-CoV-2 was detected in conjunctival and nasopharyngeal samples in 2 patients from this cohort. Conjunctival congestion was reported in a cohort of 1099 patients with COVID-19 treated at multiple centers throughout China, but at a much lower incidence, approximately 0.8%.¹³ Because SARS-CoV-2 can cause conjunctival disease and has been detected in samples from the external surface of the eye, it appears the virus is transmissible from tears or contact with the eye itself.

Neurologic

Common reported neurologic symptoms include dizziness, headache, impaired consciousness, ataxia, and cerebrovascular events. In a cohort of 214 patients from Wuhan, China, 36.4% had some form of neurological insult.¹⁵ These symptoms were more common in those with severe illness (P = 0.02).¹⁵ Two interesting neurologic symptoms that have been described are anosmia (loss of smell) and ageusia (loss of taste), which are being found primarily in tandem. It is still unclear how many people with COVID-19 are experiencing these symptoms, but a report from Italy estimates 19.4% of 320 patients examined had chemosensory dysfunction.¹⁶ The aforementioned report from Wuhan, China, found that 5.1% had anosmia and 5.6% had ageusia.¹⁵ The presence of anosmia/ageusia in some patients suggests that SARS-CoV-2 may enter the central nervous system (CNS) through a retrograde neuronal route.¹⁵ In addition, a case report from Japan described a 24-year-old man who presented with meningitis/encephalitis and had SARS-CoV-2 RNA present in his cerebrospinal fluid, showing that SARS-CoV-2 can penetrate into the CNS.¹⁷

SARS-CoV-2 may also have an association with Guillain–Barré syndrome, as this condition was reported in 5 patients from 3 hospitals in Northern Italy.¹⁸ The symptoms of Guillain–Barré syndrome presented 5 to 10 days after the typical COVID-19 symptoms, and evolved over 36 hours to 4 days afterwards. Four of the 5 patients experienced flaccid tetraparesis or tetraplegia, and 3 required mechanical ventilation.¹⁸

Another possible cause of neurologic injury in COVID-19 is damage to endothelial cells in cerebral blood vessels, causing thrombus formation and possibly increasing the risk of acute ischemic stroke.^15,19 Supporting this mechanism of injury, significantly lower platelet counts were noted in patients with CNS symptoms (P = 0.005).¹⁵ Other hematological impacts of COVID-19 have been reported, particularly hypercoagulability, as evidenced by elevated D-dimer levels.^13,20 This hypercoagulable state is linked to overproduction of proinflammatory cytokines (cytokine storm), leading to dysregulation of coagulation pathways and reduced concentrations of anticoagulants, such as protein C, antithrombin III, and tissue factor pathway inhibitor.²¹

Cutaneous

Cutaneous findings emerging in persons with COVID-19 demonstrate features of small-vessel and capillary occlusion, including erythematous skin eruptions and petechial rash. One report from Italy noted that 20.4% of patients with COVID-19 (n = 88) had a cutaneous finding, with a cutaneous manifestation developing in 8 at the onset of illness and in 10 following hospital admission.²² Fourteen patients had an erythematous rash, primarily on the trunk, with 3 patients having a diffuse urticarial appearing rash, and 1 patient developing vesicles.²² The severity of illness did not appear to correlate with the cutaneous manifestation, and the lesions healed within a few days.

One case report described a patient from Bangkok who was thought to be suffering from dengue fever, but was found to have SARS-CoV-2 infection. He initially presented with skin rash and petechiae, and later developed respiratory disease.²³

Other dermatologic findings of COVID-19 resemble chilblains disease, colloquially referred to as “COVID toes.” Two women, 27 and 35 years old, presented to a dermatology clinic in Qatar with a chief complaint of skin rash, described as red-purple papules on the dorsal aspects of the fingers bilaterally.²² Both patients had an unremarkable medical and drug history, but recent travel to the United Kingdom dictated SARS-CoV-2 screening, which was positive.²⁴ An Italian case report describes a 23-year-old man who tested positive for SARS-CoV-2 and had violaceous plaques on an erythematous background on his feet, without any lesions on his hands.²⁵ Since chilblains is less common in the warmer months and these events correspond with the COVID-19 pandemic, SARS-CoV-2 infection is the suspected etiology. The pathophysiology of these lesions is unclear, and more research is needed. As more data become available, we may see cutaneous manifestations in patients with COVID-19 similar to those commonly reported with other viral infectious processes.

Musculoskeletal

Of 138 patients hospitalized in Wuhan, China, for COVID-19, 34.8% presented with myalgia; the presence of myalgia does not appear to be correlated with an increased likelihood of ICU admission.⁶ Myalgia or arthralgia was also reported in 14.9% among the cohort of 1099 COVID-19 patients in China.¹³ These musculoskeletal symptoms are described among large muscle groups found in the extremities, trunk, and back, and should raise suspicion in patients who present with other signs and symptoms concerning for COVID-19.

Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect a human cells that express the ACE2 receptor, which would allow for a broad spectrum of illnesses. The potential for SARS-CoV-2 to induce a hypercoagulable state allows it to indirectly damage various organ systems,²⁰ leading to cerebrovascular disease, myocardial injury, and a chilblain-like rash. Clinicians must be aware of these unique features, as early recognition of persons who present with COVID-19 will allow for prompt testing, institution of infection control and isolation practices, and treatment, as needed, among those infected. Also, this is a pandemic involving a novel virus affecting different populations throughout the world, and these signs and symptoms may occur with varying frequency across populations. Therefore, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Corresponding author: Norman L. Beatty, MD, [email protected].

