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Cardiology groups push back on hydroxychloroquine, azithromycin for COVID-19
The .
“Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for COVID-19; both drugs are listed as definite causes of torsade de pointes” and increase in the risk of other arrhythmias and sudden death, the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society said in a joint statement April 8 in Circulation.
The statement came amid ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite lack of strong data.
In addition to underlying cardiovascular disease, “seriously ill patients often have comorbidities that can increase risk of serious arrhythmias,” including hypokalemia, hypomagnesemia, fever, and systemic inflammation, the groups said.
They recommended withholding the drugs in patients with baseline QT prolongation (e.g., QTc of at least 500 msec) or with known congenital long QT syndrome; monitoring cardiac rhythm and QT interval and withdrawing hydroxychloroquine and azithromycin if QTc exceeds 500 msec; correcting hypokalemia to levels greater than 4 mEq/L and hypomagnesemia to more than 2 mg/dL; and avoiding other QTc-prolonging agents when possible.
The groups noted that, “in patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.” There is also a possible compounding arrhythmic effect when hydroxychloroquine and azithromycin are used together, but that has not been studied.
There’s a known risk of torsade de pointes with chloroquine and a possible risk with the antiviral HIV combination drug lopinavir-ritonavir, two other candidates for COVID-19 treatment. Hydroxychloroquine and chloroquine, both antimalarials, might help prevent or treat infection by interfering with angiotensin-converting enzyme 2 receptors, which the COVID-19 virus uses for cell entry, the groups said.
“The urgency of COVID-19 must not diminish the scientific rigor with which we approach COVID-19 treatment. While these medications may work against COVID-19 individually or in combination, we recommend caution with these medications for patients with existing cardiovascular disease,” Robert A. Harrington, MD, AHA president and chair of the department of medicine at Stanford (Calif.) University, emphasized in a press release.
SOURCE: Roden DM et al. Circulation. 2020 Apr 8. doi:10.1161/CIRCULATIONAHA.120.047521.
The .
“Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for COVID-19; both drugs are listed as definite causes of torsade de pointes” and increase in the risk of other arrhythmias and sudden death, the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society said in a joint statement April 8 in Circulation.
The statement came amid ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite lack of strong data.
In addition to underlying cardiovascular disease, “seriously ill patients often have comorbidities that can increase risk of serious arrhythmias,” including hypokalemia, hypomagnesemia, fever, and systemic inflammation, the groups said.
They recommended withholding the drugs in patients with baseline QT prolongation (e.g., QTc of at least 500 msec) or with known congenital long QT syndrome; monitoring cardiac rhythm and QT interval and withdrawing hydroxychloroquine and azithromycin if QTc exceeds 500 msec; correcting hypokalemia to levels greater than 4 mEq/L and hypomagnesemia to more than 2 mg/dL; and avoiding other QTc-prolonging agents when possible.
The groups noted that, “in patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.” There is also a possible compounding arrhythmic effect when hydroxychloroquine and azithromycin are used together, but that has not been studied.
There’s a known risk of torsade de pointes with chloroquine and a possible risk with the antiviral HIV combination drug lopinavir-ritonavir, two other candidates for COVID-19 treatment. Hydroxychloroquine and chloroquine, both antimalarials, might help prevent or treat infection by interfering with angiotensin-converting enzyme 2 receptors, which the COVID-19 virus uses for cell entry, the groups said.
“The urgency of COVID-19 must not diminish the scientific rigor with which we approach COVID-19 treatment. While these medications may work against COVID-19 individually or in combination, we recommend caution with these medications for patients with existing cardiovascular disease,” Robert A. Harrington, MD, AHA president and chair of the department of medicine at Stanford (Calif.) University, emphasized in a press release.
SOURCE: Roden DM et al. Circulation. 2020 Apr 8. doi:10.1161/CIRCULATIONAHA.120.047521.
The .
“Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for COVID-19; both drugs are listed as definite causes of torsade de pointes” and increase in the risk of other arrhythmias and sudden death, the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society said in a joint statement April 8 in Circulation.
The statement came amid ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite lack of strong data.
In addition to underlying cardiovascular disease, “seriously ill patients often have comorbidities that can increase risk of serious arrhythmias,” including hypokalemia, hypomagnesemia, fever, and systemic inflammation, the groups said.
They recommended withholding the drugs in patients with baseline QT prolongation (e.g., QTc of at least 500 msec) or with known congenital long QT syndrome; monitoring cardiac rhythm and QT interval and withdrawing hydroxychloroquine and azithromycin if QTc exceeds 500 msec; correcting hypokalemia to levels greater than 4 mEq/L and hypomagnesemia to more than 2 mg/dL; and avoiding other QTc-prolonging agents when possible.
The groups noted that, “in patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.” There is also a possible compounding arrhythmic effect when hydroxychloroquine and azithromycin are used together, but that has not been studied.
There’s a known risk of torsade de pointes with chloroquine and a possible risk with the antiviral HIV combination drug lopinavir-ritonavir, two other candidates for COVID-19 treatment. Hydroxychloroquine and chloroquine, both antimalarials, might help prevent or treat infection by interfering with angiotensin-converting enzyme 2 receptors, which the COVID-19 virus uses for cell entry, the groups said.
“The urgency of COVID-19 must not diminish the scientific rigor with which we approach COVID-19 treatment. While these medications may work against COVID-19 individually or in combination, we recommend caution with these medications for patients with existing cardiovascular disease,” Robert A. Harrington, MD, AHA president and chair of the department of medicine at Stanford (Calif.) University, emphasized in a press release.
SOURCE: Roden DM et al. Circulation. 2020 Apr 8. doi:10.1161/CIRCULATIONAHA.120.047521.
COVID-19: Dramatic changes to telepsychiatry rules and regs
In the wake of the coronavirus pandemic,
Under the 1135 emergency waiver, Medicare has expanded telehealth services to include patients across the country – not just in rural areas or under other limited conditions, as was previously the case. In addition, there’s now a waiver to the Ryan Haight Act that allows the prescribing of controlled substances via telemedicine.
Peter Yellowlees, MD, from University of California, Davis, reported that outpatient service at his center was converted to an almost 100% telepsychiatry service from mid- to late March.
He and John Torous, MD, director of digital psychiatry at Beth Israel Deaconess Medical Center, Boston, led a free webinar late last month sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA).
During the hour-long event, they answered questions and offered tips on changes in licensure, patient safety, new prescribing rules, and equipment needed.
“Clinicians need to be aware of these changes so they can ensure they are reaching as many people as possible and taking advantage of the reduced barriers to offering safe and effective video visits,” Dr. Torous said in an interview.
‘This is huge’
The new 1135 waiver “basically says CMS will pay for any patient on Medicare who is seen by video by any provider who is correctly licensed in any state in this country,” Dr. Yellowlees told webinar attendees.
“You don’t need to be licensed in the state where the patient is if the patient is on Medicare. This opens up a huge number of patients we can now see on video,” he said. “And you can bill at normal Medicare rates for whatever you normally get for your in-person patients.”
Although this temporary rule only applies to Medicare and not to private insurers, or to patients on Medicaid, “these are really big changes. This is huge,” Dr. Torous said.
Previously, the “originating site” rule stated that, for the most part, clinicians had to be licensed in the state where the patient was located and not where the physician was stationed.
Asked about college students receiving mental health care who were in school in the psychiatrist’s area but are now back home in a state where the clinician doesn’t have a license, Dr. Yellowlees said that scenario could be a bit “tricky.”
“Most of those patients probably aren’t on Medicare. Legally, you [usually] can’t see them on video if they have private insurance or Medicaid. So, hopefully you can give them a 3-month supply of medication and then recommend they see a local provider,” he said.
Still, all states have their own rules, Dr. Yellowlees said. He and Dr. Torous noted that the Federation of State Medical Boards has a “very up-to-date” listing of policies at FSMB.org, all of which are organized by state. In addition, the American Psychiatric Association provides a telepsychiatry toolkit on its website.
Ryan Haight Act and prescribing
Physicians are now permitted to prescribe medication to patients assessed via telemedicine.
For those with substance use disorders, the U.S. Drug Enforcement Administration has announced a new waiver for the Ryan Haight Online Pharmacy Consumer Protection Act.
The waiver states that “practitioners in all areas of the United States may issue prescriptions for all schedule II-V controlled substances” – as long as it’s for a legitimate medical purpose; real-time, two-way interactive communication with patients has been used; and the clinician “is acting in accordance with applicable Federal and State laws.”
“It’s now possible to prescribe all the normal psychiatric drugs but also benzodiazepines, stimulants, and potentially narcotics over telepsychiatry,” even at a first visit via video, Dr. Yellowlees said.
However, he noted at this point the waiver is current for only 60 days. “This isn’t a permanent condition. It could be extended or even shortened at any given time.”
In addition, SAMHSA has relaxed some of its own regulations regarding telehealth and opioid treatment programs. An FAQ section on the organization’s website provides guidance for providing methadone and buprenorphine treatment.
“Some of the previous regulations will probably be put back in place later on, but the new changes are helpful now,” Dr. Yellowlees said.
Simple equipment needed
Regarding equipment, Dr. Yellowlees noted that the most important component is just a laptop, tablet, or smartphone – for the clinician and for the patient.
“You don’t need fancy new technology with a separate camera or microphone,” he said. However, it might be worth investing in a little better system down the line, he added.
Simple platforms that can be used to meet virtually with patients include FaceTime, Google Hangouts, and Skype.
Although some of these (such as FaceTime) are not HIPAA compliant, “that’s okay for now” under the new rules, Dr. Yellowlees said. While the health system/commercial version of Skype is compliant, the normal consumer-downloaded version is not, he noted.
“I would still strongly suggest using HIPAA-compliant video-conferencing programs in the long run,” he added.
Either way, it’s important for various safety practices to be put into place. For example, clinicians should be careful because the consumer version of Skype can show names of patients who were previously spoken with.
A business associate agreement (BAA) is something that HIPAA-compliant video systems will offer and which should be signed. It’s an agreement that “you’ll be, essentially, looking through a tunnel at the persona at the other end, and the company cannot get inside the tunnel and watch you while you’re having your interview,” said Dr. Yellowlees.
“There are multiple videoconferencing systems around that you can use,” he added. “The three major ones are from Zoom, Vidyo, and VSee, but there are probably 40 or 50 more.”
“There are a lot out there, and we’re certainly not endorsing any one of them,” Dr. Torous added.
When evaluating potential programs, Dr. Yellowlees suggested looking at Yelp-style reviews or telemedicine review sites, or talk with colleagues.
“Basically, you want systems that offer high-definition video quality and the ability to ‘lock’ and ‘unlock’ the rooms. And you want it to have an app so mobile devices can use it,” he said.
Phone vs. video
Some patients, especially older ones, may be resistant to the idea of video chats, preferring to talk via telephone instead.
“If you can use video, it’s better to do that if you can, especially when setting up the systems are relatively simple,” Dr. Yellowlees said, adding that it might just be an issue of patients needing help to get started.
However, “for some people, this is a barrier that we have to respect,” Dr. Torous said.
Either way, clinicians should check the American Medical Association’s website for information about coding for both video and phone visits.
Asked whether a clinician needs written consent from patients for conducting telepsychiatry visits, Dr. Yellowlees said it’s important to check state-by-state rules. For example, California allows a verbal consent.
In many cases, “simply jot down a note that consent was given and how” and write down the address where the patient is located at time of visit, such as for their home, he said.
If a patient wants to conduct a telehealth session while in their car, Dr. Yellowlees suggested getting the address of the parking lot. For safety, clinicians also are advised asking for the cell phone number of the patient as well as that of a loved one.
Vital signs
When it comes to checking vital signs, Dr. Yellowlees suggested asking patients to purchase an inexpensive blood pressure (BP) monitor, thermometer, etc, prior to an appointment.
“Ask them to do a BP test on video and show you the readings. For the AIMS [Abnormal Involuntary Movement Scale] test, or to check for tardive dyskinesia, instruct patients to come close to the camera to show movement.”
In addition, most psychiatric rating scales are available online, which patients can fill out before a telehealth visit. The Serious Mental Illness (SMI) Adviser mobile app also includes several of these scales, Dr. Torous noted.
Overall, “there have been dramatic changes in the rules and regulations governing [telepsychiatry] that, for the next 60 days, make it easier to offer telehealth to patients,” Dr. Torous said.
Therefore, all psychiatrists need to “get on board,” as soon as possible, Dr. Yellowlees added.
The webinar was funded in part by a grant from SAMHSA.
A version of this article originally appeared on Medscape.com.
In the wake of the coronavirus pandemic,
Under the 1135 emergency waiver, Medicare has expanded telehealth services to include patients across the country – not just in rural areas or under other limited conditions, as was previously the case. In addition, there’s now a waiver to the Ryan Haight Act that allows the prescribing of controlled substances via telemedicine.
Peter Yellowlees, MD, from University of California, Davis, reported that outpatient service at his center was converted to an almost 100% telepsychiatry service from mid- to late March.
