Children and adolescents with cancer report significantly more fatigue than their counterparts without cancer, and cancer-related fatigue (CRF) is “one of the most prevalent and distressing symptoms reported during childhood cancer therapy,” according to Austin L. Brown, PhD, and his colleagues.

Cerebrospinal fluid (CSF) profiles suggest three metabolites are significantly associated with CRF in children with acute lymphoblastic leukemia (ALL), according to a report published in the Journal of Pain and Symptom Management.

The researchers assessed the clinical and demographic characteristics of 171 pediatric ALL patients, who were divided into discovery (n = 86) and replication (n = 85) cohorts.

The entire population had a mean age at diagnosis of 8.48 years; was 56.1% male; and 85.4% had B-lineage ALL. A total of 63.7% received high- or very-high-risk treatment.

CSF samples were obtained and subjected to metabolomic analysis, according to Dr. Brown, an assistant professor at the Baylor College of Medicine, Houston, and colleagues.

The researchers analyzed postinduction CSF from the aforementioned 171 patients as well as diagnostic CSF from 48 patients in an additional replication cohort.
 

Significant metabolites

Analysis of postinduction CSF showed that three metabolites were significantly associated with fatigue in both the discovery and replication cohorts, comprising gamma-glutamylglutamine, dimethylglycine, and asparagine (P < .05).

In diagnostic CSF samples, the abundance of gamma-glutamylglutamine was significantly associated with fatigue (P =.0062).

The metabolites have been implicated in neurotransmitter transportation and glutathione recycling, suggesting glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF, according to the researchers.

“Ultimately, this line of investigation may aid in the development of new prevention and treatment approaches informed by an improved understanding of the etiology and risk factors for cancer-related fatigue,” the researchers concluded.

The study was sponsored by the National Cancer Institute and several nonprofit organizations. The authors reported that they had no conflicts of interest.

[email protected]

SOURCE: Brown AL et al. J Pain Symptom Manage. 2020 Sep 1. doi: 10.1016/j.jpainsymman.2020.08.030.

Children and adolescents with cancer report significantly more fatigue than their counterparts without cancer, and cancer-related fatigue (CRF) is “one of the most prevalent and distressing symptoms reported during childhood cancer therapy,” according to Austin L. Brown, PhD, and his colleagues.

Cerebrospinal fluid (CSF) profiles suggest three metabolites are significantly associated with CRF in children with acute lymphoblastic leukemia (ALL), according to a report published in the Journal of Pain and Symptom Management.

The researchers assessed the clinical and demographic characteristics of 171 pediatric ALL patients, who were divided into discovery (n = 86) and replication (n = 85) cohorts.

The entire population had a mean age at diagnosis of 8.48 years; was 56.1% male; and 85.4% had B-lineage ALL. A total of 63.7% received high- or very-high-risk treatment.

CSF samples were obtained and subjected to metabolomic analysis, according to Dr. Brown, an assistant professor at the Baylor College of Medicine, Houston, and colleagues.

The researchers analyzed postinduction CSF from the aforementioned 171 patients as well as diagnostic CSF from 48 patients in an additional replication cohort.
 

Significant metabolites

Analysis of postinduction CSF showed that three metabolites were significantly associated with fatigue in both the discovery and replication cohorts, comprising gamma-glutamylglutamine, dimethylglycine, and asparagine (P < .05).

In diagnostic CSF samples, the abundance of gamma-glutamylglutamine was significantly associated with fatigue (P =.0062).

The metabolites have been implicated in neurotransmitter transportation and glutathione recycling, suggesting glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF, according to the researchers.

“Ultimately, this line of investigation may aid in the development of new prevention and treatment approaches informed by an improved understanding of the etiology and risk factors for cancer-related fatigue,” the researchers concluded.

The study was sponsored by the National Cancer Institute and several nonprofit organizations. The authors reported that they had no conflicts of interest.

[email protected]

SOURCE: Brown AL et al. J Pain Symptom Manage. 2020 Sep 1. doi: 10.1016/j.jpainsymman.2020.08.030.

Children and adolescents with cancer report significantly more fatigue than their counterparts without cancer, and cancer-related fatigue (CRF) is “one of the most prevalent and distressing symptoms reported during childhood cancer therapy,” according to Austin L. Brown, PhD, and his colleagues.

Cerebrospinal fluid (CSF) profiles suggest three metabolites are significantly associated with CRF in children with acute lymphoblastic leukemia (ALL), according to a report published in the Journal of Pain and Symptom Management.

The researchers assessed the clinical and demographic characteristics of 171 pediatric ALL patients, who were divided into discovery (n = 86) and replication (n = 85) cohorts.

The entire population had a mean age at diagnosis of 8.48 years; was 56.1% male; and 85.4% had B-lineage ALL. A total of 63.7% received high- or very-high-risk treatment.

CSF samples were obtained and subjected to metabolomic analysis, according to Dr. Brown, an assistant professor at the Baylor College of Medicine, Houston, and colleagues.

The researchers analyzed postinduction CSF from the aforementioned 171 patients as well as diagnostic CSF from 48 patients in an additional replication cohort.
 

Significant metabolites

Analysis of postinduction CSF showed that three metabolites were significantly associated with fatigue in both the discovery and replication cohorts, comprising gamma-glutamylglutamine, dimethylglycine, and asparagine (P < .05).

In diagnostic CSF samples, the abundance of gamma-glutamylglutamine was significantly associated with fatigue (P =.0062).

The metabolites have been implicated in neurotransmitter transportation and glutathione recycling, suggesting glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF, according to the researchers.

“Ultimately, this line of investigation may aid in the development of new prevention and treatment approaches informed by an improved understanding of the etiology and risk factors for cancer-related fatigue,” the researchers concluded.

The study was sponsored by the National Cancer Institute and several nonprofit organizations. The authors reported that they had no conflicts of interest.

[email protected]

SOURCE: Brown AL et al. J Pain Symptom Manage. 2020 Sep 1. doi: 10.1016/j.jpainsymman.2020.08.030.

As the COVID-19 crisis pandemic continues, many physicians are not only battling the medical challenges it has wrought but they’re also dealing with its financial ramifications at home.

“Some of our physician clients have seen their income decrease by as much as 50%,” says Joel Greenwald, MD, CEO of Greenwald Wealth Management in St. Louis Park, Minnesota. “Many physicians had previously figured that whatever financial obligations they had wouldn’t be a problem because whatever amount they were making would continue, and if there were a decline it would be gradual.” However, assumption is now creating financial strain for many doctors.

Vikram Tarugu, MD, a gastroenterologist and CEO of Detox of South Florida in Okeechobee, Florida, says he has watched his budget for years, but has become even more careful with his spending in the past few months.

“It has helped me a lot to adjust to the new normal when it comes to the financial side of things,” Dr. Tarugu said. “Patients aren’t coming in as much as they used to, so my income has really been affected.”

Primary care physicians have seen a 55% decrease in revenue and a 20%-30% decrease in patient volume as a result of COVID-19. The impact has been even more severe for specialists. Even for physicians whose practices remain busy and whose family members haven’t lost their jobs or income, broader concerns about the economy may be reason enough for physicians to adopt cost-cutting measures.

In Medscape’s Physician Compensation Report 2020, we asked physicians to share their best cost-cutting tips. Many illustrate the lengths to which physicians are going to conserve money.  

Here’s a look at some of the advice they shared, along with guidance from experts on how to make it work for you:
 

1. Create a written budget, even if you think it’s pointless.

Physicians said their most important piece of advice includes the following: “Use a formal budget to track progress,” “write out a budget,” “plan intermittent/large expenses in advance,” “Make sure all expenses are paid before you spend on leisure.”