Financial disclosures: None.

From the University of Florida College of Medicine, Division of Infectious Diseases and Global Medicine, Gainesville, FL.

Abstract

• Objective: To review current reports on atypical manifestations of coronavirus disease 2019 (COVID-19).
• Methods: Review of the literature.
• Results: Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect human cells that express the angiotensin-converting enzyme 2 receptor, which would allow for a broad spectrum of illnesses affecting the renal, cardiac, and gastrointestinal organ systems. Neurologic, cutaneous, and musculoskeletal manifestations have also been reported. The potential for SARS-CoV-2 to induce a hypercoagulable state provides another avenue for the virus to indirectly damage various organ systems, as evidenced by reports of cerebrovascular disease, myocardial injury, and a chilblain-like rash in patients with COVID-19.
• Conclusion: Because the signs and symptoms of COVID-19 may occur with varying frequency across populations, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Keywords: coronavirus; severe acute respiratory syndrome coronavirus-2; SARS-CoV-2; pandemic.

Coronavirus disease 2019 (COVID-19), the syndrome caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported in Wuhan, China, in early December 2019.¹ Since then, the virus has spread quickly around the world, with the World Health Organization (WHO) declaring the coronavirus outbreak a global pandemic on March 11, 2020. As of May 21, 2020, more than 5,000,000 cases of COVID-19 have been confirmed, and more than 328,000 deaths related to COVID-19 have been reported globally.² These numbers are expected to increase, due to the reproduction number (R0) of SARS-CoV-2. R0 represents the number of new infections generated by an infectious person in a totally naïve population.³ The WHO estimates that the R0 of SARS-CoV-2 is 1.95, with other estimates ranging from 1.4 to 6.49.³ To control the pathogen, the R0 needs to be brought under a value of 1.

A fundamental tool in lowering the R0 is prompt testing and isolation of those who display signs and symptoms of infection. SARS-CoV-2 is still a novel pathogen about which we know relatively little. The common symptoms of COVID-19 are now well known—including fever, fatigue, anorexia, cough, and shortness of breath—but atypical manifestations of this viral continue to be reported and described. To help clinicians across specialties and settings identify patients with possible infection, we have summarized findings from current reports on COVID-19 manifestations involving the renal, cardiac, gastrointestinal (GI), and other organ systems.

Renal

During the 2003 SARS-CoV-1 outbreak, acute kidney injury (AKI) was an uncommon complication of the infection, but early reports suggest that AKI may occur more commonly with COVID-19.⁴ In a study of 193 patients with laboratory-confirmed COVID-19 treated in 3 Chinese hospitals, 59% presented with proteinuria, 44% with hematuria, 14% with increased blood urea nitrogen, and 10% with increased levels of serum creatinine.⁴ These markers, indicative of AKI, may be associated with increased mortality. Among this cohort, those with AKI had a mortality risk 5.3 times higher than those who did not have AKI.⁴ The pathophysiology of renal disease in COVID-19 may be related to dehydration or inflammatory mediators, causing decreased renal perfusion and cytokine storm, but evidence also suggests that SARS-CoV-2 is able to directly infect kidney cells.⁵ The virus infects cells by using angiotensin-converting enzyme 2 (ACE2) on the cell membrane as a cell entry receptor; ACE2 is expressed on the kidney, heart, and GI cells, and this may allow SARS-CoV-2 to directly infect and damage these organs. Other potential mechanisms of renal injury include overproduction of proinflammatory cytokines and administration of nephrotoxic drugs. No matter the mechanism, however, increased serum creatinine and blood urea nitrogen correlate with an increased likelihood of requiring intensive care unit (ICU) admission.⁶ Therefore, clinicians should carefully monitor renal function in patients with COVID-19.

Cardiac

In a report of 138 Chinese patients hospitalized for COVID-19, 36 required ICU admission: 44.4% of these had arrhythmias and 22.2% had developed acute cardiac injury.⁶ In addition, the cardiac cell injury biomarker troponin I was more likely to be elevated in ICU patients.⁶ A study of 21 patients admitted to the ICU in Washington State found elevated levels of brain natriuretic peptide.⁷ These biomarkers reflect the presence of myocardial stress, but do not necessarily indicate direct myocardial infection. Case reports of fulminant myocarditis in those with COVID-19 have begun to surface, however.^8,9 An examination of 68 deaths in persons with COVID-19 concluded that 7% were caused by myocarditis with circulatory failure.¹⁰

The pathophysiology of myocardial injury in COVID-19 is likely multifactorial. This includes increased inflammatory mediators, hypoxemia, and metabolic changes that can directly damage myocardial tissue. These factors can also exacerbate comorbid conditions, such as coronary artery disease, leading to ischemia and dysfunction of preexisting electrical conduction abnormalities. However, pathologic evidence of myocarditis and the presence of the ACE2 receptor, which may be a mediator of cardiac function, on cardiac muscle cells suggest that SARS-CoV-2 is capable of directly infecting and damaging myocardial cells. Other proposed mechanisms include infection-mediated downregulation of ACE2, causing cardiac dysfunction, or thrombus formation.¹¹ Although respiratory failure is the most common source of advanced illness in COVID-19 patients, myocarditis and arrhythmias can be life-threatening manifestations of the disease.