He and John Torous, MD, director of digital psychiatry at Beth Israel Deaconess Medical Center, Boston, led a free webinar late last month sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA).
During the hour-long event, they answered questions and offered tips on changes in licensure, patient safety, new prescribing rules, and equipment needed.
“Clinicians need to be aware of these changes so they can ensure they are reaching as many people as possible and taking advantage of the reduced barriers to offering safe and effective video visits,” Dr. Torous said in an interview.
‘This is huge’
The new 1135 waiver “basically says CMS will pay for any patient on Medicare who is seen by video by any provider who is correctly licensed in any state in this country,” Dr. Yellowlees told webinar attendees.
“You don’t need to be licensed in the state where the patient is if the patient is on Medicare. This opens up a huge number of patients we can now see on video,” he said. “And you can bill at normal Medicare rates for whatever you normally get for your in-person patients.”
Although this temporary rule only applies to Medicare and not to private insurers, or to patients on Medicaid, “these are really big changes. This is huge,” Dr. Torous said.
Previously, the “originating site” rule stated that, for the most part, clinicians had to be licensed in the state where the patient was located and not where the physician was stationed.
Asked about college students receiving mental health care who were in school in the psychiatrist’s area but are now back home in a state where the clinician doesn’t have a license, Dr. Yellowlees said that scenario could be a bit “tricky.”
“Most of those patients probably aren’t on Medicare. Legally, you [usually] can’t see them on video if they have private insurance or Medicaid. So, hopefully you can give them a 3-month supply of medication and then recommend they see a local provider,” he said.
Still, all states have their own rules, Dr. Yellowlees said. He and Dr. Torous noted that the Federation of State Medical Boards has a “very up-to-date” listing of policies at FSMB.org, all of which are organized by state. In addition, the American Psychiatric Association provides a telepsychiatry toolkit on its website.
Ryan Haight Act and prescribing
Physicians are now permitted to prescribe medication to patients assessed via telemedicine.
For those with substance use disorders, the U.S. Drug Enforcement Administration has announced a new waiver for the Ryan Haight Online Pharmacy Consumer Protection Act.
The waiver states that “practitioners in all areas of the United States may issue prescriptions for all schedule II-V controlled substances” – as long as it’s for a legitimate medical purpose; real-time, two-way interactive communication with patients has been used; and the clinician “is acting in accordance with applicable Federal and State laws.”
“It’s now possible to prescribe all the normal psychiatric drugs but also benzodiazepines, stimulants, and potentially narcotics over telepsychiatry,” even at a first visit via video, Dr. Yellowlees said.
However, he noted at this point the waiver is current for only 60 days. “This isn’t a permanent condition. It could be extended or even shortened at any given time.”
In addition, SAMHSA has relaxed some of its own regulations regarding telehealth and opioid treatment programs. An FAQ section on the organization’s website provides guidance for providing methadone and buprenorphine treatment.
“Some of the previous regulations will probably be put back in place later on, but the new changes are helpful now,” Dr. Yellowlees said.
Simple equipment needed
Regarding equipment, Dr. Yellowlees noted that the most important component is just a laptop, tablet, or smartphone – for the clinician and for the patient.
“You don’t need fancy new technology with a separate camera or microphone,” he said. However, it might be worth investing in a little better system down the line, he added.
Simple platforms that can be used to meet virtually with patients include FaceTime, Google Hangouts, and Skype.
Although some of these (such as FaceTime) are not HIPAA compliant, “that’s okay for now” under the new rules, Dr. Yellowlees said. While the health system/commercial version of Skype is compliant, the normal consumer-downloaded version is not, he noted.
“I would still strongly suggest using HIPAA-compliant video-conferencing programs in the long run,” he added.
Either way, it’s important for various safety practices to be put into place. For example, clinicians should be careful because the consumer version of Skype can show names of patients who were previously spoken with.
A business associate agreement (BAA) is something that HIPAA-compliant video systems will offer and which should be signed. It’s an agreement that “you’ll be, essentially, looking through a tunnel at the persona at the other end, and the company cannot get inside the tunnel and watch you while you’re having your interview,” said Dr. Yellowlees.
“There are multiple videoconferencing systems around that you can use,” he added. “The three major ones are from Zoom, Vidyo, and VSee, but there are probably 40 or 50 more.”
“There are a lot out there, and we’re certainly not endorsing any one of them,” Dr. Torous added.
When evaluating potential programs, Dr. Yellowlees suggested looking at Yelp-style reviews or telemedicine review sites, or talk with colleagues.
“Basically, you want systems that offer high-definition video quality and the ability to ‘lock’ and ‘unlock’ the rooms. And you want it to have an app so mobile devices can use it,” he said.
Phone vs. video
Some patients, especially older ones, may be resistant to the idea of video chats, preferring to talk via telephone instead.
“If you can use video, it’s better to do that if you can, especially when setting up the systems are relatively simple,” Dr. Yellowlees said, adding that it might just be an issue of patients needing help to get started.
However, “for some people, this is a barrier that we have to respect,” Dr. Torous said.
Either way, clinicians should check the American Medical Association’s website for information about coding for both video and phone visits.
Asked whether a clinician needs written consent from patients for conducting telepsychiatry visits, Dr. Yellowlees said it’s important to check state-by-state rules. For example, California allows a verbal consent.
In many cases, “simply jot down a note that consent was given and how” and write down the address where the patient is located at time of visit, such as for their home, he said.
If a patient wants to conduct a telehealth session while in their car, Dr. Yellowlees suggested getting the address of the parking lot. For safety, clinicians also are advised asking for the cell phone number of the patient as well as that of a loved one.
Vital signs
When it comes to checking vital signs, Dr. Yellowlees suggested asking patients to purchase an inexpensive blood pressure (BP) monitor, thermometer, etc, prior to an appointment.
“Ask them to do a BP test on video and show you the readings. For the AIMS [Abnormal Involuntary Movement Scale] test, or to check for tardive dyskinesia, instruct patients to come close to the camera to show movement.”
In addition, most psychiatric rating scales are available online, which patients can fill out before a telehealth visit. The Serious Mental Illness (SMI) Adviser mobile app also includes several of these scales, Dr. Torous noted.
Overall, “there have been dramatic changes in the rules and regulations governing [telepsychiatry] that, for the next 60 days, make it easier to offer telehealth to patients,” Dr. Torous said.
Therefore, all psychiatrists need to “get on board,” as soon as possible, Dr. Yellowlees added.
The webinar was funded in part by a grant from SAMHSA.
A version of this article originally appeared on Medscape.com.
In the wake of the coronavirus pandemic,
Under the 1135 emergency waiver, Medicare has expanded telehealth services to include patients across the country – not just in rural areas or under other limited conditions, as was previously the case. In addition, there’s now a waiver to the Ryan Haight Act that allows the prescribing of controlled substances via telemedicine.
Peter Yellowlees, MD, from University of California, Davis, reported that outpatient service at his center was converted to an almost 100% telepsychiatry service from mid- to late March.
He and John Torous, MD, director of digital psychiatry at Beth Israel Deaconess Medical Center, Boston, led a free webinar late last month sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA).
During the hour-long event, they answered questions and offered tips on changes in licensure, patient safety, new prescribing rules, and equipment needed.
“Clinicians need to be aware of these changes so they can ensure they are reaching as many people as possible and taking advantage of the reduced barriers to offering safe and effective video visits,” Dr. Torous said in an interview.
‘This is huge’
The new 1135 waiver “basically says CMS will pay for any patient on Medicare who is seen by video by any provider who is correctly licensed in any state in this country,” Dr. Yellowlees told webinar attendees.
“You don’t need to be licensed in the state where the patient is if the patient is on Medicare. This opens up a huge number of patients we can now see on video,” he said. “And you can bill at normal Medicare rates for whatever you normally get for your in-person patients.”
Although this temporary rule only applies to Medicare and not to private insurers, or to patients on Medicaid, “these are really big changes. This is huge,” Dr. Torous said.
Previously, the “originating site” rule stated that, for the most part, clinicians had to be licensed in the state where the patient was located and not where the physician was stationed.
Asked about college students receiving mental health care who were in school in the psychiatrist’s area but are now back home in a state where the clinician doesn’t have a license, Dr. Yellowlees said that scenario could be a bit “tricky.”
“Most of those patients probably aren’t on Medicare. Legally, you [usually] can’t see them on video if they have private insurance or Medicaid. So, hopefully you can give them a 3-month supply of medication and then recommend they see a local provider,” he said.
Still, all states have their own rules, Dr. Yellowlees said. He and Dr. Torous noted that the Federation of State Medical Boards has a “very up-to-date” listing of policies at FSMB.org, all of which are organized by state. In addition, the American Psychiatric Association provides a telepsychiatry toolkit on its website.
Ryan Haight Act and prescribing
Physicians are now permitted to prescribe medication to patients assessed via telemedicine.
For those with substance use disorders, the U.S. Drug Enforcement Administration has announced a new waiver for the Ryan Haight Online Pharmacy Consumer Protection Act.
The waiver states that “practitioners in all areas of the United States may issue prescriptions for all schedule II-V controlled substances” – as long as it’s for a legitimate medical purpose; real-time, two-way interactive communication with patients has been used; and the clinician “is acting in accordance with applicable Federal and State laws.”
“It’s now possible to prescribe all the normal psychiatric drugs but also benzodiazepines, stimulants, and potentially narcotics over telepsychiatry,” even at a first visit via video, Dr. Yellowlees said.
However, he noted at this point the waiver is current for only 60 days. “This isn’t a permanent condition. It could be extended or even shortened at any given time.”
In addition, SAMHSA has relaxed some of its own regulations regarding telehealth and opioid treatment programs. An FAQ section on the organization’s website provides guidance for providing methadone and buprenorphine treatment.
“Some of the previous regulations will probably be put back in place later on, but the new changes are helpful now,” Dr. Yellowlees said.
Simple equipment needed
Regarding equipment, Dr. Yellowlees noted that the most important component is just a laptop, tablet, or smartphone – for the clinician and for the patient.
“You don’t need fancy new technology with a separate camera or microphone,” he said. However, it might be worth investing in a little better system down the line, he added.
Simple platforms that can be used to meet virtually with patients include FaceTime, Google Hangouts, and Skype.
Although some of these (such as FaceTime) are not HIPAA compliant, “that’s okay for now” under the new rules, Dr. Yellowlees said. While the health system/commercial version of Skype is compliant, the normal consumer-downloaded version is not, he noted.
“I would still strongly suggest using HIPAA-compliant video-conferencing programs in the long run,” he added.
Either way, it’s important for various safety practices to be put into place. For example, clinicians should be careful because the consumer version of Skype can show names of patients who were previously spoken with.
A business associate agreement (BAA) is something that HIPAA-compliant video systems will offer and which should be signed. It’s an agreement that “you’ll be, essentially, looking through a tunnel at the persona at the other end, and the company cannot get inside the tunnel and watch you while you’re having your interview,” said Dr. Yellowlees.
“There are multiple videoconferencing systems around that you can use,” he added. “The three major ones are from Zoom, Vidyo, and VSee, but there are probably 40 or 50 more.”
“There are a lot out there, and we’re certainly not endorsing any one of them,” Dr. Torous added.
When evaluating potential programs, Dr. Yellowlees suggested looking at Yelp-style reviews or telemedicine review sites, or talk with colleagues.
“Basically, you want systems that offer high-definition video quality and the ability to ‘lock’ and ‘unlock’ the rooms. And you want it to have an app so mobile devices can use it,” he said.
Phone vs. video
Some patients, especially older ones, may be resistant to the idea of video chats, preferring to talk via telephone instead.
“If you can use video, it’s better to do that if you can, especially when setting up the systems are relatively simple,” Dr. Yellowlees said, adding that it might just be an issue of patients needing help to get started.
However, “for some people, this is a barrier that we have to respect,” Dr. Torous said.
Either way, clinicians should check the American Medical Association’s website for information about coding for both video and phone visits.
Asked whether a clinician needs written consent from patients for conducting telepsychiatry visits, Dr. Yellowlees said it’s important to check state-by-state rules. For example, California allows a verbal consent.
In many cases, “simply jot down a note that consent was given and how” and write down the address where the patient is located at time of visit, such as for their home, he said.
If a patient wants to conduct a telehealth session while in their car, Dr. Yellowlees suggested getting the address of the parking lot. For safety, clinicians also are advised asking for the cell phone number of the patient as well as that of a loved one.
Vital signs
When it comes to checking vital signs, Dr. Yellowlees suggested asking patients to purchase an inexpensive blood pressure (BP) monitor, thermometer, etc, prior to an appointment.
“Ask them to do a BP test on video and show you the readings. For the AIMS [Abnormal Involuntary Movement Scale] test, or to check for tardive dyskinesia, instruct patients to come close to the camera to show movement.”
In addition, most psychiatric rating scales are available online, which patients can fill out before a telehealth visit. The Serious Mental Illness (SMI) Adviser mobile app also includes several of these scales, Dr. Torous noted.