Nearly 7 in 10 physicians say they have a budget for personal expenses, yet only one-quarter of those who do have a formal, written budget. Writing out a spending plan is key to being intentional about your spending, making sure that you’re living within your means, and identifying areas in which you may be able to cut back.

“Financial planning is all about cash flow, and everybody should know the amount of money coming in, how much is going out, and the difference between the two,” says Amy Guerich, a partner with Stepp & Rothwell, a Kansas City–based financial planning firm. “That’s important in good times, but it’s even more important now when we see physicians taking pay cuts.”

Many physicians have found that budget apps or software programs are easier to work with than anticipated; some even walk you through the process of creating a budget. To get the most out of the apps, you’ll need to check them regularly and make changes based on their data.

“Sometimes there’s this false belief that just by signing up, you are automatically going to be better at budgeting,” says Scott Snider, CFP, a certified financial planner and partner with Mellen Money Management in Ponte Vedra Beach, Florida. “Basically, these apps are a great way to identify problem areas of spending. We have a tendency as humans to underestimate how much we spend on things like Starbucks, dining out, and Amazon shopping.”

One of the doctors’ tips that requires the most willpower is to “pay all expenses before spending on leisure.” That’s because we live in an instant gratification world, and want everything right away, Ms. Guerich said.

“I also think there’s an element of ‘keeping up with the Joneses’ and pressure associated with this profession,” she said. “The stereotype is that physicians are high-income earners so ‘We should be able to do that’ or ‘Mom and dad are doctors, so they can afford it.’ “

Creating and then revisiting your budget progress on a monthly or quarterly basis can give you a feeling of accomplishment and keep you motivated to stay with it.  

Keep in mind that budgeting is a continual process rather than a singular event, and you’ll likely adjust it over time as your income and goals change. 
 

2. Save more as you earn more.

Respondents to our Physician Compensation Report gave the following recommendations: “Pay yourself first,” “I put half of my bonus into an investment account no matter how much it is,” “I allocate extra money and put it into a savings account.”

Dr. Greenwald said, “I have a rule that every client needs to be saving 20% of their gross income toward retirement, including whatever the employer is putting in.”

Putting a portion of every paycheck into savings is key to making progress toward financial goals. Start by building an emergency fund with at least 3-6 months’ worth of expenses in it and making sure you’re saving at least enough for retirement to get any potential employer match.

Mr. Snider suggests increasing the percentage you save every time you get a raise.

“The thought behind that strategy is that when a doctor receives a pay raise – even if it’s just a cost-of-living raise of 3% – an extra 1% saved doesn’t reduce their take-home pay year-over-year,” he says. “In fact, they still take home more money, and they save more money. Win-win.”
 

3. Focus on paying down your debt.

Physicians told us how they were working to pay down debt with the following recommendations:  “Accelerate debt reduction,” “I make additional principal payment to our home mortgage,” “We are aggressively attacking our remaining student loans.”

Reducing or eliminating debt is key to increasing cash flow, which can make it easier to meet all of your other financial goals. One-quarter of physicians have credit card debt, which typically carries interest rates higher than other types of debt, making it far more expensive. Focus on paying off such high-interest debt first, before moving on to other types of debt such as auto loans, student loans, or a mortgage.

“Credit card debt and any unsecured debt should be paid before anything else,” Mr. Snider says. “Getting rid of those high interest rates should be a priority. And that type of debt has less flexible terms than student debt.”
 

4. Great opportunity to take advantage of record-low interest rates.

Physicians said that, to save money, they are recommending the following: “Consolidating student debt into our mortgage,” “Accelerating payments of the principle on our mortgage,” “Making sure we have an affordable mortgage.”

With interest rates at an all-time low, even those who’ve recently refinanced might see significant savings by refinancing again. Given the associated fees, it typically makes sense to refinance if you can reduce your mortgage rate by at least a point, and you’re planning to stay in the home for at least 5 years.

“Depending on how much lower your rate is, refinancing can make a big difference in your monthly payments,” Ms. Guerich said. “For physicians who might need an emergency reserve but don’t have cash on hand, a HELOC [Home Equity Line of Credit] is a great way to accomplish that.”
 

5. Be wary of credit cards dangers; use cards wisely.

Physician respondents recommended the following:  “Use 0% interest offers on credit cards,” “Only have one card and pay it off every month,” “Never carry over balance.”

Nearly 80% of physicians have three or more credit cards, with 18% reporting that they have seven or more. When used wisely, credit cards can be an important tool for managing finances. Many credit cards come with tools that can help with budgeting, and credit cards rewards and perks can offer real value to users. That said, rewards typically are not valuable enough to offset the cost of interest on balances (or the associated damage to your credit score) that aren’t paid off each month.

“If you’re paying a high rate on credit card balances that carry over every month, regardless of your income, that could be a symptom that you may be spending more than you should,” says Dan Keady, a CFP and chief financial planning strategist at financial services firm TIAA.

6. Give less to Uncle Sam: Keep it for yourself.

Physicians said that they do the following: “Maximize tax-free/deferred savings (401k, HSA, etc.),” “Give to charity to reduce tax,” “Use pre-tax dollars for childcare and healthcare.”

Not only does saving in workplace retirement accounts help you build your nest egg, but it also reduces the amount that you have to pay in taxes in a given year. Physicians should also take advantage of other ways to reduce their income for tax purposes, such as saving money in a health savings account or flexible savings account.

The 401(k) or 403(b) contribution limit for this year is $19,500 ($26,000) for those age 50 years and older. Self-employed physicians can save even more money via a Simplified Employee Pension (SEP) IRA, says Ms. Guerich said. They can save up to 25% of compensation, up to $57,000 in 2020.
 

7. Automate everything and spare yourself the headache.

Physicians said the following: “Designate money from your paycheck directly to tax deferred and taxable accounts automatically,” “Use automatic payment for credit card balance monthly,” “Automate your savings.”

You probably already automate your 401(k) contributions, but you can also automate bill payments, emergency savings contributions and other financial tasks. For busy physicians, this can make it easier to stick to your financial plan and achieve your goals.

“The older you get, the busier you get, said Mr. Snider says. “Automation can definitely help with that. But make sure you are checking in quarterly to make sure that everything is still in line with your plan. The problem with automation is when you forget about it completely and just let everything sit there.”
 

8. Save separately for big purchases.

Sometimes it’s the big major expenses that can start to derail a budget. Physicians told us the following tactics for large purchases:  “We buy affordable cars and take budget vacations,” “I buy used cars,” “We save in advance for new cars and only buy cars with cash.”

The decision of which car to purchase or where to go on a family vacation is a personal one, and some physicians take great enjoyment and pride in driving a luxury vehicle or traveling to exotic locales. The key, experts say, is to factor the cost of that car into the rest of your budget, and make sure that it’s not preventing you from achieving other financial goals.

“I don’t like to judge or tell clients how they should spend their money,” said Andrew Musbach, a certified financial planner and cofounder of MD Wealth Management in Chelsea, Mich. “Some people like cars, we have clients that have two planes, others want a second house or like to travel. Each person has their own interest where they may spend more relative to other people, but as long as they are meeting their savings targets, I encourage them to spend their money and enjoy what they enjoy most, guilt free.”

Mr. Snider suggests setting up a savings account separate from emergency or retirement accounts to set aside money if you have a goal for a large future purchase, such as a boat or a second home.

“That way, the funds don’t get commingled, and it’s explicitly clear whether or not the doctor is on target,” he says. “It also prevents them from treating their emergency savings account as an ATM machine.”
 