Gastrointestinal

As noted, ACE2 is expressed in the GI tract. In 73 patients hospitalized for COVID-19, 53.4% tested positive for SARS-CoV-2 RNA in stool, and 23.4% continued to have RNA-positive stool samples even after their respiratory samples tested negative.¹² These findings suggest the potential for SARS-CoV-2 to spread through fecal-oral transmission in those who are asymptomatic, pre-symptomatic, or symptomatic. This mode of transmission has yet to be determined conclusively, and more research is needed. However, GI symptoms have been reported in persons with COVID-19. Among 138 hospitalized patients, 10.1% had complaints of diarrhea and nausea and 3.6% reported vomiting.⁶ Those who reported nausea and diarrhea noted that they developed these symptoms 1 to 2 days before they developed fever.⁶ Also, among a cohort of 1099 Chinese patients with COVID-19, 3.8% complained of diarrhea.¹³ Although diarrhea does not occur in a majority of patients, GI complaints, such as nausea, vomiting, or diarrhea, should raise clinical suspicion for COVID-19, and in known areas of active transmission, testing of patients with GI symptoms is likely warranted.

Ocular

Ocular manifestations of COVID-19 are now being described, and should be taken into consideration when examining a patient. In a study of 38 patients with COVID-19 from Hubei province, China, 31.6% had ocular findings consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, and increased ocular secretions.¹⁴ SARS-CoV-2 was detected in conjunctival and nasopharyngeal samples in 2 patients from this cohort. Conjunctival congestion was reported in a cohort of 1099 patients with COVID-19 treated at multiple centers throughout China, but at a much lower incidence, approximately 0.8%.¹³ Because SARS-CoV-2 can cause conjunctival disease and has been detected in samples from the external surface of the eye, it appears the virus is transmissible from tears or contact with the eye itself.

Neurologic

Common reported neurologic symptoms include dizziness, headache, impaired consciousness, ataxia, and cerebrovascular events. In a cohort of 214 patients from Wuhan, China, 36.4% had some form of neurological insult.¹⁵ These symptoms were more common in those with severe illness (P = 0.02).¹⁵ Two interesting neurologic symptoms that have been described are anosmia (loss of smell) and ageusia (loss of taste), which are being found primarily in tandem. It is still unclear how many people with COVID-19 are experiencing these symptoms, but a report from Italy estimates 19.4% of 320 patients examined had chemosensory dysfunction.¹⁶ The aforementioned report from Wuhan, China, found that 5.1% had anosmia and 5.6% had ageusia.¹⁵ The presence of anosmia/ageusia in some patients suggests that SARS-CoV-2 may enter the central nervous system (CNS) through a retrograde neuronal route.¹⁵ In addition, a case report from Japan described a 24-year-old man who presented with meningitis/encephalitis and had SARS-CoV-2 RNA present in his cerebrospinal fluid, showing that SARS-CoV-2 can penetrate into the CNS.¹⁷

SARS-CoV-2 may also have an association with Guillain–Barré syndrome, as this condition was reported in 5 patients from 3 hospitals in Northern Italy.¹⁸ The symptoms of Guillain–Barré syndrome presented 5 to 10 days after the typical COVID-19 symptoms, and evolved over 36 hours to 4 days afterwards. Four of the 5 patients experienced flaccid tetraparesis or tetraplegia, and 3 required mechanical ventilation.¹⁸

Another possible cause of neurologic injury in COVID-19 is damage to endothelial cells in cerebral blood vessels, causing thrombus formation and possibly increasing the risk of acute ischemic stroke.^15,19 Supporting this mechanism of injury, significantly lower platelet counts were noted in patients with CNS symptoms (P = 0.005).¹⁵ Other hematological impacts of COVID-19 have been reported, particularly hypercoagulability, as evidenced by elevated D-dimer levels.^13,20 This hypercoagulable state is linked to overproduction of proinflammatory cytokines (cytokine storm), leading to dysregulation of coagulation pathways and reduced concentrations of anticoagulants, such as protein C, antithrombin III, and tissue factor pathway inhibitor.²¹

Cutaneous

Cutaneous findings emerging in persons with COVID-19 demonstrate features of small-vessel and capillary occlusion, including erythematous skin eruptions and petechial rash. One report from Italy noted that 20.4% of patients with COVID-19 (n = 88) had a cutaneous finding, with a cutaneous manifestation developing in 8 at the onset of illness and in 10 following hospital admission.²² Fourteen patients had an erythematous rash, primarily on the trunk, with 3 patients having a diffuse urticarial appearing rash, and 1 patient developing vesicles.²² The severity of illness did not appear to correlate with the cutaneous manifestation, and the lesions healed within a few days.

One case report described a patient from Bangkok who was thought to be suffering from dengue fever, but was found to have SARS-CoV-2 infection. He initially presented with skin rash and petechiae, and later developed respiratory disease.²³

Other dermatologic findings of COVID-19 resemble chilblains disease, colloquially referred to as “COVID toes.” Two women, 27 and 35 years old, presented to a dermatology clinic in Qatar with a chief complaint of skin rash, described as red-purple papules on the dorsal aspects of the fingers bilaterally.²² Both patients had an unremarkable medical and drug history, but recent travel to the United Kingdom dictated SARS-CoV-2 screening, which was positive.²⁴ An Italian case report describes a 23-year-old man who tested positive for SARS-CoV-2 and had violaceous plaques on an erythematous background on his feet, without any lesions on his hands.²⁵ Since chilblains is less common in the warmer months and these events correspond with the COVID-19 pandemic, SARS-CoV-2 infection is the suspected etiology. The pathophysiology of these lesions is unclear, and more research is needed. As more data become available, we may see cutaneous manifestations in patients with COVID-19 similar to those commonly reported with other viral infectious processes.