Overall, “there have been dramatic changes in the rules and regulations governing [telepsychiatry] that, for the next 60 days, make it easier to offer telehealth to patients,” Dr. Torous said.
Therefore, all psychiatrists need to “get on board,” as soon as possible, Dr. Yellowlees added.
The webinar was funded in part by a grant from SAMHSA.
A version of this article originally appeared on Medscape.com.
FDA approves first generic albuterol inhaler
The Food and Drug Administration has approved the first generic of Proventil HFA (albuterol sulfate) metered-dose inhaler, 90 mcg/inhalation, according to a release from the agency. This inhaler is indicated for prevention of bronchospasm in patients aged 4 years and older. Specifically, these are patients with reversible obstructive airway disease or exercise-induced bronchospasm.
“The FDA recognizes the increased demand for albuterol products during the novel coronavirus pandemic,” said FDA Commissioner Stephen M. Hahn, MD.
The most common side effects include upper respiratory tract infection, rhinitis, nausea, vomiting, rapid heart rate, tremor, and nervousness.
This approval comes as part of FDA’s efforts to guide industry through the development process of generic products, according to the release. Complex combination products – such as this inhaler, which comprises both medication and a delivery system – can be more challenging to develop than solid oral dosage forms, such as tablets.
The FDA released a draft guidance in March 2020 specific to proposed generic albuterol sulfate metered-dose inhalers, including drug products referencing Proventil HFA. As with other similar guidances, it details the steps companies need to take in developing generics in order to submit complete applications for those products. The full news release regarding this approval is available on the FDA website.
This article was updated 4/8/20.
The Food and Drug Administration has approved the first generic of Proventil HFA (albuterol sulfate) metered-dose inhaler, 90 mcg/inhalation, according to a release from the agency. This inhaler is indicated for prevention of bronchospasm in patients aged 4 years and older. Specifically, these are patients with reversible obstructive airway disease or exercise-induced bronchospasm.
“The FDA recognizes the increased demand for albuterol products during the novel coronavirus pandemic,” said FDA Commissioner Stephen M. Hahn, MD.
The most common side effects include upper respiratory tract infection, rhinitis, nausea, vomiting, rapid heart rate, tremor, and nervousness.
This approval comes as part of FDA’s efforts to guide industry through the development process of generic products, according to the release. Complex combination products – such as this inhaler, which comprises both medication and a delivery system – can be more challenging to develop than solid oral dosage forms, such as tablets.
The FDA released a draft guidance in March 2020 specific to proposed generic albuterol sulfate metered-dose inhalers, including drug products referencing Proventil HFA. As with other similar guidances, it details the steps companies need to take in developing generics in order to submit complete applications for those products. The full news release regarding this approval is available on the FDA website.
This article was updated 4/8/20.
The Food and Drug Administration has approved the first generic of Proventil HFA (albuterol sulfate) metered-dose inhaler, 90 mcg/inhalation, according to a release from the agency. This inhaler is indicated for prevention of bronchospasm in patients aged 4 years and older. Specifically, these are patients with reversible obstructive airway disease or exercise-induced bronchospasm.
“The FDA recognizes the increased demand for albuterol products during the novel coronavirus pandemic,” said FDA Commissioner Stephen M. Hahn, MD.
The most common side effects include upper respiratory tract infection, rhinitis, nausea, vomiting, rapid heart rate, tremor, and nervousness.
This approval comes as part of FDA’s efforts to guide industry through the development process of generic products, according to the release. Complex combination products – such as this inhaler, which comprises both medication and a delivery system – can be more challenging to develop than solid oral dosage forms, such as tablets.
The FDA released a draft guidance in March 2020 specific to proposed generic albuterol sulfate metered-dose inhalers, including drug products referencing Proventil HFA. As with other similar guidances, it details the steps companies need to take in developing generics in order to submit complete applications for those products. The full news release regarding this approval is available on the FDA website.
This article was updated 4/8/20.
Comorbidities the rule in New York’s COVID-19 deaths
In New York state, just over 86% of reported COVID-19 deaths involved at least one comorbidity, according to the state’s department of health.
As of midnight on April 6, there had been 5,489 fatalities caused by COVID-19 in the state, of which 86.2% (4,732) had at least one underlying condition, the New York State Department of Health reported April 7 on its COVID-19 tracker.
The leading comorbidity, seen in 55.4% of all deaths, was hypertension. In comparison, a recent estimate from the U.S. Department of Health & Human Services put the prevalence of high blood pressure at about 45% in the overall adult population.
In New York, the rest of the 10 most common comorbidities in COVID-19 fatalities were diabetes (37.3%), hyperlipidemia (18.5%), coronary artery disease (12.4%), renal disease (11.0%), dementia (9.1%), chronic obstructive pulmonary disease (8.3%), cancer (8.1%), atrial fibrillation (7.1%), and heart failure (7.1%), the NYSDOH said.
Other data on the tracker site show that 63% of all deaths involved a patient who was aged 70 years or older and that 61% of COVID-19 patients who have died in New York were male and 38.8% were female (sex unknown for 0.2%). Among all individuals who have tested positive, 54.8% were male and 44.6% were female (sex unknown for 0.6%).
As of the end of day on April 6, a total of 340,058 persons had been tested in the state and 40.8% (138,863) were positive for the SARS-CoV-2 virus. By county, the highest positive rates are in New York City: Queens at 57.4%, Brooklyn at 52.4%, and the Bronx at 52.3%, according to the NYSDOH.
In New York state, just over 86% of reported COVID-19 deaths involved at least one comorbidity, according to the state’s department of health.
As of midnight on April 6, there had been 5,489 fatalities caused by COVID-19 in the state, of which 86.2% (4,732) had at least one underlying condition, the New York State Department of Health reported April 7 on its COVID-19 tracker.
The leading comorbidity, seen in 55.4% of all deaths, was hypertension. In comparison, a recent estimate from the U.S. Department of Health & Human Services put the prevalence of high blood pressure at about 45% in the overall adult population.
In New York, the rest of the 10 most common comorbidities in COVID-19 fatalities were diabetes (37.3%), hyperlipidemia (18.5%), coronary artery disease (12.4%), renal disease (11.0%), dementia (9.1%), chronic obstructive pulmonary disease (8.3%), cancer (8.1%), atrial fibrillation (7.1%), and heart failure (7.1%), the NYSDOH said.
Other data on the tracker site show that 63% of all deaths involved a patient who was aged 70 years or older and that 61% of COVID-19 patients who have died in New York were male and 38.8% were female (sex unknown for 0.2%). Among all individuals who have tested positive, 54.8% were male and 44.6% were female (sex unknown for 0.6%).
As of the end of day on April 6, a total of 340,058 persons had been tested in the state and 40.8% (138,863) were positive for the SARS-CoV-2 virus. By county, the highest positive rates are in New York City: Queens at 57.4%, Brooklyn at 52.4%, and the Bronx at 52.3%, according to the NYSDOH.
In New York state, just over 86% of reported COVID-19 deaths involved at least one comorbidity, according to the state’s department of health.
As of midnight on April 6, there had been 5,489 fatalities caused by COVID-19 in the state, of which 86.2% (4,732) had at least one underlying condition, the New York State Department of Health reported April 7 on its COVID-19 tracker.
The leading comorbidity, seen in 55.4% of all deaths, was hypertension. In comparison, a recent estimate from the U.S. Department of Health & Human Services put the prevalence of high blood pressure at about 45% in the overall adult population.
In New York, the rest of the 10 most common comorbidities in COVID-19 fatalities were diabetes (37.3%), hyperlipidemia (18.5%), coronary artery disease (12.4%), renal disease (11.0%), dementia (9.1%), chronic obstructive pulmonary disease (8.3%), cancer (8.1%), atrial fibrillation (7.1%), and heart failure (7.1%), the NYSDOH said.
Other data on the tracker site show that 63% of all deaths involved a patient who was aged 70 years or older and that 61% of COVID-19 patients who have died in New York were male and 38.8% were female (sex unknown for 0.2%). Among all individuals who have tested positive, 54.8% were male and 44.6% were female (sex unknown for 0.6%).
As of the end of day on April 6, a total of 340,058 persons had been tested in the state and 40.8% (138,863) were positive for the SARS-CoV-2 virus. By county, the highest positive rates are in New York City: Queens at 57.4%, Brooklyn at 52.4%, and the Bronx at 52.3%, according to the NYSDOH.
SARS-CoV-2 escapes cotton, surgical masks of infected
June 9, 2020 — Editor’s note: The study on which this news story is based has been retracted by the journal. The retraction notice can be found here.
according to Seongman Bae, MD, of the University of Ulsan College of Medicine in Seoul, South Korea, and associates.
The report was published in Annals of Internal Medicine.
Because the COVID-19 pandemic has caused a shortage of N95 and surgical masks, cotton masks have gained interest as a substitute, as surgical masks have been shown to effectively filter influenza virus, the researchers wrote. However, the size of and concentrations of SARS-CoV-2 in aerosols generated during coughing are unknown.
To compare the effectiveness of cotton and surgical masks, a group of patients infected with SARS-CoV-2 coughed into petri dishes while wearing no mask, a surgical mask, and a cotton mask. The mask surfaces were swabbed afterward to assess viral positivity on the mask itself.
The median nasopharyngeal and saliva viral load was 5.66 log copies/mL and 4.00 log copies/mL, respectively. The median viral loads after coughing was 2.56 log copies/mL without a mask, 2.42 log copies/mL with a surgical mask, and 1.85 log copies/mL with a cotton mask. All outer surfaces of the mask were positive for SARS-CoV-2, while most inner surfaces were negative.
The investigators acknowledged that the test did not include N95 masks and does not reflect the actual infection transmission, and that they didn’t know whether cotton or surgical masks shorten the travel distance of droplets while coughing.
“Further study is needed to recommend whether face masks decrease transmission of virus from asymptomatic individuals or those with suspected COVID-19 who are not coughing,” they added.
The study was funded by a grant from the government-wide R&D Fund Project for Infectious Disease Research. The investigators reported that they had no conflicts of interest.
SOURCE: Bae S et al. Ann Intern Med. 2020 Apr 6. doi: 10.7326/M20-1342.
Correction, 4/9/20: The headline of an earlier version of this article misstated a finding of this study. Whether cotton and surgical masks can block transmission was not investigated.
June 9, 2020 — Editor’s note: The study on which this news story is based has been retracted by the journal. The retraction notice can be found here.
according to Seongman Bae, MD, of the University of Ulsan College of Medicine in Seoul, South Korea, and associates.
The report was published in Annals of Internal Medicine.
Because the COVID-19 pandemic has caused a shortage of N95 and surgical masks, cotton masks have gained interest as a substitute, as surgical masks have been shown to effectively filter influenza virus, the researchers wrote. However, the size of and concentrations of SARS-CoV-2 in aerosols generated during coughing are unknown.
To compare the effectiveness of cotton and surgical masks, a group of patients infected with SARS-CoV-2 coughed into petri dishes while wearing no mask, a surgical mask, and a cotton mask. The mask surfaces were swabbed afterward to assess viral positivity on the mask itself.
The median nasopharyngeal and saliva viral load was 5.66 log copies/mL and 4.00 log copies/mL, respectively. The median viral loads after coughing was 2.56 log copies/mL without a mask, 2.42 log copies/mL with a surgical mask, and 1.85 log copies/mL with a cotton mask. All outer surfaces of the mask were positive for SARS-CoV-2, while most inner surfaces were negative.
The investigators acknowledged that the test did not include N95 masks and does not reflect the actual infection transmission, and that they didn’t know whether cotton or surgical masks shorten the travel distance of droplets while coughing.
“Further study is needed to recommend whether face masks decrease transmission of virus from asymptomatic individuals or those with suspected COVID-19 who are not coughing,” they added.
The study was funded by a grant from the government-wide R&D Fund Project for Infectious Disease Research. The investigators reported that they had no conflicts of interest.
SOURCE: Bae S et al. Ann Intern Med. 2020 Apr 6. doi: 10.7326/M20-1342.
Correction, 4/9/20: The headline of an earlier version of this article misstated a finding of this study. Whether cotton and surgical masks can block transmission was not investigated.
June 9, 2020 — Editor’s note: The study on which this news story is based has been retracted by the journal. The retraction notice can be found here.
according to Seongman Bae, MD, of the University of Ulsan College of Medicine in Seoul, South Korea, and associates.
The report was published in Annals of Internal Medicine.
Because the COVID-19 pandemic has caused a shortage of N95 and surgical masks, cotton masks have gained interest as a substitute, as surgical masks have been shown to effectively filter influenza virus, the researchers wrote. However, the size of and concentrations of SARS-CoV-2 in aerosols generated during coughing are unknown.
To compare the effectiveness of cotton and surgical masks, a group of patients infected with SARS-CoV-2 coughed into petri dishes while wearing no mask, a surgical mask, and a cotton mask. The mask surfaces were swabbed afterward to assess viral positivity on the mask itself.