9. Start saving for college when the kids are little.  

Respondents said the following: “We are buying less to save for the kids’ college education,” “We set up direct deposit into college and retirement savings plans,” “We have a 529 account for college savings.”

Helping pay for their children’s college education is an important financial goal for many physicians. The earlier that you start saving, the less you’ll have to save overall, thanks to compound interest. State 529 accounts are often a good place to start, especially if your state offers a tax incentive for doing so.

Mr. Snider recommends that physicians start small, with an initial investment of $1,000 per month and $100 per month contributions. Assuming a 7% rate of return and 17 years’ worth of savings, this would generate just over $42,000. (Note, current typical rates of return are less than 7%).

“Ideally, as other goals are accomplished and personal debt gets paid off, the doctor is ramping up their savings to have at least 50% of college expenses covered from their 529 college savings,” he says.
 

10. Watch out for the temptation of impulse purchases.

Physicians said the following: “Avoid impulse purchases,” “Avoid impulse shopping, make a list for the store and stick to it,” “Wait to buy things on sale.”

Nothing wrecks a budget like an impulse buy. More than half (54%) of U.S. shoppers have admitted to spending $100 or more on an impulse purchase. And 20% of shoppers have spent at least $1,000 on an impulse buy. Avoid buyers’ remorse by waiting a few days to make large purchase decisions or by limiting your unplanned spending to a certain dollar amount within your budget.

Online shopping may be a particular temptation. Dr. Tarugu, the Florida gastroenterologist, has focused on reducing those impulse buys as well, deleting all online shopping apps from his and his family’s phones.

“You won’t notice how much you have ordered online until it arrives at your doorstep,” he said. “It’s really important to keep it at bay.”

Mr. Keady, the TIAA chief planning strategist, recommended this tactic: Calculate the number of patients (or hours) you’d need to see in order to earn the cash required to make the purchase.

“Then, in a mindful way, figure out the amount of value derived from the purchase,” he said.
 

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

As the COVID-19 crisis pandemic continues, many physicians are not only battling the medical challenges it has wrought but they’re also dealing with its financial ramifications at home.

“Some of our physician clients have seen their income decrease by as much as 50%,” says Joel Greenwald, MD, CEO of Greenwald Wealth Management in St. Louis Park, Minnesota. “Many physicians had previously figured that whatever financial obligations they had wouldn’t be a problem because whatever amount they were making would continue, and if there were a decline it would be gradual.” However, assumption is now creating financial strain for many doctors.

Vikram Tarugu, MD, a gastroenterologist and CEO of Detox of South Florida in Okeechobee, Florida, says he has watched his budget for years, but has become even more careful with his spending in the past few months.

“It has helped me a lot to adjust to the new normal when it comes to the financial side of things,” Dr. Tarugu said. “Patients aren’t coming in as much as they used to, so my income has really been affected.”

Primary care physicians have seen a 55% decrease in revenue and a 20%-30% decrease in patient volume as a result of COVID-19. The impact has been even more severe for specialists. Even for physicians whose practices remain busy and whose family members haven’t lost their jobs or income, broader concerns about the economy may be reason enough for physicians to adopt cost-cutting measures.

In Medscape’s Physician Compensation Report 2020, we asked physicians to share their best cost-cutting tips. Many illustrate the lengths to which physicians are going to conserve money.  

Here’s a look at some of the advice they shared, along with guidance from experts on how to make it work for you:
 

1. Create a written budget, even if you think it’s pointless.

Physicians said their most important piece of advice includes the following: “Use a formal budget to track progress,” “write out a budget,” “plan intermittent/large expenses in advance,” “Make sure all expenses are paid before you spend on leisure.”

Nearly 7 in 10 physicians say they have a budget for personal expenses, yet only one-quarter of those who do have a formal, written budget. Writing out a spending plan is key to being intentional about your spending, making sure that you’re living within your means, and identifying areas in which you may be able to cut back.

“Financial planning is all about cash flow, and everybody should know the amount of money coming in, how much is going out, and the difference between the two,” says Amy Guerich, a partner with Stepp & Rothwell, a Kansas City–based financial planning firm. “That’s important in good times, but it’s even more important now when we see physicians taking pay cuts.”

Many physicians have found that budget apps or software programs are easier to work with than anticipated; some even walk you through the process of creating a budget. To get the most out of the apps, you’ll need to check them regularly and make changes based on their data.

“Sometimes there’s this false belief that just by signing up, you are automatically going to be better at budgeting,” says Scott Snider, CFP, a certified financial planner and partner with Mellen Money Management in Ponte Vedra Beach, Florida. “Basically, these apps are a great way to identify problem areas of spending. We have a tendency as humans to underestimate how much we spend on things like Starbucks, dining out, and Amazon shopping.”

One of the doctors’ tips that requires the most willpower is to “pay all expenses before spending on leisure.” That’s because we live in an instant gratification world, and want everything right away, Ms. Guerich said.

“I also think there’s an element of ‘keeping up with the Joneses’ and pressure associated with this profession,” she said. “The stereotype is that physicians are high-income earners so ‘We should be able to do that’ or ‘Mom and dad are doctors, so they can afford it.’ “

Creating and then revisiting your budget progress on a monthly or quarterly basis can give you a feeling of accomplishment and keep you motivated to stay with it.  

Keep in mind that budgeting is a continual process rather than a singular event, and you’ll likely adjust it over time as your income and goals change. 
 

2. Save more as you earn more.

Respondents to our Physician Compensation Report gave the following recommendations: “Pay yourself first,” “I put half of my bonus into an investment account no matter how much it is,” “I allocate extra money and put it into a savings account.”

Dr. Greenwald said, “I have a rule that every client needs to be saving 20% of their gross income toward retirement, including whatever the employer is putting in.”

Putting a portion of every paycheck into savings is key to making progress toward financial goals. Start by building an emergency fund with at least 3-6 months’ worth of expenses in it and making sure you’re saving at least enough for retirement to get any potential employer match.

Mr. Snider suggests increasing the percentage you save every time you get a raise.

“The thought behind that strategy is that when a doctor receives a pay raise – even if it’s just a cost-of-living raise of 3% – an extra 1% saved doesn’t reduce their take-home pay year-over-year,” he says. “In fact, they still take home more money, and they save more money. Win-win.”
 

3. Focus on paying down your debt.

Physicians told us how they were working to pay down debt with the following recommendations:  “Accelerate debt reduction,” “I make additional principal payment to our home mortgage,” “We are aggressively attacking our remaining student loans.”

Reducing or eliminating debt is key to increasing cash flow, which can make it easier to meet all of your other financial goals. One-quarter of physicians have credit card debt, which typically carries interest rates higher than other types of debt, making it far more expensive. Focus on paying off such high-interest debt first, before moving on to other types of debt such as auto loans, student loans, or a mortgage.

“Credit card debt and any unsecured debt should be paid before anything else,” Mr. Snider says. “Getting rid of those high interest rates should be a priority. And that type of debt has less flexible terms than student debt.”
 

4. Great opportunity to take advantage of record-low interest rates.

Physicians said that, to save money, they are recommending the following: “Consolidating student debt into our mortgage,” “Accelerating payments of the principle on our mortgage,” “Making sure we have an affordable mortgage.”

With interest rates at an all-time low, even those who’ve recently refinanced might see significant savings by refinancing again. Given the associated fees, it typically makes sense to refinance if you can reduce your mortgage rate by at least a point, and you’re planning to stay in the home for at least 5 years.

“Depending on how much lower your rate is, refinancing can make a big difference in your monthly payments,” Ms. Guerich said. “For physicians who might need an emergency reserve but don’t have cash on hand, a HELOC [Home Equity Line of Credit] is a great way to accomplish that.”
 