Musculoskeletal

Of 138 patients hospitalized in Wuhan, China, for COVID-19, 34.8% presented with myalgia; the presence of myalgia does not appear to be correlated with an increased likelihood of ICU admission.⁶ Myalgia or arthralgia was also reported in 14.9% among the cohort of 1099 COVID-19 patients in China.¹³ These musculoskeletal symptoms are described among large muscle groups found in the extremities, trunk, and back, and should raise suspicion in patients who present with other signs and symptoms concerning for COVID-19.

Evidence regarding atypical features of COVID-19 is accumulating. SARS-CoV-2 can infect a human cells that express the ACE2 receptor, which would allow for a broad spectrum of illnesses. The potential for SARS-CoV-2 to induce a hypercoagulable state allows it to indirectly damage various organ systems,²⁰ leading to cerebrovascular disease, myocardial injury, and a chilblain-like rash. Clinicians must be aware of these unique features, as early recognition of persons who present with COVID-19 will allow for prompt testing, institution of infection control and isolation practices, and treatment, as needed, among those infected. Also, this is a pandemic involving a novel virus affecting different populations throughout the world, and these signs and symptoms may occur with varying frequency across populations. Therefore, it is important to keep differentials broad when assessing patients with a clinical illness that may indeed be COVID-19.

Corresponding author: Norman L. Beatty, MD, [email protected].

Financial disclosures: None.

Study Overview

Objective. To assess the efficacy, safety, and clinical benefit of remdesivir in hospitalized adults with confirmed pneumonia due to severe SARS-CoV-2 infection.

Design. Randomized, investigator-initiated, placebo-controlled, double-blind, multicenter trial.

Setting and participants. The trial took place between February 6, 2020 and March 12, 2020, at 10 hospitals in Wuhan, China. Study participants included adult patients (aged ≥ 18 years) admitted to hospital who tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction assay and had the following clinical characteristics: radiographic evidence of pneumonia; hypoxia with oxygen saturation ≤ 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300 mm Hg; and symptom onset to enrollment ≤ 12 days. Some of the exclusion criteria for participation in the study were pregnancy or breast feeding, liver cirrhosis, abnormal liver enzymes ≥ 5 times the upper limit of normal, severe renal impairment or receipt of renal replacement therapy, plan for transfer to a non-study hospital, and enrollment in a trial for COVID-19 within the previous month.

Intervention. Participants were randomized in a 2:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200 mg on day 1 followed by 100 mg daily on days 2-10) or the same volume of placebo for 10 days. Clinical and safety data assessed included laboratory testing, electrocardiogram, and medication adverse effects. Testing of oropharyngeal and nasopharyngeal swab samples, anal swab samples, sputum, and stool was performed for viral RNA detection and quantification on days 1, 3, 5, 7, 10, 14, 21, and 28.

Main outcome measures. The primary endpoint of this study was time to clinical improvement within 28 days after randomization. Clinical improvement was defined as a 2-point reduction in participants’ admission status on a 6-point ordinal scale (1 = discharged or clinical recovery, 6 = death) or live discharge from hospital, whichever came first. Secondary outcomes included all-cause mortality at day 28 and duration of hospital admission, oxygen support, and invasive mechanical ventilation. Virological measures and safety outcomes ascertained included treatment-emergent adverse events, serious adverse events, and premature discontinuation of remdesivir.

The sample size estimate for the original study design was a total of 453 patients (302 in the remdesivir group and 151 in the placebo group). This sample size would provide 80% power, assuming a hazard ratio (HR) of 1.4 comparing remdesivir to placebo, and corresponding to a change in time to clinical improvement of 6 days. The analysis of primary outcome was performed on an intention-to-treat basis. Time to clinical improvement within 28 days was assessed with Kaplan-Meier plots.

Main results. A total of 255 patients were screened, of whom 237 were enrolled and randomized to remdesivir (158) or placebo (79) group. Of the participants in the remdesivir group, 155 started study treatment and 150 completed treatment per protocol. For the participants in the placebo group, 78 started study treatment and 76 completed treatment per-protocol. Study enrollment was terminated after March 12, 2020, before attaining the prespecified sample size, because no additional patients met study eligibility criteria due to various public health measures implemented in Wuhan. The median age of participants was 65 years (IQR, 56-71), the majority were men (56% in remdesivir group vs 65% in placebo group), and the most common comorbidities included hypertension, diabetes, and coronary artery disease. Median time from symptom onset to study enrollment was 10 days (IQR, 9-12). The time to clinical improvement between treatments (21 days for remdesivir group vs 23 days for placebo group) was not significantly different (HR, 1.23; 95% confidence interval [CI], 0.87-1.75). In addition, in participants who received treatment within 10 days of symptom onset, those who were administered remdesivir had a nonsignificant (HR, 1.52; 95% CI, 0.95-2.43) but faster time (18 days) to clinical improvement, compared to those administered placebo (23 days). Moreover, treatment with remdesivir versus placebo did not lead to differences in secondary outcomes (eg, 28-day mortality and duration of hospital stay, oxygen support, and invasive mechanical ventilation), changes in viral load over time, or adverse events between the groups.

Conclusion. This study found that, compared with placebo, intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of SARS-CoV-2 in hospitalized adults with severe COVID-19. A numeric reduction in time to clinical improvement with early remdesivir treatment (ie, within 10 days of symptom onset) that approached statistical significance was observed in this underpowered study.