The median nasopharyngeal and saliva viral load was 5.66 log copies/mL and 4.00 log copies/mL, respectively. The median viral loads after coughing was 2.56 log copies/mL without a mask, 2.42 log copies/mL with a surgical mask, and 1.85 log copies/mL with a cotton mask. All outer surfaces of the mask were positive for SARS-CoV-2, while most inner surfaces were negative.
The investigators acknowledged that the test did not include N95 masks and does not reflect the actual infection transmission, and that they didn’t know whether cotton or surgical masks shorten the travel distance of droplets while coughing.
“Further study is needed to recommend whether face masks decrease transmission of virus from asymptomatic individuals or those with suspected COVID-19 who are not coughing,” they added.
The study was funded by a grant from the government-wide R&D Fund Project for Infectious Disease Research. The investigators reported that they had no conflicts of interest.
SOURCE: Bae S et al. Ann Intern Med. 2020 Apr 6. doi: 10.7326/M20-1342.
Correction, 4/9/20: The headline of an earlier version of this article misstated a finding of this study. Whether cotton and surgical masks can block transmission was not investigated.
FROM ANNALS OF INTERNAL MEDICINE
Asthma: Newer Tx options mean more targeted therapy
Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.1 As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include
The pathophysiology of asthma provides key targets for therapy
There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology2:
Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.2-4
In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).
Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.10 Longstanding inflammation can lead to structural changes and reduced airflow reversibility.
Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.12,13
What we’ve learned about asthma can inform treatment decisions
Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV1 > 12% or FVC > 200 mL from baseline).2 If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.
Continue to: Additional diagnostic considerations...
Additional diagnostic considerations may impact the treatment plan for patients with asthma:
Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.14
Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.2,5,15
Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.16-18
Getting a handle on an ever-expanding asthma Tx arsenal
The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.
Continue to: Over the past decade...
Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.
Inhaled medications
This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting
ICS is the first choice for long-term control of persistent asthma.2 Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.19-22
LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death23—a concern that has not been demonstrated with the combination of ICS-LABA.
LABAs cause smooth muscle relaxation in the lungs.24 There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).
Continue to: Once-daily fluticasone furoate/vilanterol...
Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV1.25 In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.26
Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV1 improved with olodeaterol when compared to placebo.27
Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.28 However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.29
The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.15
Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M1 and M3.30 Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.13 The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.
Continue to: Glycopyrronium bromide...
Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.31
Biological therapies
In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.
Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.32
All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 315,33-47 summarizes all approved biologicals for the management of severe asthma.
Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).34 Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).33,34
Continue to: Its efficacy and safety...
Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.15
Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.
Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).37
Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.38
GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.
Continue to: Reslizumab (Cinqair)...
Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.44
Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.45 In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV1 and asthma symptoms.46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.
Bronchial thermoplasty
Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.
Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.48 In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.49
However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).50
Continue to: Both treatment groups...
Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV1 for up to 5 years.51
The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.52
In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.
Immunotherapy
Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).
Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.
Continue to: SCIT
SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.53
SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.
A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.54 A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.55
In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.56 Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.
Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.15
Continue to: Azithromycin
Azithromycin
Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.
The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.57 While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.
The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.58
The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.59
The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.
Continue to: A new era
A new era
We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.
It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.
CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; [email protected]
1. Centers for Disease Control and Prevention. Most recent national asthma data. Updated May 2019. www.cdc.gov/asthma/most_recent_national_asthma_data.htm. Accessed March 6, 2020.
2. National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): Guidelines for the diagnosis and management of asthma—summary report 2007. J Allergy Clin Immunol. 2007;120(5 suppl):S94-S138.
3. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma [published correction appears in Am J Respir Crit Care Med. 2009;180(8):796]. Am J Respir Crit Care Med. 2009;180:388–395.
4. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15:57–65.
5. Busse WW. Inflammation in asthma: the cornerstone of the disease and target of therapy. J Allergy Clin Immunol. 1998;102(4 pt 2):S17-S22.
6. Lane SJ, Lee TH. Mast cell effector mechanisms. J Allergy Clin Immunol. 1996;98(5 pt 2):S67-S71.
7. Robinson DS, Bentley AM, Hartnell A, et al. Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness. Thorax. 1993;48:26-32.
8. Grigoraş A, Grigoraş CC, Giuşcă SE, et al. Remodeling of basement membrane in patients with asthma. Rom J Morphol Embryol. 2016;57:115-119.
9. Huang SK, Xiao HQ, Kleine-Tebbe J, et al. IL-13 expression at the sites of allergen challenge in patients with asthma. J Immunol. 1995;155:2688-2694.
10. Hansbro PM, Starkey MR, Mattes J, et al. Pulmonary immunity during respiratory infections in early life and the development of severe asthma. Ann Am Thorac Soc. 2014;11 suppl 5:S297-S302.
11. Apter AJ, Reisine ST, Willard A, et al. The effect of inhaled albuterol in moderate to severe asthma. J Allergy Clin Immunol. 1996;98:295-301.
12. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363:1715-1726.
13. Kerstjens HA, O’Byrne PM. Tiotropium for the treatment of asthma: a drug safety evaluation. Expert Opin Drug Saf. 2016;15:1115-1124.
14. Global Initiative for Asthma. Diagnosis of diseases of chronic air flow limitation: asthma, COPD and asthma-COPD overlap syndrome (ACOS) 2014. https://ginasthma.org/wp-content/uploads/2019/11/GINA_GOLD_ACOS_2014-wms.pdf. Accessed March 12, 2020.
15. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2019. https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf. Accessed March 12, 2020.
16. Khanbabaee G, Enayat J, Chavoshzadeh Z, et al. Serum level of specific IgG antibody for aspergillus and its association with severity of asthma in asthmatic children. Acta Microbiol Immunol Hung. 2012;59:43-50.
17. Agbetile J, Bourne M, Fairs A, et al. Effectiveness of voriconazole in the treatment of aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol. 2014;134:33-39.
18. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342:756-762.
19. Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011;163:29-43.
20. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132:1033-1044.
21. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J. 2002;19:182-191.
22. Newton R, Giembycz MA. Understanding how long-acting β2-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma—an update. Br J Pharmacol. 2016;173:3405-3430.
23. Wijesinghe M, Perrin K, Harwood M, et al. The risk of asthma mortality with inhaled long acting beta-agonists. Postgrad Med J. 2008;84:467-472.
24. Cazzola M, Page CP, Rogliani P, et al. β2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013;187:690-696.
25. Bernstein DI, Bateman ED, Woodcock A, et al. Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma. J Asthma. 2015;52:1073-1083.
26. Devillier P, Humbert M, Boye A, et al. Efficacy and safety of once-daily fluticasone furoate/vilanterol (FF/VI) versus twice-daily inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) in patients with uncontrolled asthma: an open-label, randomized, controlled trial. Respir Med. 2018;141:111-120.
27. Beeh KM, LaForce C, Gahlemann M, et al. Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat(R) in patients with moderate to severe persistent asthma. Respir Res. 2015;16:87.
28. LaForce C, Alexander M, Deckelmann R, et al. Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day dose-ranging study. Allergy. 2008;63:103-111.
29. Beasley RW, Donohue JF, Mehta R, et al. Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial. BMJ Open. 2015;5:e006131.
30. Aalbers R, Park HS. Positioning of long-acting muscarinic antagonists in the management of asthma. Allergy Asthma Immunol Res. 2017;9:386-393.
31. Lee LA, Briggs A, Edwards LD, et al. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir Med. 2015;109:63-73.
32. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965-976.
33. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.
34. Hanania NA, Wenzel S, Rosen K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804-811.
35. Slavin RG, Ferioli C, Tannenbaum SJ, et al. Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. J Allergy Clin Immunol. 2009;123:107-113.e3.
36. Ledford D, Busse W, Trzaskoma B, et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. J Allergy Clin Immunol. 2017;140:162-169.e2.
37. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207.
38. Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5:390-400.
39. Lugogo N, Domingo C, Chanez P, et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;38:2058-2070.e1.
40. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197.
41. Castro M, Zangrilli J, Wechsler ME. Corrections. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:e15.
42. Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150:789-798.
43. Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: Effects across a broad range of eosinophil counts. Chest. 2016;150:799-810.
44. Mukherjee M, Aleman Paramo F, Kjarsgaard M, et al. Weight-adjusted intravenous reslizumab in severe asthma with inadequate response to fixed-dose subcutaneous mepolizumab. Am J Respir Crit Care Med. 2018;197:38-46.
45. Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125:1344-1353.e2.
46. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-2127.
47. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388:2128-2141.
48. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356:1327-1337.
49. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176:1185-1191.
50. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181:116-124.
51. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013;132:1295-1302.
52. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: A comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J. 2017;50:1700017.
53. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;(8):CD001186.
54. Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015;(8):CD011293.
55. Mosbech H, Deckelmann R, de Blay F, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134:568575.e7.
56. Virchow JC, Backer V, Kuna P, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma: a randomized clinical trial. JAMA. 2016;315:1715-1725.
57. Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma : the AZALEA randomized clinical trial. JAMA Intern Med. 2016;176:1630-1637.
58. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329.
59. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659-668.
Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.1 As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include
The pathophysiology of asthma provides key targets for therapy
There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology2:
Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.2-4
In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).
Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.10 Longstanding inflammation can lead to structural changes and reduced airflow reversibility.
Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.12,13
What we’ve learned about asthma can inform treatment decisions
Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV1 > 12% or FVC > 200 mL from baseline).2 If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.
Continue to: Additional diagnostic considerations...
Additional diagnostic considerations may impact the treatment plan for patients with asthma:
Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.14
Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.2,5,15
Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.16-18
Getting a handle on an ever-expanding asthma Tx arsenal
The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.
Continue to: Over the past decade...
Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.
Inhaled medications
This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting
ICS is the first choice for long-term control of persistent asthma.2 Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.19-22
LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death23—a concern that has not been demonstrated with the combination of ICS-LABA.
LABAs cause smooth muscle relaxation in the lungs.24 There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).
Continue to: Once-daily fluticasone furoate/vilanterol...
Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV1.25 In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.26
Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV1 improved with olodeaterol when compared to placebo.27
Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.28 However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.29
The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.15
Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M1 and M3.30 Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.13 The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.
Continue to: Glycopyrronium bromide...
Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.31
Biological therapies
In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.
Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.32
All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 315,33-47 summarizes all approved biologicals for the management of severe asthma.
Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).34 Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).33,34
Continue to: Its efficacy and safety...
Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.15
Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.
Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).37
Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.38
GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.
Continue to: Reslizumab (Cinqair)...
Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.44
Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.45 In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV1 and asthma symptoms.46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.
Bronchial thermoplasty
Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.
Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.48 In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.49
However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).50
Continue to: Both treatment groups...
Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV1 for up to 5 years.51
The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.52
In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.
Immunotherapy
Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).
Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.
Continue to: SCIT
SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.53
SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.
A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.54 A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.55
In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.56 Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.
Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.15
Continue to: Azithromycin
Azithromycin
Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.
The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.57 While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.
The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.58
The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.59
The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.
Continue to: A new era
A new era
We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.
It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.
CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; [email protected]
Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.1 As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include
The pathophysiology of asthma provides key targets for therapy
There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology2:
Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.2-4
In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).
Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.10 Longstanding inflammation can lead to structural changes and reduced airflow reversibility.
Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.12,13
What we’ve learned about asthma can inform treatment decisions
Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV1 > 12% or FVC > 200 mL from baseline).2 If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.
Continue to: Additional diagnostic considerations...
Additional diagnostic considerations may impact the treatment plan for patients with asthma:
Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.14
Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.2,5,15
Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.16-18
Getting a handle on an ever-expanding asthma Tx arsenal
The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.
Continue to: Over the past decade...
Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.
Inhaled medications
This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting
ICS is the first choice for long-term control of persistent asthma.2 Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.19-22
LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death23—a concern that has not been demonstrated with the combination of ICS-LABA.
LABAs cause smooth muscle relaxation in the lungs.24 There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).
Continue to: Once-daily fluticasone furoate/vilanterol...
Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV1.25 In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.26
Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV1 improved with olodeaterol when compared to placebo.27
Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.28 However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.29
The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.15
Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M1 and M3.30 Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.13 The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.
Continue to: Glycopyrronium bromide...
Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.31
Biological therapies
In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.
Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.32
All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 315,33-47 summarizes all approved biologicals for the management of severe asthma.
Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).34 Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).33,34
Continue to: Its efficacy and safety...
Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.15
Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.
Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).37
Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.38
GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.
Continue to: Reslizumab (Cinqair)...
Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.44
Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.45 In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV1 and asthma symptoms.46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.
Bronchial thermoplasty
Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.
Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.48 In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.49
However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).50
Continue to: Both treatment groups...
Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV1 for up to 5 years.51
The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.52
In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.
Immunotherapy
Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).
Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.
Continue to: SCIT
SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.53
SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.
A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.54 A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.55
In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.56 Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.
Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.15
Continue to: Azithromycin
Azithromycin
Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.
The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.57 While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.
The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.58
The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.59
The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.
Continue to: A new era
A new era
We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.
It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.
CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; [email protected]
1. Centers for Disease Control and Prevention. Most recent national asthma data. Updated May 2019. www.cdc.gov/asthma/most_recent_national_asthma_data.htm. Accessed March 6, 2020.