5. Be wary of credit cards dangers; use cards wisely.

Physician respondents recommended the following:  “Use 0% interest offers on credit cards,” “Only have one card and pay it off every month,” “Never carry over balance.”

Nearly 80% of physicians have three or more credit cards, with 18% reporting that they have seven or more. When used wisely, credit cards can be an important tool for managing finances. Many credit cards come with tools that can help with budgeting, and credit cards rewards and perks can offer real value to users. That said, rewards typically are not valuable enough to offset the cost of interest on balances (or the associated damage to your credit score) that aren’t paid off each month.

“If you’re paying a high rate on credit card balances that carry over every month, regardless of your income, that could be a symptom that you may be spending more than you should,” says Dan Keady, a CFP and chief financial planning strategist at financial services firm TIAA.

6. Give less to Uncle Sam: Keep it for yourself.

Physicians said that they do the following: “Maximize tax-free/deferred savings (401k, HSA, etc.),” “Give to charity to reduce tax,” “Use pre-tax dollars for childcare and healthcare.”

Not only does saving in workplace retirement accounts help you build your nest egg, but it also reduces the amount that you have to pay in taxes in a given year. Physicians should also take advantage of other ways to reduce their income for tax purposes, such as saving money in a health savings account or flexible savings account.

The 401(k) or 403(b) contribution limit for this year is $19,500 ($26,000) for those age 50 years and older. Self-employed physicians can save even more money via a Simplified Employee Pension (SEP) IRA, says Ms. Guerich said. They can save up to 25% of compensation, up to $57,000 in 2020.
 

7. Automate everything and spare yourself the headache.

Physicians said the following: “Designate money from your paycheck directly to tax deferred and taxable accounts automatically,” “Use automatic payment for credit card balance monthly,” “Automate your savings.”

You probably already automate your 401(k) contributions, but you can also automate bill payments, emergency savings contributions and other financial tasks. For busy physicians, this can make it easier to stick to your financial plan and achieve your goals.

“The older you get, the busier you get, said Mr. Snider says. “Automation can definitely help with that. But make sure you are checking in quarterly to make sure that everything is still in line with your plan. The problem with automation is when you forget about it completely and just let everything sit there.”
 

8. Save separately for big purchases.

Sometimes it’s the big major expenses that can start to derail a budget. Physicians told us the following tactics for large purchases:  “We buy affordable cars and take budget vacations,” “I buy used cars,” “We save in advance for new cars and only buy cars with cash.”

The decision of which car to purchase or where to go on a family vacation is a personal one, and some physicians take great enjoyment and pride in driving a luxury vehicle or traveling to exotic locales. The key, experts say, is to factor the cost of that car into the rest of your budget, and make sure that it’s not preventing you from achieving other financial goals.

“I don’t like to judge or tell clients how they should spend their money,” said Andrew Musbach, a certified financial planner and cofounder of MD Wealth Management in Chelsea, Mich. “Some people like cars, we have clients that have two planes, others want a second house or like to travel. Each person has their own interest where they may spend more relative to other people, but as long as they are meeting their savings targets, I encourage them to spend their money and enjoy what they enjoy most, guilt free.”

Mr. Snider suggests setting up a savings account separate from emergency or retirement accounts to set aside money if you have a goal for a large future purchase, such as a boat or a second home.

“That way, the funds don’t get commingled, and it’s explicitly clear whether or not the doctor is on target,” he says. “It also prevents them from treating their emergency savings account as an ATM machine.”
 

9. Start saving for college when the kids are little.  

Respondents said the following: “We are buying less to save for the kids’ college education,” “We set up direct deposit into college and retirement savings plans,” “We have a 529 account for college savings.”

Helping pay for their children’s college education is an important financial goal for many physicians. The earlier that you start saving, the less you’ll have to save overall, thanks to compound interest. State 529 accounts are often a good place to start, especially if your state offers a tax incentive for doing so.

Mr. Snider recommends that physicians start small, with an initial investment of $1,000 per month and $100 per month contributions. Assuming a 7% rate of return and 17 years’ worth of savings, this would generate just over $42,000. (Note, current typical rates of return are less than 7%).

“Ideally, as other goals are accomplished and personal debt gets paid off, the doctor is ramping up their savings to have at least 50% of college expenses covered from their 529 college savings,” he says.
 

10. Watch out for the temptation of impulse purchases.

Physicians said the following: “Avoid impulse purchases,” “Avoid impulse shopping, make a list for the store and stick to it,” “Wait to buy things on sale.”

Nothing wrecks a budget like an impulse buy. More than half (54%) of U.S. shoppers have admitted to spending $100 or more on an impulse purchase. And 20% of shoppers have spent at least $1,000 on an impulse buy. Avoid buyers’ remorse by waiting a few days to make large purchase decisions or by limiting your unplanned spending to a certain dollar amount within your budget.

Online shopping may be a particular temptation. Dr. Tarugu, the Florida gastroenterologist, has focused on reducing those impulse buys as well, deleting all online shopping apps from his and his family’s phones.

“You won’t notice how much you have ordered online until it arrives at your doorstep,” he said. “It’s really important to keep it at bay.”

Mr. Keady, the TIAA chief planning strategist, recommended this tactic: Calculate the number of patients (or hours) you’d need to see in order to earn the cash required to make the purchase.

“Then, in a mindful way, figure out the amount of value derived from the purchase,” he said.
 

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

As the COVID-19 crisis pandemic continues, many physicians are not only battling the medical challenges it has wrought but they’re also dealing with its financial ramifications at home.

“Some of our physician clients have seen their income decrease by as much as 50%,” says Joel Greenwald, MD, CEO of Greenwald Wealth Management in St. Louis Park, Minnesota. “Many physicians had previously figured that whatever financial obligations they had wouldn’t be a problem because whatever amount they were making would continue, and if there were a decline it would be gradual.” However, assumption is now creating financial strain for many doctors.

Vikram Tarugu, MD, a gastroenterologist and CEO of Detox of South Florida in Okeechobee, Florida, says he has watched his budget for years, but has become even more careful with his spending in the past few months.

“It has helped me a lot to adjust to the new normal when it comes to the financial side of things,” Dr. Tarugu said. “Patients aren’t coming in as much as they used to, so my income has really been affected.”

Primary care physicians have seen a 55% decrease in revenue and a 20%-30% decrease in patient volume as a result of COVID-19. The impact has been even more severe for specialists. Even for physicians whose practices remain busy and whose family members haven’t lost their jobs or income, broader concerns about the economy may be reason enough for physicians to adopt cost-cutting measures.

In Medscape’s Physician Compensation Report 2020, we asked physicians to share their best cost-cutting tips. Many illustrate the lengths to which physicians are going to conserve money.  

Here’s a look at some of the advice they shared, along with guidance from experts on how to make it work for you:
 

1. Create a written budget, even if you think it’s pointless.

Physicians said their most important piece of advice includes the following: “Use a formal budget to track progress,” “write out a budget,” “plan intermittent/large expenses in advance,” “Make sure all expenses are paid before you spend on leisure.”

Nearly 7 in 10 physicians say they have a budget for personal expenses, yet only one-quarter of those who do have a formal, written budget. Writing out a spending plan is key to being intentional about your spending, making sure that you’re living within your means, and identifying areas in which you may be able to cut back.

“Financial planning is all about cash flow, and everybody should know the amount of money coming in, how much is going out, and the difference between the two,” says Amy Guerich, a partner with Stepp & Rothwell, a Kansas City–based financial planning firm. “That’s important in good times, but it’s even more important now when we see physicians taking pay cuts.”