Commentary

Within a few short months since its emergence. SARS-CoV-2 infection has caused a global pandemic, posing a dire threat to public health due to its adverse effects on morbidity (eg, respiratory failure, thromboembolic diseases, multiorgan failure) and mortality. To date, no pharmacologic treatment has been shown to effectively improve clinical outcomes in patients with COVID-19. Multiple ongoing clinical trials are being conducted globally to determine potential therapeutic treatments for severe COVID-19. The first clinical trials of hydroxychloroquine and lopinavir-ritonavir, agents traditionally used for other indications, such as malaria and HIV, did not show a clear benefit in COVID-19.^1,2 Remdesivir, a nucleoside analogue prodrug, is a broad-spectrum antiviral agent that was previously used for treatment of Ebola and has been shown to have inhibitory effects on pathogenic coronaviruses. The study reported by Wang and colleagues was the first randomized controlled trial (RCT) aimed at evaluating whether remdesivir improves outcomes in patients with severe COVID-19. Thus, the worsening COVID-19 pandemic, coupled with the absence of a curative treatment, underscore the urgency of this trial.

The study was grounded on observational data from several recent case reports and case series centering on the potential efficacy of remdesivir in treating COVID-19.³ The study itself was designed well (ie, randomized, placebo-controlled, double-blind, multicenter) and carefully implemented (ie, high protocol adherence to treatments, no loss to follow-up). The principal limitation of this study was its inability to reach the estimated statistical power of study. Due to successful epidemic control in Wuhan, which led to marked reductions in hospital admission of patients with COVID-19, and implementation of stringent termination criteria per the study protocol, only 237 participants were enrolled, instead of the 453, as specified by the sample estimate. This corresponded to a reduction of statistical power from 80% to 58%. Due to this limitation, the study was underpowered, rendering its findings inconclusive.

Despite this limitation, the study found that those treated with remdesivir within 10 days of symptom onset had a numerically faster time (although not statistically significant) to clinical improvement. This leads to an interesting question: whether remdesivir administration early in COVID-19 course could improve clinical outcomes, a question that warrants further investigation by an adequately powered trial. Also, data from this study provided evidence that intravenous remdesivir administration is likely safe in adults during the treatment period, although the long-term drug effects, as well as the safety profile in pediatric patients, remain unknown at this time.

While the study reported by Wang and colleagues was underpowered and is thus inconclusive, several other ongoing RCTs are evaluating the potential clinical benefit of remdesivir treatment in patients hospitalized with COVID-19. On the date of online publication of this report in The Lancet, the National Institutes of Health (NIH) published a news release summarizing preliminary findings from the Adaptive COVID-19 Treatment Trial (ACTT), which showed positive effects of remdesivir on clinical recovery from advanced COVID-19.⁴ The ACTT, the first RCT launched in the United States to evaluate experimental treatment for COVID-19, included 1063 hospitalized participants with advanced COVID-19 and lung involvement. Participants who were administered remdesivir had a 31% faster time to recovery compared to those in the placebo group (median time to recovery, 11 days vs 15 days, respectively; P < 0.001), and had near statistically significant improved survival (mortality rate, 8.0% vs 11.6%, respectively; P = 0.059). In response to these findings, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ While the findings noted from the NIH news release are very encouraging and provide the first evidence of a potentially beneficial antiviral treatment for severe COVID-19 in humans, the scientific community awaits the peer-reviewed publication of the ACTT to better assess the safety and effectiveness of remdesivir therapy and determine the trial’s implications in the management of COVID-19.

The discovery of an effective pharmacologic intervention for COVID-19 is of utmost urgency. While the present study was unable to answer the question of whether remdesivir is effective in improving clinical outcomes in patients with severe COVID-19, other ongoing or completed (ie, ACTT) studies will likely address this knowledge gap in the coming months. The FDA’s emergency use authorization for remdesivir provides a glimpse into this possibility.

–Katerina Oikonomou, MD, Brookdale Department of Geriatrics & Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

–Fred Ko, MD

Study Overview

Objective. To assess the efficacy, safety, and clinical benefit of remdesivir in hospitalized adults with confirmed pneumonia due to severe SARS-CoV-2 infection.

Design. Randomized, investigator-initiated, placebo-controlled, double-blind, multicenter trial.

Setting and participants. The trial took place between February 6, 2020 and March 12, 2020, at 10 hospitals in Wuhan, China. Study participants included adult patients (aged ≥ 18 years) admitted to hospital who tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction assay and had the following clinical characteristics: radiographic evidence of pneumonia; hypoxia with oxygen saturation ≤ 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300 mm Hg; and symptom onset to enrollment ≤ 12 days. Some of the exclusion criteria for participation in the study were pregnancy or breast feeding, liver cirrhosis, abnormal liver enzymes ≥ 5 times the upper limit of normal, severe renal impairment or receipt of renal replacement therapy, plan for transfer to a non-study hospital, and enrollment in a trial for COVID-19 within the previous month.

Intervention. Participants were randomized in a 2:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200 mg on day 1 followed by 100 mg daily on days 2-10) or the same volume of placebo for 10 days. Clinical and safety data assessed included laboratory testing, electrocardiogram, and medication adverse effects. Testing of oropharyngeal and nasopharyngeal swab samples, anal swab samples, sputum, and stool was performed for viral RNA detection and quantification on days 1, 3, 5, 7, 10, 14, 21, and 28.