2. National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): Guidelines for the diagnosis and management of asthma—summary report 2007. J Allergy Clin Immunol. 2007;120(5 suppl):S94-S138.
3. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma [published correction appears in Am J Respir Crit Care Med. 2009;180(8):796]. Am J Respir Crit Care Med. 2009;180:388–395.
4. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15:57–65.
5. Busse WW. Inflammation in asthma: the cornerstone of the disease and target of therapy. J Allergy Clin Immunol. 1998;102(4 pt 2):S17-S22.
6. Lane SJ, Lee TH. Mast cell effector mechanisms. J Allergy Clin Immunol. 1996;98(5 pt 2):S67-S71.
7. Robinson DS, Bentley AM, Hartnell A, et al. Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness. Thorax. 1993;48:26-32.
8. Grigoraş A, Grigoraş CC, Giuşcă SE, et al. Remodeling of basement membrane in patients with asthma. Rom J Morphol Embryol. 2016;57:115-119.
9. Huang SK, Xiao HQ, Kleine-Tebbe J, et al. IL-13 expression at the sites of allergen challenge in patients with asthma. J Immunol. 1995;155:2688-2694.
10. Hansbro PM, Starkey MR, Mattes J, et al. Pulmonary immunity during respiratory infections in early life and the development of severe asthma. Ann Am Thorac Soc. 2014;11 suppl 5:S297-S302.
11. Apter AJ, Reisine ST, Willard A, et al. The effect of inhaled albuterol in moderate to severe asthma. J Allergy Clin Immunol. 1996;98:295-301.
12. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363:1715-1726.
13. Kerstjens HA, O’Byrne PM. Tiotropium for the treatment of asthma: a drug safety evaluation. Expert Opin Drug Saf. 2016;15:1115-1124.
14. Global Initiative for Asthma. Diagnosis of diseases of chronic air flow limitation: asthma, COPD and asthma-COPD overlap syndrome (ACOS) 2014. https://ginasthma.org/wp-content/uploads/2019/11/GINA_GOLD_ACOS_2014-wms.pdf. Accessed March 12, 2020.
15. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2019. https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf. Accessed March 12, 2020.
16. Khanbabaee G, Enayat J, Chavoshzadeh Z, et al. Serum level of specific IgG antibody for aspergillus and its association with severity of asthma in asthmatic children. Acta Microbiol Immunol Hung. 2012;59:43-50.
17. Agbetile J, Bourne M, Fairs A, et al. Effectiveness of voriconazole in the treatment of aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol. 2014;134:33-39.
18. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342:756-762.
19. Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011;163:29-43.
20. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132:1033-1044.
21. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J. 2002;19:182-191.
22. Newton R, Giembycz MA. Understanding how long-acting β2-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma—an update. Br J Pharmacol. 2016;173:3405-3430.
23. Wijesinghe M, Perrin K, Harwood M, et al. The risk of asthma mortality with inhaled long acting beta-agonists. Postgrad Med J. 2008;84:467-472.
24. Cazzola M, Page CP, Rogliani P, et al. β2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013;187:690-696.
25. Bernstein DI, Bateman ED, Woodcock A, et al. Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma. J Asthma. 2015;52:1073-1083.
26. Devillier P, Humbert M, Boye A, et al. Efficacy and safety of once-daily fluticasone furoate/vilanterol (FF/VI) versus twice-daily inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) in patients with uncontrolled asthma: an open-label, randomized, controlled trial. Respir Med. 2018;141:111-120.
27. Beeh KM, LaForce C, Gahlemann M, et al. Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat(R) in patients with moderate to severe persistent asthma. Respir Res. 2015;16:87.
28. LaForce C, Alexander M, Deckelmann R, et al. Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day dose-ranging study. Allergy. 2008;63:103-111.
29. Beasley RW, Donohue JF, Mehta R, et al. Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial. BMJ Open. 2015;5:e006131.
30. Aalbers R, Park HS. Positioning of long-acting muscarinic antagonists in the management of asthma. Allergy Asthma Immunol Res. 2017;9:386-393.
31. Lee LA, Briggs A, Edwards LD, et al. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir Med. 2015;109:63-73.
32. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965-976.
33. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.
34. Hanania NA, Wenzel S, Rosen K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804-811.
35. Slavin RG, Ferioli C, Tannenbaum SJ, et al. Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. J Allergy Clin Immunol. 2009;123:107-113.e3.
36. Ledford D, Busse W, Trzaskoma B, et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. J Allergy Clin Immunol. 2017;140:162-169.e2.
37. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207.
38. Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5:390-400.
39. Lugogo N, Domingo C, Chanez P, et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;38:2058-2070.e1.
40. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197.
41. Castro M, Zangrilli J, Wechsler ME. Corrections. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:e15.
42. Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150:789-798.
43. Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: Effects across a broad range of eosinophil counts. Chest. 2016;150:799-810.
44. Mukherjee M, Aleman Paramo F, Kjarsgaard M, et al. Weight-adjusted intravenous reslizumab in severe asthma with inadequate response to fixed-dose subcutaneous mepolizumab. Am J Respir Crit Care Med. 2018;197:38-46.
45. Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125:1344-1353.e2.
46. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-2127.
47. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388:2128-2141.
48. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356:1327-1337.
49. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176:1185-1191.
50. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181:116-124.
51. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013;132:1295-1302.
52. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: A comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J. 2017;50:1700017.
53. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;(8):CD001186.
54. Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015;(8):CD011293.
55. Mosbech H, Deckelmann R, de Blay F, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134:568575.e7.
56. Virchow JC, Backer V, Kuna P, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma: a randomized clinical trial. JAMA. 2016;315:1715-1725.
57. Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma : the AZALEA randomized clinical trial. JAMA Intern Med. 2016;176:1630-1637.
58. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329.
59. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659-668.
1. Centers for Disease Control and Prevention. Most recent national asthma data. Updated May 2019. www.cdc.gov/asthma/most_recent_national_asthma_data.htm. Accessed March 6, 2020.
2. National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): Guidelines for the diagnosis and management of asthma—summary report 2007. J Allergy Clin Immunol. 2007;120(5 suppl):S94-S138.
3. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma [published correction appears in Am J Respir Crit Care Med. 2009;180(8):796]. Am J Respir Crit Care Med. 2009;180:388–395.
4. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15:57–65.
5. Busse WW. Inflammation in asthma: the cornerstone of the disease and target of therapy. J Allergy Clin Immunol. 1998;102(4 pt 2):S17-S22.
6. Lane SJ, Lee TH. Mast cell effector mechanisms. J Allergy Clin Immunol. 1996;98(5 pt 2):S67-S71.
7. Robinson DS, Bentley AM, Hartnell A, et al. Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness. Thorax. 1993;48:26-32.
8. Grigoraş A, Grigoraş CC, Giuşcă SE, et al. Remodeling of basement membrane in patients with asthma. Rom J Morphol Embryol. 2016;57:115-119.
9. Huang SK, Xiao HQ, Kleine-Tebbe J, et al. IL-13 expression at the sites of allergen challenge in patients with asthma. J Immunol. 1995;155:2688-2694.
10. Hansbro PM, Starkey MR, Mattes J, et al. Pulmonary immunity during respiratory infections in early life and the development of severe asthma. Ann Am Thorac Soc. 2014;11 suppl 5:S297-S302.
11. Apter AJ, Reisine ST, Willard A, et al. The effect of inhaled albuterol in moderate to severe asthma. J Allergy Clin Immunol. 1996;98:295-301.
12. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363:1715-1726.
13. Kerstjens HA, O’Byrne PM. Tiotropium for the treatment of asthma: a drug safety evaluation. Expert Opin Drug Saf. 2016;15:1115-1124.
14. Global Initiative for Asthma. Diagnosis of diseases of chronic air flow limitation: asthma, COPD and asthma-COPD overlap syndrome (ACOS) 2014. https://ginasthma.org/wp-content/uploads/2019/11/GINA_GOLD_ACOS_2014-wms.pdf. Accessed March 12, 2020.
15. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2019. https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf. Accessed March 12, 2020.
16. Khanbabaee G, Enayat J, Chavoshzadeh Z, et al. Serum level of specific IgG antibody for aspergillus and its association with severity of asthma in asthmatic children. Acta Microbiol Immunol Hung. 2012;59:43-50.
17. Agbetile J, Bourne M, Fairs A, et al. Effectiveness of voriconazole in the treatment of aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol. 2014;134:33-39.
18. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342:756-762.
19. Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011;163:29-43.
20. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132:1033-1044.
21. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J. 2002;19:182-191.
22. Newton R, Giembycz MA. Understanding how long-acting β2-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma—an update. Br J Pharmacol. 2016;173:3405-3430.
23. Wijesinghe M, Perrin K, Harwood M, et al. The risk of asthma mortality with inhaled long acting beta-agonists. Postgrad Med J. 2008;84:467-472.
24. Cazzola M, Page CP, Rogliani P, et al. β2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013;187:690-696.
25. Bernstein DI, Bateman ED, Woodcock A, et al. Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma. J Asthma. 2015;52:1073-1083.
26. Devillier P, Humbert M, Boye A, et al. Efficacy and safety of once-daily fluticasone furoate/vilanterol (FF/VI) versus twice-daily inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) in patients with uncontrolled asthma: an open-label, randomized, controlled trial. Respir Med. 2018;141:111-120.
27. Beeh KM, LaForce C, Gahlemann M, et al. Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat(R) in patients with moderate to severe persistent asthma. Respir Res. 2015;16:87.
28. LaForce C, Alexander M, Deckelmann R, et al. Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day dose-ranging study. Allergy. 2008;63:103-111.
29. Beasley RW, Donohue JF, Mehta R, et al. Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial. BMJ Open. 2015;5:e006131.
30. Aalbers R, Park HS. Positioning of long-acting muscarinic antagonists in the management of asthma. Allergy Asthma Immunol Res. 2017;9:386-393.
31. Lee LA, Briggs A, Edwards LD, et al. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir Med. 2015;109:63-73.
32. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965-976.
33. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.
34. Hanania NA, Wenzel S, Rosen K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804-811.
35. Slavin RG, Ferioli C, Tannenbaum SJ, et al. Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. J Allergy Clin Immunol. 2009;123:107-113.e3.
36. Ledford D, Busse W, Trzaskoma B, et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. J Allergy Clin Immunol. 2017;140:162-169.e2.
37. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-1207.
38. Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5:390-400.
39. Lugogo N, Domingo C, Chanez P, et al. Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;38:2058-2070.e1.
40. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-1197.
41. Castro M, Zangrilli J, Wechsler ME. Corrections. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:e15.
42. Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150:789-798.
43. Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: Effects across a broad range of eosinophil counts. Chest. 2016;150:799-810.
44. Mukherjee M, Aleman Paramo F, Kjarsgaard M, et al. Weight-adjusted intravenous reslizumab in severe asthma with inadequate response to fixed-dose subcutaneous mepolizumab. Am J Respir Crit Care Med. 2018;197:38-46.
45. Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125:1344-1353.e2.
46. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-2127.
47. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388:2128-2141.
48. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356:1327-1337.
49. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176:1185-1191.
50. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181:116-124.
51. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013;132:1295-1302.
52. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: A comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J. 2017;50:1700017.
53. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;(8):CD001186.
54. Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015;(8):CD011293.
55. Mosbech H, Deckelmann R, de Blay F, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134:568575.e7.
56. Virchow JC, Backer V, Kuna P, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma: a randomized clinical trial. JAMA. 2016;315:1715-1725.
57. Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma : the AZALEA randomized clinical trial. JAMA Intern Med. 2016;176:1630-1637.
58. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-329.
59. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659-668.
PRACTICE RECOMMENDATIONS
› Consider inhaled corticosteroids (ICS) as your first choice for a long-term control agent to treat asthma; add a long-acting beta agonist (LABA) when needed. A
› Use long-acting muscarinic antagonists (LAMA) as add-on therapy for patients whose asthma is uncontrolled despite the use of low-dose ICS-LABA, or as an alternative to high-dose ICS-LABA. A
› Consider biological therapies for patients with asthma exacerbations that require steroids at least twice a year. B
› Use azithromycin as an add-on therapy to ICS-LABA for a select group of patients with uncontrolled persistent asthma (neutrophilic phenotype). C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
‘The kids will be all right,’ won’t they?
Pediatric patients and COVID-19
The coronavirus disease 2019 (COVID-19) pandemic affects us in many ways. Pediatric patients, interestingly, are largely unaffected clinically by this disease. Less than 1% of documented infections occur in children under 10 years old, according to a review of over 72,000 cases from China.1 In that review, most children were asymptomatic or had mild illness, only three required intensive care, and only one death had been reported as of March 10, 2020. This is in stark contrast to the shocking morbidity and mortality statistics we are becoming all too familiar with on the adult side.