Many physicians have found that budget apps or software programs are easier to work with than anticipated; some even walk you through the process of creating a budget. To get the most out of the apps, you’ll need to check them regularly and make changes based on their data.

“Sometimes there’s this false belief that just by signing up, you are automatically going to be better at budgeting,” says Scott Snider, CFP, a certified financial planner and partner with Mellen Money Management in Ponte Vedra Beach, Florida. “Basically, these apps are a great way to identify problem areas of spending. We have a tendency as humans to underestimate how much we spend on things like Starbucks, dining out, and Amazon shopping.”

One of the doctors’ tips that requires the most willpower is to “pay all expenses before spending on leisure.” That’s because we live in an instant gratification world, and want everything right away, Ms. Guerich said.

“I also think there’s an element of ‘keeping up with the Joneses’ and pressure associated with this profession,” she said. “The stereotype is that physicians are high-income earners so ‘We should be able to do that’ or ‘Mom and dad are doctors, so they can afford it.’ “

Creating and then revisiting your budget progress on a monthly or quarterly basis can give you a feeling of accomplishment and keep you motivated to stay with it.  

Keep in mind that budgeting is a continual process rather than a singular event, and you’ll likely adjust it over time as your income and goals change. 
 

2. Save more as you earn more.

Respondents to our Physician Compensation Report gave the following recommendations: “Pay yourself first,” “I put half of my bonus into an investment account no matter how much it is,” “I allocate extra money and put it into a savings account.”

Dr. Greenwald said, “I have a rule that every client needs to be saving 20% of their gross income toward retirement, including whatever the employer is putting in.”

Putting a portion of every paycheck into savings is key to making progress toward financial goals. Start by building an emergency fund with at least 3-6 months’ worth of expenses in it and making sure you’re saving at least enough for retirement to get any potential employer match.

Mr. Snider suggests increasing the percentage you save every time you get a raise.

“The thought behind that strategy is that when a doctor receives a pay raise – even if it’s just a cost-of-living raise of 3% – an extra 1% saved doesn’t reduce their take-home pay year-over-year,” he says. “In fact, they still take home more money, and they save more money. Win-win.”
 

3. Focus on paying down your debt.

Physicians told us how they were working to pay down debt with the following recommendations:  “Accelerate debt reduction,” “I make additional principal payment to our home mortgage,” “We are aggressively attacking our remaining student loans.”

Reducing or eliminating debt is key to increasing cash flow, which can make it easier to meet all of your other financial goals. One-quarter of physicians have credit card debt, which typically carries interest rates higher than other types of debt, making it far more expensive. Focus on paying off such high-interest debt first, before moving on to other types of debt such as auto loans, student loans, or a mortgage.

“Credit card debt and any unsecured debt should be paid before anything else,” Mr. Snider says. “Getting rid of those high interest rates should be a priority. And that type of debt has less flexible terms than student debt.”
 

4. Great opportunity to take advantage of record-low interest rates.

Physicians said that, to save money, they are recommending the following: “Consolidating student debt into our mortgage,” “Accelerating payments of the principle on our mortgage,” “Making sure we have an affordable mortgage.”

With interest rates at an all-time low, even those who’ve recently refinanced might see significant savings by refinancing again. Given the associated fees, it typically makes sense to refinance if you can reduce your mortgage rate by at least a point, and you’re planning to stay in the home for at least 5 years.

“Depending on how much lower your rate is, refinancing can make a big difference in your monthly payments,” Ms. Guerich said. “For physicians who might need an emergency reserve but don’t have cash on hand, a HELOC [Home Equity Line of Credit] is a great way to accomplish that.”
 

5. Be wary of credit cards dangers; use cards wisely.

Physician respondents recommended the following:  “Use 0% interest offers on credit cards,” “Only have one card and pay it off every month,” “Never carry over balance.”

Nearly 80% of physicians have three or more credit cards, with 18% reporting that they have seven or more. When used wisely, credit cards can be an important tool for managing finances. Many credit cards come with tools that can help with budgeting, and credit cards rewards and perks can offer real value to users. That said, rewards typically are not valuable enough to offset the cost of interest on balances (or the associated damage to your credit score) that aren’t paid off each month.

“If you’re paying a high rate on credit card balances that carry over every month, regardless of your income, that could be a symptom that you may be spending more than you should,” says Dan Keady, a CFP and chief financial planning strategist at financial services firm TIAA.

6. Give less to Uncle Sam: Keep it for yourself.

Physicians said that they do the following: “Maximize tax-free/deferred savings (401k, HSA, etc.),” “Give to charity to reduce tax,” “Use pre-tax dollars for childcare and healthcare.”

Not only does saving in workplace retirement accounts help you build your nest egg, but it also reduces the amount that you have to pay in taxes in a given year. Physicians should also take advantage of other ways to reduce their income for tax purposes, such as saving money in a health savings account or flexible savings account.

The 401(k) or 403(b) contribution limit for this year is $19,500 ($26,000) for those age 50 years and older. Self-employed physicians can save even more money via a Simplified Employee Pension (SEP) IRA, says Ms. Guerich said. They can save up to 25% of compensation, up to $57,000 in 2020.
 

7. Automate everything and spare yourself the headache.

Physicians said the following: “Designate money from your paycheck directly to tax deferred and taxable accounts automatically,” “Use automatic payment for credit card balance monthly,” “Automate your savings.”

You probably already automate your 401(k) contributions, but you can also automate bill payments, emergency savings contributions and other financial tasks. For busy physicians, this can make it easier to stick to your financial plan and achieve your goals.

“The older you get, the busier you get, said Mr. Snider says. “Automation can definitely help with that. But make sure you are checking in quarterly to make sure that everything is still in line with your plan. The problem with automation is when you forget about it completely and just let everything sit there.”
 

8. Save separately for big purchases.

Sometimes it’s the big major expenses that can start to derail a budget. Physicians told us the following tactics for large purchases:  “We buy affordable cars and take budget vacations,” “I buy used cars,” “We save in advance for new cars and only buy cars with cash.”

The decision of which car to purchase or where to go on a family vacation is a personal one, and some physicians take great enjoyment and pride in driving a luxury vehicle or traveling to exotic locales. The key, experts say, is to factor the cost of that car into the rest of your budget, and make sure that it’s not preventing you from achieving other financial goals.

“I don’t like to judge or tell clients how they should spend their money,” said Andrew Musbach, a certified financial planner and cofounder of MD Wealth Management in Chelsea, Mich. “Some people like cars, we have clients that have two planes, others want a second house or like to travel. Each person has their own interest where they may spend more relative to other people, but as long as they are meeting their savings targets, I encourage them to spend their money and enjoy what they enjoy most, guilt free.”

Mr. Snider suggests setting up a savings account separate from emergency or retirement accounts to set aside money if you have a goal for a large future purchase, such as a boat or a second home.

“That way, the funds don’t get commingled, and it’s explicitly clear whether or not the doctor is on target,” he says. “It also prevents them from treating their emergency savings account as an ATM machine.”
 

9. Start saving for college when the kids are little.  

Respondents said the following: “We are buying less to save for the kids’ college education,” “We set up direct deposit into college and retirement savings plans,” “We have a 529 account for college savings.”

Helping pay for their children’s college education is an important financial goal for many physicians. The earlier that you start saving, the less you’ll have to save overall, thanks to compound interest. State 529 accounts are often a good place to start, especially if your state offers a tax incentive for doing so.

Mr. Snider recommends that physicians start small, with an initial investment of $1,000 per month and $100 per month contributions. Assuming a 7% rate of return and 17 years’ worth of savings, this would generate just over $42,000. (Note, current typical rates of return are less than 7%).