Main outcome measures. The primary endpoint of this study was time to clinical improvement within 28 days after randomization. Clinical improvement was defined as a 2-point reduction in participants’ admission status on a 6-point ordinal scale (1 = discharged or clinical recovery, 6 = death) or live discharge from hospital, whichever came first. Secondary outcomes included all-cause mortality at day 28 and duration of hospital admission, oxygen support, and invasive mechanical ventilation. Virological measures and safety outcomes ascertained included treatment-emergent adverse events, serious adverse events, and premature discontinuation of remdesivir.

The sample size estimate for the original study design was a total of 453 patients (302 in the remdesivir group and 151 in the placebo group). This sample size would provide 80% power, assuming a hazard ratio (HR) of 1.4 comparing remdesivir to placebo, and corresponding to a change in time to clinical improvement of 6 days. The analysis of primary outcome was performed on an intention-to-treat basis. Time to clinical improvement within 28 days was assessed with Kaplan-Meier plots.

Main results. A total of 255 patients were screened, of whom 237 were enrolled and randomized to remdesivir (158) or placebo (79) group. Of the participants in the remdesivir group, 155 started study treatment and 150 completed treatment per protocol. For the participants in the placebo group, 78 started study treatment and 76 completed treatment per-protocol. Study enrollment was terminated after March 12, 2020, before attaining the prespecified sample size, because no additional patients met study eligibility criteria due to various public health measures implemented in Wuhan. The median age of participants was 65 years (IQR, 56-71), the majority were men (56% in remdesivir group vs 65% in placebo group), and the most common comorbidities included hypertension, diabetes, and coronary artery disease. Median time from symptom onset to study enrollment was 10 days (IQR, 9-12). The time to clinical improvement between treatments (21 days for remdesivir group vs 23 days for placebo group) was not significantly different (HR, 1.23; 95% confidence interval [CI], 0.87-1.75). In addition, in participants who received treatment within 10 days of symptom onset, those who were administered remdesivir had a nonsignificant (HR, 1.52; 95% CI, 0.95-2.43) but faster time (18 days) to clinical improvement, compared to those administered placebo (23 days). Moreover, treatment with remdesivir versus placebo did not lead to differences in secondary outcomes (eg, 28-day mortality and duration of hospital stay, oxygen support, and invasive mechanical ventilation), changes in viral load over time, or adverse events between the groups.

Conclusion. This study found that, compared with placebo, intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of SARS-CoV-2 in hospitalized adults with severe COVID-19. A numeric reduction in time to clinical improvement with early remdesivir treatment (ie, within 10 days of symptom onset) that approached statistical significance was observed in this underpowered study.

Commentary

Within a few short months since its emergence. SARS-CoV-2 infection has caused a global pandemic, posing a dire threat to public health due to its adverse effects on morbidity (eg, respiratory failure, thromboembolic diseases, multiorgan failure) and mortality. To date, no pharmacologic treatment has been shown to effectively improve clinical outcomes in patients with COVID-19. Multiple ongoing clinical trials are being conducted globally to determine potential therapeutic treatments for severe COVID-19. The first clinical trials of hydroxychloroquine and lopinavir-ritonavir, agents traditionally used for other indications, such as malaria and HIV, did not show a clear benefit in COVID-19.^1,2 Remdesivir, a nucleoside analogue prodrug, is a broad-spectrum antiviral agent that was previously used for treatment of Ebola and has been shown to have inhibitory effects on pathogenic coronaviruses. The study reported by Wang and colleagues was the first randomized controlled trial (RCT) aimed at evaluating whether remdesivir improves outcomes in patients with severe COVID-19. Thus, the worsening COVID-19 pandemic, coupled with the absence of a curative treatment, underscore the urgency of this trial.

The study was grounded on observational data from several recent case reports and case series centering on the potential efficacy of remdesivir in treating COVID-19.³ The study itself was designed well (ie, randomized, placebo-controlled, double-blind, multicenter) and carefully implemented (ie, high protocol adherence to treatments, no loss to follow-up). The principal limitation of this study was its inability to reach the estimated statistical power of study. Due to successful epidemic control in Wuhan, which led to marked reductions in hospital admission of patients with COVID-19, and implementation of stringent termination criteria per the study protocol, only 237 participants were enrolled, instead of the 453, as specified by the sample estimate. This corresponded to a reduction of statistical power from 80% to 58%. Due to this limitation, the study was underpowered, rendering its findings inconclusive.

Despite this limitation, the study found that those treated with remdesivir within 10 days of symptom onset had a numerically faster time (although not statistically significant) to clinical improvement. This leads to an interesting question: whether remdesivir administration early in COVID-19 course could improve clinical outcomes, a question that warrants further investigation by an adequately powered trial. Also, data from this study provided evidence that intravenous remdesivir administration is likely safe in adults during the treatment period, although the long-term drug effects, as well as the safety profile in pediatric patients, remain unknown at this time.