From a social standpoint, however, our pediatric patients’ lives have been turned upside down. Their schedules and routines upended, their education and friendships interrupted, and many are likely experiencing real anxiety and fear.2 For countless children, school is a major source of social, emotional, and nutritional support that has been cut off. Some will lose parents, grandparents, or other loved ones to this disease. Parents will lose jobs and will be unable to afford necessities. Pediatric patients will experience delays of procedures or treatments because of the pandemic. Some have projected that rates of child abuse will increase as has been reported during natural disasters.3
Pediatricians around the country are coming together to tackle these issues in creative ways, including the rapid expansion of virtual/telehealth programs. The school systems are developing strategies to deliver online content, and even food, to their students’ homes. Hopefully these tactics will mitigate some of the potential effects on the mental and physical well-being of these patients.
How about my kids? Will they be all right? I am lucky that my husband and I will have jobs throughout this ordeal. Unfortunately, given my role as a hospitalist and my husband’s as a pulmonary/critical care physician, these same jobs that will keep our kids nourished and supported pose the greatest threat to them. As health care workers, we are worried about protecting our families, which may include vulnerable members. The Spanish health ministry announced that medical professionals account for approximately one in eight documented COVID-19 infections in Spain.4 With inadequate supplies of personal protective equipment (PPE) in our own nation, we are concerned that our statistics could be similar.
There are multiple strategies to protect ourselves and our families during this difficult time. First, appropriate PPE is essential and integrity with the process must be maintained always. Hospital leaders can protect us by tirelessly working to acquire PPE. In Grand Rapids, Mich., our health system has partnered with multiple local manufacturing companies, including Steelcase, who are producing PPE for our workforce.5 Leaders can diligently update their system’s PPE recommendations to be in line with the latest CDC recommendations and disseminate the information regularly. Hospitalists should frequently check with their Infection Prevention department to make sure they understand if there have been any changes to the recommendations. Innovative solutions for sterilization of PPE, stethoscopes, badges and other equipment, such as with the use of UV boxes or hydrogen peroxide vapor,6 should be explored to minimize contamination. Hospitalists should bring a set of clothes and shoes to change into upon arrival to work and to change out of prior to leaving the hospital.
We must also keep our heads strong. Currently the anxiety amongst physicians is palpable but there is solidarity. Hospital leaders must ensure that hospitalists have easy access to free mental health resources, such as virtual counseling. Wellness teams must rise to the occasion with innovative tactics to support us. For example, Spectrum Health’s wellness team is sponsoring a blog where physicians can discuss COVID-19–related challenges openly. Hospitalist leaders should ensure that there is a structure for debriefing after critical incidents, which are sure to increase in frequency. Email lists and discussion boards sponsored by professional society also provide a collaborative venue for some of these discussions. We must take advantage of these resources and communicate with each other.
For me, in the end it comes back to the kids. My kids and most pediatric patients are not likely to be hospitalized from COVID-19, but they are also not immune to the toll that fighting this pandemic will take on our families. We took an oath to protect our patients, but what do we owe to our own children? At a minimum we can optimize how we protect ourselves every day, both physically and mentally. As we come together as a strong community to fight this pandemic, in addition to saving lives, we are working to ensure that, in the end, the kids will be all right.
Dr. Hadley is chief of pediatric hospital medicine at Spectrum Health/Helen DeVos Children’s Hospital in Grand Rapids, Mich., and clinical assistant professor at Michigan State University, East Lansing.
References
1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.
2. Hagan JF Jr; American Academy of Pediatrics Committee on Psychosocial Aspects of Child and Family Health; Task Force on Terrorism. Psychosocial implications of disaster or terrorism on children: A guide for the pediatrician. Pediatrics. 2005;116(3):787-795.
3. Gearhart S et al. The impact of natural disasters on domestic violence: An analysis of reports of simple assault in Florida (1997-2007). Violence Gend. 2018 Jun. doi: 10.1089/vio.2017.0077.
4. Minder R, Peltier E. Virus knocks thousands of health workers out of action in Europe. The New York Times. March 24, 2020.
5. McVicar B. West Michigan businesses hustle to produce medical supplies amid coronavirus pandemic. MLive. March 25, 2020.
6. Kenney PA et al. Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse. medRxiv preprint. 2020 Mar. doi: 10.1101/2020.03.24.20041087.
Pediatric patients and COVID-19
Pediatric patients and COVID-19
The coronavirus disease 2019 (COVID-19) pandemic affects us in many ways. Pediatric patients, interestingly, are largely unaffected clinically by this disease. Less than 1% of documented infections occur in children under 10 years old, according to a review of over 72,000 cases from China.1 In that review, most children were asymptomatic or had mild illness, only three required intensive care, and only one death had been reported as of March 10, 2020. This is in stark contrast to the shocking morbidity and mortality statistics we are becoming all too familiar with on the adult side.
From a social standpoint, however, our pediatric patients’ lives have been turned upside down. Their schedules and routines upended, their education and friendships interrupted, and many are likely experiencing real anxiety and fear.2 For countless children, school is a major source of social, emotional, and nutritional support that has been cut off. Some will lose parents, grandparents, or other loved ones to this disease. Parents will lose jobs and will be unable to afford necessities. Pediatric patients will experience delays of procedures or treatments because of the pandemic. Some have projected that rates of child abuse will increase as has been reported during natural disasters.3
Pediatricians around the country are coming together to tackle these issues in creative ways, including the rapid expansion of virtual/telehealth programs. The school systems are developing strategies to deliver online content, and even food, to their students’ homes. Hopefully these tactics will mitigate some of the potential effects on the mental and physical well-being of these patients.
How about my kids? Will they be all right? I am lucky that my husband and I will have jobs throughout this ordeal. Unfortunately, given my role as a hospitalist and my husband’s as a pulmonary/critical care physician, these same jobs that will keep our kids nourished and supported pose the greatest threat to them. As health care workers, we are worried about protecting our families, which may include vulnerable members. The Spanish health ministry announced that medical professionals account for approximately one in eight documented COVID-19 infections in Spain.4 With inadequate supplies of personal protective equipment (PPE) in our own nation, we are concerned that our statistics could be similar.
There are multiple strategies to protect ourselves and our families during this difficult time. First, appropriate PPE is essential and integrity with the process must be maintained always. Hospital leaders can protect us by tirelessly working to acquire PPE. In Grand Rapids, Mich., our health system has partnered with multiple local manufacturing companies, including Steelcase, who are producing PPE for our workforce.5 Leaders can diligently update their system’s PPE recommendations to be in line with the latest CDC recommendations and disseminate the information regularly. Hospitalists should frequently check with their Infection Prevention department to make sure they understand if there have been any changes to the recommendations. Innovative solutions for sterilization of PPE, stethoscopes, badges and other equipment, such as with the use of UV boxes or hydrogen peroxide vapor,6 should be explored to minimize contamination. Hospitalists should bring a set of clothes and shoes to change into upon arrival to work and to change out of prior to leaving the hospital.
We must also keep our heads strong. Currently the anxiety amongst physicians is palpable but there is solidarity. Hospital leaders must ensure that hospitalists have easy access to free mental health resources, such as virtual counseling. Wellness teams must rise to the occasion with innovative tactics to support us. For example, Spectrum Health’s wellness team is sponsoring a blog where physicians can discuss COVID-19–related challenges openly. Hospitalist leaders should ensure that there is a structure for debriefing after critical incidents, which are sure to increase in frequency. Email lists and discussion boards sponsored by professional society also provide a collaborative venue for some of these discussions. We must take advantage of these resources and communicate with each other.
For me, in the end it comes back to the kids. My kids and most pediatric patients are not likely to be hospitalized from COVID-19, but they are also not immune to the toll that fighting this pandemic will take on our families. We took an oath to protect our patients, but what do we owe to our own children? At a minimum we can optimize how we protect ourselves every day, both physically and mentally. As we come together as a strong community to fight this pandemic, in addition to saving lives, we are working to ensure that, in the end, the kids will be all right.
Dr. Hadley is chief of pediatric hospital medicine at Spectrum Health/Helen DeVos Children’s Hospital in Grand Rapids, Mich., and clinical assistant professor at Michigan State University, East Lansing.
References
1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.
2. Hagan JF Jr; American Academy of Pediatrics Committee on Psychosocial Aspects of Child and Family Health; Task Force on Terrorism. Psychosocial implications of disaster or terrorism on children: A guide for the pediatrician. Pediatrics. 2005;116(3):787-795.
3. Gearhart S et al. The impact of natural disasters on domestic violence: An analysis of reports of simple assault in Florida (1997-2007). Violence Gend. 2018 Jun. doi: 10.1089/vio.2017.0077.
4. Minder R, Peltier E. Virus knocks thousands of health workers out of action in Europe. The New York Times. March 24, 2020.
5. McVicar B. West Michigan businesses hustle to produce medical supplies amid coronavirus pandemic. MLive. March 25, 2020.
6. Kenney PA et al. Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse. medRxiv preprint. 2020 Mar. doi: 10.1101/2020.03.24.20041087.
The coronavirus disease 2019 (COVID-19) pandemic affects us in many ways. Pediatric patients, interestingly, are largely unaffected clinically by this disease. Less than 1% of documented infections occur in children under 10 years old, according to a review of over 72,000 cases from China.1 In that review, most children were asymptomatic or had mild illness, only three required intensive care, and only one death had been reported as of March 10, 2020. This is in stark contrast to the shocking morbidity and mortality statistics we are becoming all too familiar with on the adult side.
From a social standpoint, however, our pediatric patients’ lives have been turned upside down. Their schedules and routines upended, their education and friendships interrupted, and many are likely experiencing real anxiety and fear.2 For countless children, school is a major source of social, emotional, and nutritional support that has been cut off. Some will lose parents, grandparents, or other loved ones to this disease. Parents will lose jobs and will be unable to afford necessities. Pediatric patients will experience delays of procedures or treatments because of the pandemic. Some have projected that rates of child abuse will increase as has been reported during natural disasters.3
Pediatricians around the country are coming together to tackle these issues in creative ways, including the rapid expansion of virtual/telehealth programs. The school systems are developing strategies to deliver online content, and even food, to their students’ homes. Hopefully these tactics will mitigate some of the potential effects on the mental and physical well-being of these patients.
How about my kids? Will they be all right? I am lucky that my husband and I will have jobs throughout this ordeal. Unfortunately, given my role as a hospitalist and my husband’s as a pulmonary/critical care physician, these same jobs that will keep our kids nourished and supported pose the greatest threat to them. As health care workers, we are worried about protecting our families, which may include vulnerable members. The Spanish health ministry announced that medical professionals account for approximately one in eight documented COVID-19 infections in Spain.4 With inadequate supplies of personal protective equipment (PPE) in our own nation, we are concerned that our statistics could be similar.
There are multiple strategies to protect ourselves and our families during this difficult time. First, appropriate PPE is essential and integrity with the process must be maintained always. Hospital leaders can protect us by tirelessly working to acquire PPE. In Grand Rapids, Mich., our health system has partnered with multiple local manufacturing companies, including Steelcase, who are producing PPE for our workforce.5 Leaders can diligently update their system’s PPE recommendations to be in line with the latest CDC recommendations and disseminate the information regularly. Hospitalists should frequently check with their Infection Prevention department to make sure they understand if there have been any changes to the recommendations. Innovative solutions for sterilization of PPE, stethoscopes, badges and other equipment, such as with the use of UV boxes or hydrogen peroxide vapor,6 should be explored to minimize contamination. Hospitalists should bring a set of clothes and shoes to change into upon arrival to work and to change out of prior to leaving the hospital.
We must also keep our heads strong. Currently the anxiety amongst physicians is palpable but there is solidarity. Hospital leaders must ensure that hospitalists have easy access to free mental health resources, such as virtual counseling. Wellness teams must rise to the occasion with innovative tactics to support us. For example, Spectrum Health’s wellness team is sponsoring a blog where physicians can discuss COVID-19–related challenges openly. Hospitalist leaders should ensure that there is a structure for debriefing after critical incidents, which are sure to increase in frequency. Email lists and discussion boards sponsored by professional society also provide a collaborative venue for some of these discussions. We must take advantage of these resources and communicate with each other.
For me, in the end it comes back to the kids. My kids and most pediatric patients are not likely to be hospitalized from COVID-19, but they are also not immune to the toll that fighting this pandemic will take on our families. We took an oath to protect our patients, but what do we owe to our own children? At a minimum we can optimize how we protect ourselves every day, both physically and mentally. As we come together as a strong community to fight this pandemic, in addition to saving lives, we are working to ensure that, in the end, the kids will be all right.
Dr. Hadley is chief of pediatric hospital medicine at Spectrum Health/Helen DeVos Children’s Hospital in Grand Rapids, Mich., and clinical assistant professor at Michigan State University, East Lansing.
References
1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648.
2. Hagan JF Jr; American Academy of Pediatrics Committee on Psychosocial Aspects of Child and Family Health; Task Force on Terrorism. Psychosocial implications of disaster or terrorism on children: A guide for the pediatrician. Pediatrics. 2005;116(3):787-795.
3. Gearhart S et al. The impact of natural disasters on domestic violence: An analysis of reports of simple assault in Florida (1997-2007). Violence Gend. 2018 Jun. doi: 10.1089/vio.2017.0077.
4. Minder R, Peltier E. Virus knocks thousands of health workers out of action in Europe. The New York Times. March 24, 2020.