“Ideally, as other goals are accomplished and personal debt gets paid off, the doctor is ramping up their savings to have at least 50% of college expenses covered from their 529 college savings,” he says.
 

10. Watch out for the temptation of impulse purchases.

Physicians said the following: “Avoid impulse purchases,” “Avoid impulse shopping, make a list for the store and stick to it,” “Wait to buy things on sale.”

Nothing wrecks a budget like an impulse buy. More than half (54%) of U.S. shoppers have admitted to spending $100 or more on an impulse purchase. And 20% of shoppers have spent at least $1,000 on an impulse buy. Avoid buyers’ remorse by waiting a few days to make large purchase decisions or by limiting your unplanned spending to a certain dollar amount within your budget.

Online shopping may be a particular temptation. Dr. Tarugu, the Florida gastroenterologist, has focused on reducing those impulse buys as well, deleting all online shopping apps from his and his family’s phones.

“You won’t notice how much you have ordered online until it arrives at your doorstep,” he said. “It’s really important to keep it at bay.”

Mr. Keady, the TIAA chief planning strategist, recommended this tactic: Calculate the number of patients (or hours) you’d need to see in order to earn the cash required to make the purchase.

“Then, in a mindful way, figure out the amount of value derived from the purchase,” he said.
 

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

Eleven high-income countries are on track to meet World Health Organization targets to eliminate hepatitis C infection by 2030, compared with 9 countries 2 years ago, researchers reported. But 28 countries, including the United States, are not expected to eliminate HCV until 2050.

“In the countries making progress, the common elements are political will, a clear national plan, and easing of restrictions on the cascade of care and testing,” Yuri Sanchez Gonzalez, PhD, director of health economics and outcomes research for biopharmaceutical company AbbVie said in an interview. That would include offering hepatitis C treatment to individuals who have liver fibrosis and those struggling with sobriety, he said. “We can’t overstate how much this is a massive driver of the hepatitis C epidemic.”

His research, presented at the digital edition of the International Liver Congress this week, showed more countries on target than in a study published 2 years ago in Liver International . “But it’s not enough,” Dr. Sanchez Gonzalez said. “We know that more than 80% of infections are in people who inject drugs. Stigmatization of drug use is still a very major issue.” Despite data clearly showing that countries who have harm-reduction programs make progress, “in many countries these programs are still illegal.”

To evaluate which countries are on target to eliminate hepatitis C by 2030, researchers performed Markov disease progression models of HCV infection in 45 high-income countries. The results showed that Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Sweden, Switzerland, and the United Kingdom are “in the green” (on target for 2030).

Austria, Malta, the Netherlands, New Zealand, and South Korea are “in the yellow” (on target for 2040), and 28 remaining countries, including the United States, are “in the red,” with targets estimated to be met by 2050.

Compared with an analysis performed 2 years ago, South Korea moved from green to yellow, while Canada, Germany, and Sweden moved from red to green. 

Researchers say that the countries moving the needle are the ones addressing barriers to care.
 

EASL: Eliminate barriers to treatment

During this week’s Congress, the European Association for the Study of the Liver (EASL) launched a policy statement recommending breaking down all barriers that prevent people who inject drugs from getting access to hepatitis C treatment, including encouragement of laws and policies that “decriminalize drug use, drug possession and drug users themselves,” said statement coauthor Mojca Maticic, MD, PhD, University of Ljubljana, Slovenia.

“To reach the desired WHO goal, combining decriminalization of personal drug consumption and integrated interventions that include hepatitis C testing and treatment should be implemented,” she added. We need to adopt “an approach based on public health promotion, respect for human rights, and evidence.”

Although harm reduction is the top strategy for making 2030 targets, having precision data also helps a lot.

“High-quality data and harm-reduction innovation to curb the overdose crisis has moved us out of the red and into the green,” Canadian researcher Jordan Feld, MD, MPH, University of Toronto, said in an interview. He points to British Columbia, Canada’s third-most populous province, putting harm reduction programs in place as key to Canadian progress.

“Given the increasing opioid epidemic, you’re creating yourself a bigger problem if you don’t treat this population,” Dr. Feld said. When a person needs 6 months to get sober in order to be treated for HCV, that’s more potential time to pass the infection to others. His study, also presented at ILC this week, outlines anticipated timing of hepatitis C in Canada’s four most populous provinces (Ontario, Quebec, British Columbia, and Alberta), and shows British Columbia will reach targets by 2028.

Lifting all restrictions clearly helps, Dr. Sanchez Gonzalez reported. He pointed to Sweden as a good example, a country that recently lifted HCV treatment restrictions for individuals living with fibrosis. Sweden moved from a red to a green spot in this analysis and is now on target for 2030.

“As long as everyone who needs treatment gets treatment, you can make tremendous progress,” he said.

Keeping track is also essential to moving the needle. Since the WHO has no enforcement power, “these studies, which offer a report card of progress, really matter,” Dr. Sanchez Gonzalez explained. When a country knows where they stand, they are more likely to take action to change. “Nobody likes to be shown in the red.”

Still, “it’s not a shaming exercise,” he said. It’s about starting a conversation, showing who’s on track, and sharing how to get on track. “Knowing that there is something in your power to move the needle toward elimination by learning from your neighbors is powerful – often, it just takes political will.”

Dr. Feld has received consulting fees from AbbVie. Dr. Sanchez Gonzalez is on staff as the Director of Economics at AbbVie. Dr. Maticic has disclosed no relevant financial relationships.

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

Eleven high-income countries are on track to meet World Health Organization targets to eliminate hepatitis C infection by 2030, compared with 9 countries 2 years ago, researchers reported. But 28 countries, including the United States, are not expected to eliminate HCV until 2050.

“In the countries making progress, the common elements are political will, a clear national plan, and easing of restrictions on the cascade of care and testing,” Yuri Sanchez Gonzalez, PhD, director of health economics and outcomes research for biopharmaceutical company AbbVie said in an interview. That would include offering hepatitis C treatment to individuals who have liver fibrosis and those struggling with sobriety, he said. “We can’t overstate how much this is a massive driver of the hepatitis C epidemic.”

His research, presented at the digital edition of the International Liver Congress this week, showed more countries on target than in a study published 2 years ago in Liver International . “But it’s not enough,” Dr. Sanchez Gonzalez said. “We know that more than 80% of infections are in people who inject drugs. Stigmatization of drug use is still a very major issue.” Despite data clearly showing that countries who have harm-reduction programs make progress, “in many countries these programs are still illegal.”

To evaluate which countries are on target to eliminate hepatitis C by 2030, researchers performed Markov disease progression models of HCV infection in 45 high-income countries. The results showed that Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Sweden, Switzerland, and the United Kingdom are “in the green” (on target for 2030).

Austria, Malta, the Netherlands, New Zealand, and South Korea are “in the yellow” (on target for 2040), and 28 remaining countries, including the United States, are “in the red,” with targets estimated to be met by 2050.

Compared with an analysis performed 2 years ago, South Korea moved from green to yellow, while Canada, Germany, and Sweden moved from red to green. 

Researchers say that the countries moving the needle are the ones addressing barriers to care.
 

EASL: Eliminate barriers to treatment

During this week’s Congress, the European Association for the Study of the Liver (EASL) launched a policy statement recommending breaking down all barriers that prevent people who inject drugs from getting access to hepatitis C treatment, including encouragement of laws and policies that “decriminalize drug use, drug possession and drug users themselves,” said statement coauthor Mojca Maticic, MD, PhD, University of Ljubljana, Slovenia.

“To reach the desired WHO goal, combining decriminalization of personal drug consumption and integrated interventions that include hepatitis C testing and treatment should be implemented,” she added. We need to adopt “an approach based on public health promotion, respect for human rights, and evidence.”