While the study reported by Wang and colleagues was underpowered and is thus inconclusive, several other ongoing RCTs are evaluating the potential clinical benefit of remdesivir treatment in patients hospitalized with COVID-19. On the date of online publication of this report in The Lancet, the National Institutes of Health (NIH) published a news release summarizing preliminary findings from the Adaptive COVID-19 Treatment Trial (ACTT), which showed positive effects of remdesivir on clinical recovery from advanced COVID-19.⁴ The ACTT, the first RCT launched in the United States to evaluate experimental treatment for COVID-19, included 1063 hospitalized participants with advanced COVID-19 and lung involvement. Participants who were administered remdesivir had a 31% faster time to recovery compared to those in the placebo group (median time to recovery, 11 days vs 15 days, respectively; P < 0.001), and had near statistically significant improved survival (mortality rate, 8.0% vs 11.6%, respectively; P = 0.059). In response to these findings, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ While the findings noted from the NIH news release are very encouraging and provide the first evidence of a potentially beneficial antiviral treatment for severe COVID-19 in humans, the scientific community awaits the peer-reviewed publication of the ACTT to better assess the safety and effectiveness of remdesivir therapy and determine the trial’s implications in the management of COVID-19.

The discovery of an effective pharmacologic intervention for COVID-19 is of utmost urgency. While the present study was unable to answer the question of whether remdesivir is effective in improving clinical outcomes in patients with severe COVID-19, other ongoing or completed (ie, ACTT) studies will likely address this knowledge gap in the coming months. The FDA’s emergency use authorization for remdesivir provides a glimpse into this possibility.

–Katerina Oikonomou, MD, Brookdale Department of Geriatrics & Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

–Fred Ko, MD

Study Overview

Objective. To assess the efficacy, safety, and clinical benefit of remdesivir in hospitalized adults with confirmed pneumonia due to severe SARS-CoV-2 infection.

Design. Randomized, investigator-initiated, placebo-controlled, double-blind, multicenter trial.

Setting and participants. The trial took place between February 6, 2020 and March 12, 2020, at 10 hospitals in Wuhan, China. Study participants included adult patients (aged ≥ 18 years) admitted to hospital who tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction assay and had the following clinical characteristics: radiographic evidence of pneumonia; hypoxia with oxygen saturation ≤ 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300 mm Hg; and symptom onset to enrollment ≤ 12 days. Some of the exclusion criteria for participation in the study were pregnancy or breast feeding, liver cirrhosis, abnormal liver enzymes ≥ 5 times the upper limit of normal, severe renal impairment or receipt of renal replacement therapy, plan for transfer to a non-study hospital, and enrollment in a trial for COVID-19 within the previous month.

Intervention. Participants were randomized in a 2:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200 mg on day 1 followed by 100 mg daily on days 2-10) or the same volume of placebo for 10 days. Clinical and safety data assessed included laboratory testing, electrocardiogram, and medication adverse effects. Testing of oropharyngeal and nasopharyngeal swab samples, anal swab samples, sputum, and stool was performed for viral RNA detection and quantification on days 1, 3, 5, 7, 10, 14, 21, and 28.

Main outcome measures. The primary endpoint of this study was time to clinical improvement within 28 days after randomization. Clinical improvement was defined as a 2-point reduction in participants’ admission status on a 6-point ordinal scale (1 = discharged or clinical recovery, 6 = death) or live discharge from hospital, whichever came first. Secondary outcomes included all-cause mortality at day 28 and duration of hospital admission, oxygen support, and invasive mechanical ventilation. Virological measures and safety outcomes ascertained included treatment-emergent adverse events, serious adverse events, and premature discontinuation of remdesivir.

The sample size estimate for the original study design was a total of 453 patients (302 in the remdesivir group and 151 in the placebo group). This sample size would provide 80% power, assuming a hazard ratio (HR) of 1.4 comparing remdesivir to placebo, and corresponding to a change in time to clinical improvement of 6 days. The analysis of primary outcome was performed on an intention-to-treat basis. Time to clinical improvement within 28 days was assessed with Kaplan-Meier plots.

Main results. A total of 255 patients were screened, of whom 237 were enrolled and randomized to remdesivir (158) or placebo (79) group. Of the participants in the remdesivir group, 155 started study treatment and 150 completed treatment per protocol. For the participants in the placebo group, 78 started study treatment and 76 completed treatment per-protocol. Study enrollment was terminated after March 12, 2020, before attaining the prespecified sample size, because no additional patients met study eligibility criteria due to various public health measures implemented in Wuhan. The median age of participants was 65 years (IQR, 56-71), the majority were men (56% in remdesivir group vs 65% in placebo group), and the most common comorbidities included hypertension, diabetes, and coronary artery disease. Median time from symptom onset to study enrollment was 10 days (IQR, 9-12). The time to clinical improvement between treatments (21 days for remdesivir group vs 23 days for placebo group) was not significantly different (HR, 1.23; 95% confidence interval [CI], 0.87-1.75). In addition, in participants who received treatment within 10 days of symptom onset, those who were administered remdesivir had a nonsignificant (HR, 1.52; 95% CI, 0.95-2.43) but faster time (18 days) to clinical improvement, compared to those administered placebo (23 days). Moreover, treatment with remdesivir versus placebo did not lead to differences in secondary outcomes (eg, 28-day mortality and duration of hospital stay, oxygen support, and invasive mechanical ventilation), changes in viral load over time, or adverse events between the groups.

Conclusion. This study found that, compared with placebo, intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of SARS-CoV-2 in hospitalized adults with severe COVID-19. A numeric reduction in time to clinical improvement with early remdesivir treatment (ie, within 10 days of symptom onset) that approached statistical significance was observed in this underpowered study.