5. McVicar B. West Michigan businesses hustle to produce medical supplies amid coronavirus pandemic. MLive. March 25, 2020.
6. Kenney PA et al. Hydrogen Peroxide Vapor sterilization of N95 respirators for reuse. medRxiv preprint. 2020 Mar. doi: 10.1101/2020.03.24.20041087.
Tips for self-care during the COVID-19 crisis
I think it’s fair to say, none of us have seen anything like this before. Yet here we are, and we must lead. We are many weeks into the COVID-19 crisis. We moved our offices home and tried not to miss a beat. Our patients need us more than ever – and in different ways.
Lest we become like the shoemaker’s daughter who has no shoes, let’s make sure we take care of ourselves. The shock waves from this pandemic are going to be massive and long lasting. I am already witnessing massive psychological growth on the part of my patients, and I hope, myself and my family. We must be strong as individuals and as a group of professionals.
Now more than ever, we need to set boundaries. So many are suffering. We must take stock of our own lives. Many of us are extremely fortunate. We have homes, families, and plenty of food. We are doctors performing essential services, and we can do so without risking our lives.
The priority is to make sure you are safe, and keeping your family and loved ones safe. As physicians, we have learned to distance ourselves from illness, but the coronavirus has affected us in disproportionate numbers.
To be physically and mentally strong, we must get enough sleep. This is exhausting for some and energizing for others. It is definitely a marathon not a sprint, so pace yourself. Eat well. This is no time for empty calories, and that goes for alcohol as well.
Create new routines. Exercise at the same time each day or perhaps twice a day. Try to be productive during certain hours, and relax at other times. Eat at similar times each day. We must strive to quickly create a “new normal” as we spend our days at home.
Find safe alternatives to your usual workout routine. Use YouTube and Instagram to help you find ways to stay fit in your own home. Ask friends for tips and consider sharing workout time with them via Zoom or FaceTime. New options are coming on line daily.
Make sure you are getting enough information to stay safe, and follow the advice of experts. Then turn off the news. I offer the same advice for financial worries. Try not to stress too much about finances right now. Most of us are feeling the pain of lost income and lost savings. Many of us have spouses or partners who suddenly found themselves out of work. Most likely, we will have ample ability to recover financially as we move forward and find ourselves with more work than ever.
Meditate. This may be advice you have been telling your patients for years but never found the time to try yourself. You can begin very simply with an app called Headspace or Calm. Google “5-minute meditation” on YouTube or find a meditation of any length you desire. If not now, when?
Reach out to one another. We can all use a caring word, or some humor or advice about how to move our practices online.
You may find your concentration is decreased, so be realistic in your expectations of yourself. I am finding shorter sessions more often are providing more comfort to some patients. Other patients are digging deeper than ever emotionally, and the work is becoming more rewarding.
Make sure you take a break to engage in positive activities. Read a book. Listen to soft music. Dim the lights. Watch the sunset, or be in nature if you can do so safely. Watch a TedTalk. Brush up on a foreign language. Take a deep breath. Journal. Puzzles, games, cooking, magazines, and humor all provide much needed respite from the stress. If you are lucky enough to be with family, try to take advantage of this unique time.
Try to avoid or minimize conflict with others. We need one another now more than ever. If you lose your cool, forgive yourself and make amends.
Even in these most challenging times, we must focus on what we are grateful for. Express gratitude to those around you as it will lift their mood as well. I know I am extremely grateful to be able to continue meaningful work when so many are unable to do so.
The next waves of this virus will be hitting our specialty directly so be strong and be prepared. It is an honor to serve, and we must rise to the occasion.
Dr. Ritvo, a psychiatrist with more than 25 years’ experience, practices in Miami Beach, Fla. She is the author of “Bekindr – The Transformative Power of Kindness” (Hellertown, Pa.: Momosa Publishing, 2018), and is the founder of the Bekindr Global Initiative, a movement aimed at cultivating kindness in the world. Dr. Ritvo also is the cofounder of the Bold Beauty Project, a nonprofit group that pairs women with disabilities with photographers who create art exhibitions to raise awareness.
I think it’s fair to say, none of us have seen anything like this before. Yet here we are, and we must lead. We are many weeks into the COVID-19 crisis. We moved our offices home and tried not to miss a beat. Our patients need us more than ever – and in different ways.
Lest we become like the shoemaker’s daughter who has no shoes, let’s make sure we take care of ourselves. The shock waves from this pandemic are going to be massive and long lasting. I am already witnessing massive psychological growth on the part of my patients, and I hope, myself and my family. We must be strong as individuals and as a group of professionals.
Now more than ever, we need to set boundaries. So many are suffering. We must take stock of our own lives. Many of us are extremely fortunate. We have homes, families, and plenty of food. We are doctors performing essential services, and we can do so without risking our lives.
The priority is to make sure you are safe, and keeping your family and loved ones safe. As physicians, we have learned to distance ourselves from illness, but the coronavirus has affected us in disproportionate numbers.
To be physically and mentally strong, we must get enough sleep. This is exhausting for some and energizing for others. It is definitely a marathon not a sprint, so pace yourself. Eat well. This is no time for empty calories, and that goes for alcohol as well.
Create new routines. Exercise at the same time each day or perhaps twice a day. Try to be productive during certain hours, and relax at other times. Eat at similar times each day. We must strive to quickly create a “new normal” as we spend our days at home.
Find safe alternatives to your usual workout routine. Use YouTube and Instagram to help you find ways to stay fit in your own home. Ask friends for tips and consider sharing workout time with them via Zoom or FaceTime. New options are coming on line daily.
Make sure you are getting enough information to stay safe, and follow the advice of experts. Then turn off the news. I offer the same advice for financial worries. Try not to stress too much about finances right now. Most of us are feeling the pain of lost income and lost savings. Many of us have spouses or partners who suddenly found themselves out of work. Most likely, we will have ample ability to recover financially as we move forward and find ourselves with more work than ever.
Meditate. This may be advice you have been telling your patients for years but never found the time to try yourself. You can begin very simply with an app called Headspace or Calm. Google “5-minute meditation” on YouTube or find a meditation of any length you desire. If not now, when?
Reach out to one another. We can all use a caring word, or some humor or advice about how to move our practices online.
You may find your concentration is decreased, so be realistic in your expectations of yourself. I am finding shorter sessions more often are providing more comfort to some patients. Other patients are digging deeper than ever emotionally, and the work is becoming more rewarding.
Make sure you take a break to engage in positive activities. Read a book. Listen to soft music. Dim the lights. Watch the sunset, or be in nature if you can do so safely. Watch a TedTalk. Brush up on a foreign language. Take a deep breath. Journal. Puzzles, games, cooking, magazines, and humor all provide much needed respite from the stress. If you are lucky enough to be with family, try to take advantage of this unique time.
Try to avoid or minimize conflict with others. We need one another now more than ever. If you lose your cool, forgive yourself and make amends.
Even in these most challenging times, we must focus on what we are grateful for. Express gratitude to those around you as it will lift their mood as well. I know I am extremely grateful to be able to continue meaningful work when so many are unable to do so.
The next waves of this virus will be hitting our specialty directly so be strong and be prepared. It is an honor to serve, and we must rise to the occasion.
Dr. Ritvo, a psychiatrist with more than 25 years’ experience, practices in Miami Beach, Fla. She is the author of “Bekindr – The Transformative Power of Kindness” (Hellertown, Pa.: Momosa Publishing, 2018), and is the founder of the Bekindr Global Initiative, a movement aimed at cultivating kindness in the world. Dr. Ritvo also is the cofounder of the Bold Beauty Project, a nonprofit group that pairs women with disabilities with photographers who create art exhibitions to raise awareness.
I think it’s fair to say, none of us have seen anything like this before. Yet here we are, and we must lead. We are many weeks into the COVID-19 crisis. We moved our offices home and tried not to miss a beat. Our patients need us more than ever – and in different ways.
Lest we become like the shoemaker’s daughter who has no shoes, let’s make sure we take care of ourselves. The shock waves from this pandemic are going to be massive and long lasting. I am already witnessing massive psychological growth on the part of my patients, and I hope, myself and my family. We must be strong as individuals and as a group of professionals.
Now more than ever, we need to set boundaries. So many are suffering. We must take stock of our own lives. Many of us are extremely fortunate. We have homes, families, and plenty of food. We are doctors performing essential services, and we can do so without risking our lives.
The priority is to make sure you are safe, and keeping your family and loved ones safe. As physicians, we have learned to distance ourselves from illness, but the coronavirus has affected us in disproportionate numbers.
To be physically and mentally strong, we must get enough sleep. This is exhausting for some and energizing for others. It is definitely a marathon not a sprint, so pace yourself. Eat well. This is no time for empty calories, and that goes for alcohol as well.
Create new routines. Exercise at the same time each day or perhaps twice a day. Try to be productive during certain hours, and relax at other times. Eat at similar times each day. We must strive to quickly create a “new normal” as we spend our days at home.
Find safe alternatives to your usual workout routine. Use YouTube and Instagram to help you find ways to stay fit in your own home. Ask friends for tips and consider sharing workout time with them via Zoom or FaceTime. New options are coming on line daily.
Make sure you are getting enough information to stay safe, and follow the advice of experts. Then turn off the news. I offer the same advice for financial worries. Try not to stress too much about finances right now. Most of us are feeling the pain of lost income and lost savings. Many of us have spouses or partners who suddenly found themselves out of work. Most likely, we will have ample ability to recover financially as we move forward and find ourselves with more work than ever.
Meditate. This may be advice you have been telling your patients for years but never found the time to try yourself. You can begin very simply with an app called Headspace or Calm. Google “5-minute meditation” on YouTube or find a meditation of any length you desire. If not now, when?
Reach out to one another. We can all use a caring word, or some humor or advice about how to move our practices online.
You may find your concentration is decreased, so be realistic in your expectations of yourself. I am finding shorter sessions more often are providing more comfort to some patients. Other patients are digging deeper than ever emotionally, and the work is becoming more rewarding.
Make sure you take a break to engage in positive activities. Read a book. Listen to soft music. Dim the lights. Watch the sunset, or be in nature if you can do so safely. Watch a TedTalk. Brush up on a foreign language. Take a deep breath. Journal. Puzzles, games, cooking, magazines, and humor all provide much needed respite from the stress. If you are lucky enough to be with family, try to take advantage of this unique time.
Try to avoid or minimize conflict with others. We need one another now more than ever. If you lose your cool, forgive yourself and make amends.
Even in these most challenging times, we must focus on what we are grateful for. Express gratitude to those around you as it will lift their mood as well. I know I am extremely grateful to be able to continue meaningful work when so many are unable to do so.
The next waves of this virus will be hitting our specialty directly so be strong and be prepared. It is an honor to serve, and we must rise to the occasion.
Dr. Ritvo, a psychiatrist with more than 25 years’ experience, practices in Miami Beach, Fla. She is the author of “Bekindr – The Transformative Power of Kindness” (Hellertown, Pa.: Momosa Publishing, 2018), and is the founder of the Bekindr Global Initiative, a movement aimed at cultivating kindness in the world. Dr. Ritvo also is the cofounder of the Bold Beauty Project, a nonprofit group that pairs women with disabilities with photographers who create art exhibitions to raise awareness.
AMA president calls for greater reliance on science in COVID-19 fight
The president of the American Medical Association is calling on politicians and the media to rely on science and evidence to help the public through the COVID-19 pandemic.
“We live in a time when misinformation, falsehoods, and outright lies spread like viruses online, through social media and even, at times, in the media at large,” Patrice A. Harris, MD, said during an April 7 address. “We have witnessed a concerning shift over the last several decades where policy decisions seem to be driven by ideology and politics instead of facts and evidence. The result is a growing mistrust in American institutions, in science, and in the counsel of leading experts whose lives are dedicated to the pursuit of evidence and reason.”
To that end, she called on everyone – from politicians to the general public – to trust the scientific evidence.
Dr. Harris noted that the scientific data on COVID-19 have already yielded important lessons about who is more likely to be affected and how easily the virus can spread. The data also point to the effectiveness of stay-at-home and shelter-in-place orders. “This is our best chance to slow the spread of the virus,” she said, adding that the enhanced emphasis on hand washing and other hygiene practices “may seem ‘simplistic,’ but they are, in fact, based in science and evidence.”
And, as the pandemic continues, Dr. Harris said that now is the time to rely on science. She said the AMA “calls on all elected officials to affirm science, evidence, and fact in their words and actions,” and she urged that the government’s scientific institutions be led by experts who are “protected from political influence.”
It is incumbent upon everyone to actively work to contain and stop the spread of misinformation related to COVID-19, she said. “We must ensure the war is against the virus and not against science,” Dr. Harris said.
The president of the American Medical Association is calling on politicians and the media to rely on science and evidence to help the public through the COVID-19 pandemic.