Although harm reduction is the top strategy for making 2030 targets, having precision data also helps a lot.

“High-quality data and harm-reduction innovation to curb the overdose crisis has moved us out of the red and into the green,” Canadian researcher Jordan Feld, MD, MPH, University of Toronto, said in an interview. He points to British Columbia, Canada’s third-most populous province, putting harm reduction programs in place as key to Canadian progress.

“Given the increasing opioid epidemic, you’re creating yourself a bigger problem if you don’t treat this population,” Dr. Feld said. When a person needs 6 months to get sober in order to be treated for HCV, that’s more potential time to pass the infection to others. His study, also presented at ILC this week, outlines anticipated timing of hepatitis C in Canada’s four most populous provinces (Ontario, Quebec, British Columbia, and Alberta), and shows British Columbia will reach targets by 2028.

Lifting all restrictions clearly helps, Dr. Sanchez Gonzalez reported. He pointed to Sweden as a good example, a country that recently lifted HCV treatment restrictions for individuals living with fibrosis. Sweden moved from a red to a green spot in this analysis and is now on target for 2030.

“As long as everyone who needs treatment gets treatment, you can make tremendous progress,” he said.

Keeping track is also essential to moving the needle. Since the WHO has no enforcement power, “these studies, which offer a report card of progress, really matter,” Dr. Sanchez Gonzalez explained. When a country knows where they stand, they are more likely to take action to change. “Nobody likes to be shown in the red.”

Still, “it’s not a shaming exercise,” he said. It’s about starting a conversation, showing who’s on track, and sharing how to get on track. “Knowing that there is something in your power to move the needle toward elimination by learning from your neighbors is powerful – often, it just takes political will.”

Dr. Feld has received consulting fees from AbbVie. Dr. Sanchez Gonzalez is on staff as the Director of Economics at AbbVie. Dr. Maticic has disclosed no relevant financial relationships.

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

Eleven high-income countries are on track to meet World Health Organization targets to eliminate hepatitis C infection by 2030, compared with 9 countries 2 years ago, researchers reported. But 28 countries, including the United States, are not expected to eliminate HCV until 2050.

“In the countries making progress, the common elements are political will, a clear national plan, and easing of restrictions on the cascade of care and testing,” Yuri Sanchez Gonzalez, PhD, director of health economics and outcomes research for biopharmaceutical company AbbVie said in an interview. That would include offering hepatitis C treatment to individuals who have liver fibrosis and those struggling with sobriety, he said. “We can’t overstate how much this is a massive driver of the hepatitis C epidemic.”

His research, presented at the digital edition of the International Liver Congress this week, showed more countries on target than in a study published 2 years ago in Liver International . “But it’s not enough,” Dr. Sanchez Gonzalez said. “We know that more than 80% of infections are in people who inject drugs. Stigmatization of drug use is still a very major issue.” Despite data clearly showing that countries who have harm-reduction programs make progress, “in many countries these programs are still illegal.”

To evaluate which countries are on target to eliminate hepatitis C by 2030, researchers performed Markov disease progression models of HCV infection in 45 high-income countries. The results showed that Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Sweden, Switzerland, and the United Kingdom are “in the green” (on target for 2030).

Austria, Malta, the Netherlands, New Zealand, and South Korea are “in the yellow” (on target for 2040), and 28 remaining countries, including the United States, are “in the red,” with targets estimated to be met by 2050.

Compared with an analysis performed 2 years ago, South Korea moved from green to yellow, while Canada, Germany, and Sweden moved from red to green. 

Researchers say that the countries moving the needle are the ones addressing barriers to care.
 

EASL: Eliminate barriers to treatment

During this week’s Congress, the European Association for the Study of the Liver (EASL) launched a policy statement recommending breaking down all barriers that prevent people who inject drugs from getting access to hepatitis C treatment, including encouragement of laws and policies that “decriminalize drug use, drug possession and drug users themselves,” said statement coauthor Mojca Maticic, MD, PhD, University of Ljubljana, Slovenia.

“To reach the desired WHO goal, combining decriminalization of personal drug consumption and integrated interventions that include hepatitis C testing and treatment should be implemented,” she added. We need to adopt “an approach based on public health promotion, respect for human rights, and evidence.”

Although harm reduction is the top strategy for making 2030 targets, having precision data also helps a lot.

“High-quality data and harm-reduction innovation to curb the overdose crisis has moved us out of the red and into the green,” Canadian researcher Jordan Feld, MD, MPH, University of Toronto, said in an interview. He points to British Columbia, Canada’s third-most populous province, putting harm reduction programs in place as key to Canadian progress.

“Given the increasing opioid epidemic, you’re creating yourself a bigger problem if you don’t treat this population,” Dr. Feld said. When a person needs 6 months to get sober in order to be treated for HCV, that’s more potential time to pass the infection to others. His study, also presented at ILC this week, outlines anticipated timing of hepatitis C in Canada’s four most populous provinces (Ontario, Quebec, British Columbia, and Alberta), and shows British Columbia will reach targets by 2028.

Lifting all restrictions clearly helps, Dr. Sanchez Gonzalez reported. He pointed to Sweden as a good example, a country that recently lifted HCV treatment restrictions for individuals living with fibrosis. Sweden moved from a red to a green spot in this analysis and is now on target for 2030.

“As long as everyone who needs treatment gets treatment, you can make tremendous progress,” he said.

Keeping track is also essential to moving the needle. Since the WHO has no enforcement power, “these studies, which offer a report card of progress, really matter,” Dr. Sanchez Gonzalez explained. When a country knows where they stand, they are more likely to take action to change. “Nobody likes to be shown in the red.”

Still, “it’s not a shaming exercise,” he said. It’s about starting a conversation, showing who’s on track, and sharing how to get on track. “Knowing that there is something in your power to move the needle toward elimination by learning from your neighbors is powerful – often, it just takes political will.”

Dr. Feld has received consulting fees from AbbVie. Dr. Sanchez Gonzalez is on staff as the Director of Economics at AbbVie. Dr. Maticic has disclosed no relevant financial relationships.

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

A 15-year-old girl was brought to the Family Medicine Clinic in Somaliland, Africa, for evaluation of intermittent abdominal pain and watery diarrhea of 12 years’ duration. Over the previous 2 months, her symptoms had worsened and included vomiting and weight loss. She denied fever, melena, or hematemesis.

Physical examination revealed a thin female with a normal abdominal exam and numerous hyperpigmented macules on the lips, buccal mucosa, fingers, and toes (FIGURE 1). Her family reported that the black spots on her lips had been there since birth. There was no known family history of similar symptoms or black spots.

Her hemoglobin was 10 g/dL (reference range, 12–15 g/dL). A probable diagnosis was discussed with the family, and they elected to travel to India for further evaluation due to limited diagnostic resources in their location. In India, computed tomography (CT) and ultrasonography showed duodenojejunal intussusception. Upper gastrointestinal (GI) endoscopy revealed multiple polyps from the lower stomach to the jejunum of the small bowel; colonoscopy was normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Our patient was given a diagnosis of Peutz-Jeghers syndrome (PJS) based on the characteristic pigmented mucocutaneous macules and numerous polyps in the stomach and small bowel. PJS is an autosomal dominant syndrome characterized by mucocutaneous pigmentation, polyposis of the GI tract, and increased cancer risk. The prevalence is approximately 1 in 100,000.¹ Genetic testing for the STK11 gene mutation, which is found in 70% of familial cases and 30% to 67% of sporadic cases, is not required for diagnosis.¹

What you’ll see. The bluish brown to black spots of PJS often are apparent at birth or in early infancy. They are most common on the lips, buccal mucosa, perioral region, palms, and soles.