Commentary

Within a few short months since its emergence. SARS-CoV-2 infection has caused a global pandemic, posing a dire threat to public health due to its adverse effects on morbidity (eg, respiratory failure, thromboembolic diseases, multiorgan failure) and mortality. To date, no pharmacologic treatment has been shown to effectively improve clinical outcomes in patients with COVID-19. Multiple ongoing clinical trials are being conducted globally to determine potential therapeutic treatments for severe COVID-19. The first clinical trials of hydroxychloroquine and lopinavir-ritonavir, agents traditionally used for other indications, such as malaria and HIV, did not show a clear benefit in COVID-19.^1,2 Remdesivir, a nucleoside analogue prodrug, is a broad-spectrum antiviral agent that was previously used for treatment of Ebola and has been shown to have inhibitory effects on pathogenic coronaviruses. The study reported by Wang and colleagues was the first randomized controlled trial (RCT) aimed at evaluating whether remdesivir improves outcomes in patients with severe COVID-19. Thus, the worsening COVID-19 pandemic, coupled with the absence of a curative treatment, underscore the urgency of this trial.

The study was grounded on observational data from several recent case reports and case series centering on the potential efficacy of remdesivir in treating COVID-19.³ The study itself was designed well (ie, randomized, placebo-controlled, double-blind, multicenter) and carefully implemented (ie, high protocol adherence to treatments, no loss to follow-up). The principal limitation of this study was its inability to reach the estimated statistical power of study. Due to successful epidemic control in Wuhan, which led to marked reductions in hospital admission of patients with COVID-19, and implementation of stringent termination criteria per the study protocol, only 237 participants were enrolled, instead of the 453, as specified by the sample estimate. This corresponded to a reduction of statistical power from 80% to 58%. Due to this limitation, the study was underpowered, rendering its findings inconclusive.

Despite this limitation, the study found that those treated with remdesivir within 10 days of symptom onset had a numerically faster time (although not statistically significant) to clinical improvement. This leads to an interesting question: whether remdesivir administration early in COVID-19 course could improve clinical outcomes, a question that warrants further investigation by an adequately powered trial. Also, data from this study provided evidence that intravenous remdesivir administration is likely safe in adults during the treatment period, although the long-term drug effects, as well as the safety profile in pediatric patients, remain unknown at this time.

While the study reported by Wang and colleagues was underpowered and is thus inconclusive, several other ongoing RCTs are evaluating the potential clinical benefit of remdesivir treatment in patients hospitalized with COVID-19. On the date of online publication of this report in The Lancet, the National Institutes of Health (NIH) published a news release summarizing preliminary findings from the Adaptive COVID-19 Treatment Trial (ACTT), which showed positive effects of remdesivir on clinical recovery from advanced COVID-19.⁴ The ACTT, the first RCT launched in the United States to evaluate experimental treatment for COVID-19, included 1063 hospitalized participants with advanced COVID-19 and lung involvement. Participants who were administered remdesivir had a 31% faster time to recovery compared to those in the placebo group (median time to recovery, 11 days vs 15 days, respectively; P < 0.001), and had near statistically significant improved survival (mortality rate, 8.0% vs 11.6%, respectively; P = 0.059). In response to these findings, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ While the findings noted from the NIH news release are very encouraging and provide the first evidence of a potentially beneficial antiviral treatment for severe COVID-19 in humans, the scientific community awaits the peer-reviewed publication of the ACTT to better assess the safety and effectiveness of remdesivir therapy and determine the trial’s implications in the management of COVID-19.

The discovery of an effective pharmacologic intervention for COVID-19 is of utmost urgency. While the present study was unable to answer the question of whether remdesivir is effective in improving clinical outcomes in patients with severe COVID-19, other ongoing or completed (ie, ACTT) studies will likely address this knowledge gap in the coming months. The FDA’s emergency use authorization for remdesivir provides a glimpse into this possibility.

–Katerina Oikonomou, MD, Brookdale Department of Geriatrics & Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

–Fred Ko, MD

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The idea of universal masking has been debated extensively. As reported in Science, previous randomized clinical studies performed on other viruses have shown no added protection, though small sample sizes and noncompliance are limiting factors. Leung et al. stated in The Lancet that the lack of proof that masks are effective should not rule them as ineffective. A study in the Journal of Medical Virology demonstrates 99.98%, 97.14%, and 95.15% efficacy for N95, surgical, and homemade masks, respectively, in blocking the avian influenza virus. On the contrary, an Annals of Internal Medicine study of four COVID-19 positive subjects found that “neither surgical masks nor cloth masks effectively filtered SARS-CoV-2 during coughs of infected patients.” READ MORE

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Biomarkers for inflammation and thrombosis may predict deaths from COVID-19 among critically ill patients, researchers said. Their prospective cohort study of 1,150 patients hospitalized in New York City also revealed a high proportion of racial and ethnic minorities, and confirmed high rates of critical illness and mortality. “Of particular interest is the finding that over three quarters of critically ill patients required a ventilator and almost one third required renal dialysis support,” Max O’Donnell, MD, MPH, assistant professor of medicine and epidemiology at Columbia University in New York, said in a press release. The study was published in The Lancet. READ MORE

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The idea of universal masking has been debated extensively. As reported in Science, previous randomized clinical studies performed on other viruses have shown no added protection, though small sample sizes and noncompliance are limiting factors. Leung et al. stated in The Lancet that the lack of proof that masks are effective should not rule them as ineffective. A study in the Journal of Medical Virology demonstrates 99.98%, 97.14%, and 95.15% efficacy for N95, surgical, and homemade masks, respectively, in blocking the avian influenza virus. On the contrary, an Annals of Internal Medicine study of four COVID-19 positive subjects found that “neither surgical masks nor cloth masks effectively filtered SARS-CoV-2 during coughs of infected patients.” READ MORE

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