“We live in a time when misinformation, falsehoods, and outright lies spread like viruses online, through social media and even, at times, in the media at large,” Patrice A. Harris, MD, said during an April 7 address. “We have witnessed a concerning shift over the last several decades where policy decisions seem to be driven by ideology and politics instead of facts and evidence. The result is a growing mistrust in American institutions, in science, and in the counsel of leading experts whose lives are dedicated to the pursuit of evidence and reason.”
To that end, she called on everyone – from politicians to the general public – to trust the scientific evidence.
Dr. Harris noted that the scientific data on COVID-19 have already yielded important lessons about who is more likely to be affected and how easily the virus can spread. The data also point to the effectiveness of stay-at-home and shelter-in-place orders. “This is our best chance to slow the spread of the virus,” she said, adding that the enhanced emphasis on hand washing and other hygiene practices “may seem ‘simplistic,’ but they are, in fact, based in science and evidence.”
And, as the pandemic continues, Dr. Harris said that now is the time to rely on science. She said the AMA “calls on all elected officials to affirm science, evidence, and fact in their words and actions,” and she urged that the government’s scientific institutions be led by experts who are “protected from political influence.”
It is incumbent upon everyone to actively work to contain and stop the spread of misinformation related to COVID-19, she said. “We must ensure the war is against the virus and not against science,” Dr. Harris said.
The president of the American Medical Association is calling on politicians and the media to rely on science and evidence to help the public through the COVID-19 pandemic.
“We live in a time when misinformation, falsehoods, and outright lies spread like viruses online, through social media and even, at times, in the media at large,” Patrice A. Harris, MD, said during an April 7 address. “We have witnessed a concerning shift over the last several decades where policy decisions seem to be driven by ideology and politics instead of facts and evidence. The result is a growing mistrust in American institutions, in science, and in the counsel of leading experts whose lives are dedicated to the pursuit of evidence and reason.”
To that end, she called on everyone – from politicians to the general public – to trust the scientific evidence.
Dr. Harris noted that the scientific data on COVID-19 have already yielded important lessons about who is more likely to be affected and how easily the virus can spread. The data also point to the effectiveness of stay-at-home and shelter-in-place orders. “This is our best chance to slow the spread of the virus,” she said, adding that the enhanced emphasis on hand washing and other hygiene practices “may seem ‘simplistic,’ but they are, in fact, based in science and evidence.”
And, as the pandemic continues, Dr. Harris said that now is the time to rely on science. She said the AMA “calls on all elected officials to affirm science, evidence, and fact in their words and actions,” and she urged that the government’s scientific institutions be led by experts who are “protected from political influence.”
It is incumbent upon everyone to actively work to contain and stop the spread of misinformation related to COVID-19, she said. “We must ensure the war is against the virus and not against science,” Dr. Harris said.
Nearly 24 tests for the novel coronavirus are available
according to the Infectious Diseases Society of America (IDSA).
“Based on what we know about influenza, it’s unlikely that all of these tests are going to perform exactly the same way,” said Angela M. Caliendo, MD, executive vice chair of the department of medicine at Brown University in Providence, R.I., at a press briefing. Although these tests are good, no test is perfect, she added.
The development and availability of testing has improved over time, but clinical laboratories still face challenges, said Kimberly E. Hanson, MD, associate professor of internal medicine at University of Utah, Salt Lake City. These challenges include shortages of devices for specimen collection, media, test tubes, and reagents. Although the goal is to test all symptomatic patients, these shortages require laboratories to prioritize health care workers and the sickest patients.
Tests are being approved through an abbreviated process
Two types of test, rapid tests and serology tests, are in use. Rapid tests use polymerase chain reactions to detect the virus in a clinical specimen. This type of testing is used to diagnose infection. Serology tests measure antibodies to the virus and are more appropriate for indicating whether a patient has been exposed to the virus.
The declaration of a national emergency enabled the FDA to activate its EUA policy, which allows for quicker approval of tests. Normally, a test must be assessed in the laboratory (such as with a mock specimen or an inactivated virus) and in a clinical study of patients. Under the EUA, clinical assessment is not required for the approval of a test. Consequently, the clinical performance of a test approved under EUA is unknown.
Collecting a specimen of good quality is critical to the quality of the test result, said Dr. Caliendo, the secretary of IDSA’s board of directors. Clinicians and investigators have used nasopharyngeal swabs, sputum, and specimens collected from deep within the lung. “We’re still collecting data to determine which is the best specimen type.” As coronavirus testing expands, particularly to drive-through testing sites, “we may be using people who are not as experienced, and so you might not get as high a quality specimen in that situation,” Dr. Caliendo added.
The timing of the test influences the quality of the result, as well, because the amount of virus is lower at the onset of symptoms than it is later. Another factor that affects the quality of the results is the test’s sensitivity.
The time to obtain results varies
The value of having several tests available is that it enables many patients to be tested simultaneously, said Dr. Hanson, a member of IDSA’s board of directors. It also helps to reduce potential problems with the supply of test kits. A test manufacturer, however, may supply parts of the test kit but not the whole kit. This requires the hospital or laboratory to obtain the remaining parts from other suppliers. Furthermore, test manufacturers may need to prioritize areas with high rates of infection or transmission when they ship their tests, which limits testing in other areas.
One reason for the lack of a national plan for testing is that the virus has affected different regions at different times, said Dr. Caliendo. Some tests are more difficult to perform than others, and not all laboratories are equally sophisticated, which can limit testing. It is necessary to test not only symptomatic patients who have been hospitalized, but also symptomatic patients in the community, said Dr. Caliendo. “Ideally, we’re going to need to couple acute diagnostics [testing while people are sick] with serologic testing. Serologic testing is going to be important for us to see who has been infected. That will give us an idea of who is left in our community who is at risk for developing infection.”
How quickly test results are available depends on the type of test and where it is administered. Recently established drive-through clinics can provide results in about 30 minutes. Tests performed in hospitals may take between 1 and 6 hours to yield results. “The issue is, do we have reagents that day?” said Dr. Caliendo. “We have to be careful whom we choose to test, and we screen that in the hospital so that we have enough tests to run as we need them.” But many locations have backlogs. “When you have a backlog of testing, you’re going to wait days, unfortunately, to get a result,” said Dr. Caliendo.
Dr. Caliendo and Dr. Hanson did not report disclosures for this briefing.
according to the Infectious Diseases Society of America (IDSA).
“Based on what we know about influenza, it’s unlikely that all of these tests are going to perform exactly the same way,” said Angela M. Caliendo, MD, executive vice chair of the department of medicine at Brown University in Providence, R.I., at a press briefing. Although these tests are good, no test is perfect, she added.
The development and availability of testing has improved over time, but clinical laboratories still face challenges, said Kimberly E. Hanson, MD, associate professor of internal medicine at University of Utah, Salt Lake City. These challenges include shortages of devices for specimen collection, media, test tubes, and reagents. Although the goal is to test all symptomatic patients, these shortages require laboratories to prioritize health care workers and the sickest patients.
Tests are being approved through an abbreviated process
Two types of test, rapid tests and serology tests, are in use. Rapid tests use polymerase chain reactions to detect the virus in a clinical specimen. This type of testing is used to diagnose infection. Serology tests measure antibodies to the virus and are more appropriate for indicating whether a patient has been exposed to the virus.
The declaration of a national emergency enabled the FDA to activate its EUA policy, which allows for quicker approval of tests. Normally, a test must be assessed in the laboratory (such as with a mock specimen or an inactivated virus) and in a clinical study of patients. Under the EUA, clinical assessment is not required for the approval of a test. Consequently, the clinical performance of a test approved under EUA is unknown.
Collecting a specimen of good quality is critical to the quality of the test result, said Dr. Caliendo, the secretary of IDSA’s board of directors. Clinicians and investigators have used nasopharyngeal swabs, sputum, and specimens collected from deep within the lung. “We’re still collecting data to determine which is the best specimen type.” As coronavirus testing expands, particularly to drive-through testing sites, “we may be using people who are not as experienced, and so you might not get as high a quality specimen in that situation,” Dr. Caliendo added.
The timing of the test influences the quality of the result, as well, because the amount of virus is lower at the onset of symptoms than it is later. Another factor that affects the quality of the results is the test’s sensitivity.
The time to obtain results varies
The value of having several tests available is that it enables many patients to be tested simultaneously, said Dr. Hanson, a member of IDSA’s board of directors. It also helps to reduce potential problems with the supply of test kits. A test manufacturer, however, may supply parts of the test kit but not the whole kit. This requires the hospital or laboratory to obtain the remaining parts from other suppliers. Furthermore, test manufacturers may need to prioritize areas with high rates of infection or transmission when they ship their tests, which limits testing in other areas.
One reason for the lack of a national plan for testing is that the virus has affected different regions at different times, said Dr. Caliendo. Some tests are more difficult to perform than others, and not all laboratories are equally sophisticated, which can limit testing. It is necessary to test not only symptomatic patients who have been hospitalized, but also symptomatic patients in the community, said Dr. Caliendo. “Ideally, we’re going to need to couple acute diagnostics [testing while people are sick] with serologic testing. Serologic testing is going to be important for us to see who has been infected. That will give us an idea of who is left in our community who is at risk for developing infection.”
How quickly test results are available depends on the type of test and where it is administered. Recently established drive-through clinics can provide results in about 30 minutes. Tests performed in hospitals may take between 1 and 6 hours to yield results. “The issue is, do we have reagents that day?” said Dr. Caliendo. “We have to be careful whom we choose to test, and we screen that in the hospital so that we have enough tests to run as we need them.” But many locations have backlogs. “When you have a backlog of testing, you’re going to wait days, unfortunately, to get a result,” said Dr. Caliendo.
Dr. Caliendo and Dr. Hanson did not report disclosures for this briefing.
according to the Infectious Diseases Society of America (IDSA).
“Based on what we know about influenza, it’s unlikely that all of these tests are going to perform exactly the same way,” said Angela M. Caliendo, MD, executive vice chair of the department of medicine at Brown University in Providence, R.I., at a press briefing. Although these tests are good, no test is perfect, she added.
The development and availability of testing has improved over time, but clinical laboratories still face challenges, said Kimberly E. Hanson, MD, associate professor of internal medicine at University of Utah, Salt Lake City. These challenges include shortages of devices for specimen collection, media, test tubes, and reagents. Although the goal is to test all symptomatic patients, these shortages require laboratories to prioritize health care workers and the sickest patients.
Tests are being approved through an abbreviated process
Two types of test, rapid tests and serology tests, are in use. Rapid tests use polymerase chain reactions to detect the virus in a clinical specimen. This type of testing is used to diagnose infection. Serology tests measure antibodies to the virus and are more appropriate for indicating whether a patient has been exposed to the virus.
The declaration of a national emergency enabled the FDA to activate its EUA policy, which allows for quicker approval of tests. Normally, a test must be assessed in the laboratory (such as with a mock specimen or an inactivated virus) and in a clinical study of patients. Under the EUA, clinical assessment is not required for the approval of a test. Consequently, the clinical performance of a test approved under EUA is unknown.
Collecting a specimen of good quality is critical to the quality of the test result, said Dr. Caliendo, the secretary of IDSA’s board of directors. Clinicians and investigators have used nasopharyngeal swabs, sputum, and specimens collected from deep within the lung. “We’re still collecting data to determine which is the best specimen type.” As coronavirus testing expands, particularly to drive-through testing sites, “we may be using people who are not as experienced, and so you might not get as high a quality specimen in that situation,” Dr. Caliendo added.
The timing of the test influences the quality of the result, as well, because the amount of virus is lower at the onset of symptoms than it is later. Another factor that affects the quality of the results is the test’s sensitivity.
The time to obtain results varies
The value of having several tests available is that it enables many patients to be tested simultaneously, said Dr. Hanson, a member of IDSA’s board of directors. It also helps to reduce potential problems with the supply of test kits. A test manufacturer, however, may supply parts of the test kit but not the whole kit. This requires the hospital or laboratory to obtain the remaining parts from other suppliers. Furthermore, test manufacturers may need to prioritize areas with high rates of infection or transmission when they ship their tests, which limits testing in other areas.
One reason for the lack of a national plan for testing is that the virus has affected different regions at different times, said Dr. Caliendo. Some tests are more difficult to perform than others, and not all laboratories are equally sophisticated, which can limit testing. It is necessary to test not only symptomatic patients who have been hospitalized, but also symptomatic patients in the community, said Dr. Caliendo. “Ideally, we’re going to need to couple acute diagnostics [testing while people are sick] with serologic testing. Serologic testing is going to be important for us to see who has been infected. That will give us an idea of who is left in our community who is at risk for developing infection.”
How quickly test results are available depends on the type of test and where it is administered. Recently established drive-through clinics can provide results in about 30 minutes. Tests performed in hospitals may take between 1 and 6 hours to yield results. “The issue is, do we have reagents that day?” said Dr. Caliendo. “We have to be careful whom we choose to test, and we screen that in the hospital so that we have enough tests to run as we need them.” But many locations have backlogs. “When you have a backlog of testing, you’re going to wait days, unfortunately, to get a result,” said Dr. Caliendo.
Dr. Caliendo and Dr. Hanson did not report disclosures for this briefing.