When PeutzJeghers syndrome is suspected, the entire GI tract should be investigated.

The polyps may cause bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction.² Intussusception is the most frequent cause of morbidity in childhood for PJS patients.^3,4 Recurrent attacks of abdominal pain likely result from recurring transient episodes of incomplete intussusception. The polyps usually are benign, but patients are at increased risk of GI and non-GI malignancies such as breast, pancreas, lung, and reproductive tract cancers.¹ Most cancers associated with PJS occur during adulthood.²

Other possible causes of hyperpigmentation

PJS can be differentiated from other causes of hyperpigmentation by clinical presentation and/or genetic testing.

Laugier-Hunziker syndrome manifests with macular hyperpigmentation of the lips and buccal mucosa and pigmented bands on the nails in young or middle-aged adults. It is not associated with intestinal polyps.

Continue to: Cronkhite-Canada syndrome

Cronkhite-Canada syndrome consists of acral and oral pigmented macules and GI polyps as well as generalized darkening of the skin, extensive alopecia, loss of taste, and nail dystrophy.

Familial lentiginosis syndromes such as Noonan syndrome and NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, ephelides) have other systemic signs such as cardiac abnormalities, and the pigmentation is not as clearly perioral.

Albright syndrome manifests with oral pigmented macules but also is associated with precocious puberty and polyostotic fibrous dysplasia.

Addison disease may cause multiple hyperpigmented macules but has other systemic involvement; adrenocorticotropic hormone levels are elevated.

Juvenile polyposis syndrome manifests with GI polyps but is not associated with mucosal pigmentation.

Continue to: Use these 4 criteria to make the diagnosis

Use these 4 criteria to make the diagnosis

The diagnosis of PJS is made using the following criteria: (1) two or more histologically confirmed PJS polyps, (2) any number of PJS polyps and a family history of PJS, (3) characteristic mucocutaneous pigmentation and a family history of PJS, or (4) any number of PJS polyps and characteristic mucocutaneous pigmentation.²

When PJS is suspected, the entire GI tract should be investigated. The hamartomatous polyps may be found from the stomach to the anal canal, but the small bowel most commonly is involved. The polyps may occur in early childhood, with one study of 14 children reporting a median age of 4.5 years.⁵ Polyp biopsy will show smooth muscle arborization. When possible, those who meet clinical criteria for PJS should undergo genetic testing for a STK11 gene mutation. PJS may occur due to de novo mutations in patients with no family history.⁶

Long-term management involves surveillance for polyps and cancer

Screening guidelines for polyps vary. Some suggest starting screening at age 8 to 10 years with esophagogastroduodenoscopy or capsule endoscopy and if negative, colonoscopy at age 18. Others suggest starting screening at 4 to 5 years of age.⁵ The recommendation is to remove polyps if technically feasible.³ Surveillance for Sertoli cell tumors (sex cord stromal tumors) should be done before puberty, and evaluation of other organs at risk of malignancy should begin by the end of adolescence.

The pigmented macules do not require treatment. Macules on the lips may disappear with time, while those on the buccal mucosa persist. The lip lesions can be lightened with chemical peels or laser.

Our patient underwent laparotomy, which revealed a grossly dilated and gangrenous small bowel segment. Intussusception was not present and was thought to have spontaneously reduced. Resection and anastomosis of the affected small bowel was performed. The patient’s postoperative course was uneventful, and her diarrhea and abdominal pain resolved. We recommended follow-up in her home city with primary care and a GI specialist and explained the need for surveillance of her condition.

CORRESPONDENCE
Josette R. McMichael, MD, Department of Dermatology, Emory University, 1525 Clifton Road NE, 1st Floor, Atlanta, GA 30322; [email protected]

A 15-year-old girl was brought to the Family Medicine Clinic in Somaliland, Africa, for evaluation of intermittent abdominal pain and watery diarrhea of 12 years’ duration. Over the previous 2 months, her symptoms had worsened and included vomiting and weight loss. She denied fever, melena, or hematemesis.

Physical examination revealed a thin female with a normal abdominal exam and numerous hyperpigmented macules on the lips, buccal mucosa, fingers, and toes (FIGURE 1). Her family reported that the black spots on her lips had been there since birth. There was no known family history of similar symptoms or black spots.

Her hemoglobin was 10 g/dL (reference range, 12–15 g/dL). A probable diagnosis was discussed with the family, and they elected to travel to India for further evaluation due to limited diagnostic resources in their location. In India, computed tomography (CT) and ultrasonography showed duodenojejunal intussusception. Upper gastrointestinal (GI) endoscopy revealed multiple polyps from the lower stomach to the jejunum of the small bowel; colonoscopy was normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Our patient was given a diagnosis of Peutz-Jeghers syndrome (PJS) based on the characteristic pigmented mucocutaneous macules and numerous polyps in the stomach and small bowel. PJS is an autosomal dominant syndrome characterized by mucocutaneous pigmentation, polyposis of the GI tract, and increased cancer risk. The prevalence is approximately 1 in 100,000.¹ Genetic testing for the STK11 gene mutation, which is found in 70% of familial cases and 30% to 67% of sporadic cases, is not required for diagnosis.¹

What you’ll see. The bluish brown to black spots of PJS often are apparent at birth or in early infancy. They are most common on the lips, buccal mucosa, perioral region, palms, and soles.

When PeutzJeghers syndrome is suspected, the entire GI tract should be investigated.

The polyps may cause bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction.² Intussusception is the most frequent cause of morbidity in childhood for PJS patients.^3,4 Recurrent attacks of abdominal pain likely result from recurring transient episodes of incomplete intussusception. The polyps usually are benign, but patients are at increased risk of GI and non-GI malignancies such as breast, pancreas, lung, and reproductive tract cancers.¹ Most cancers associated with PJS occur during adulthood.²

Other possible causes of hyperpigmentation

PJS can be differentiated from other causes of hyperpigmentation by clinical presentation and/or genetic testing.

Laugier-Hunziker syndrome manifests with macular hyperpigmentation of the lips and buccal mucosa and pigmented bands on the nails in young or middle-aged adults. It is not associated with intestinal polyps.

Continue to: Cronkhite-Canada syndrome

Cronkhite-Canada syndrome consists of acral and oral pigmented macules and GI polyps as well as generalized darkening of the skin, extensive alopecia, loss of taste, and nail dystrophy.

Familial lentiginosis syndromes such as Noonan syndrome and NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, ephelides) have other systemic signs such as cardiac abnormalities, and the pigmentation is not as clearly perioral.

Albright syndrome manifests with oral pigmented macules but also is associated with precocious puberty and polyostotic fibrous dysplasia.

Addison disease may cause multiple hyperpigmented macules but has other systemic involvement; adrenocorticotropic hormone levels are elevated.

Juvenile polyposis syndrome manifests with GI polyps but is not associated with mucosal pigmentation.

Continue to: Use these 4 criteria to make the diagnosis

Use these 4 criteria to make the diagnosis

The diagnosis of PJS is made using the following criteria: (1) two or more histologically confirmed PJS polyps, (2) any number of PJS polyps and a family history of PJS, (3) characteristic mucocutaneous pigmentation and a family history of PJS, or (4) any number of PJS polyps and characteristic mucocutaneous pigmentation.²

When PJS is suspected, the entire GI tract should be investigated. The hamartomatous polyps may be found from the stomach to the anal canal, but the small bowel most commonly is involved. The polyps may occur in early childhood, with one study of 14 children reporting a median age of 4.5 years.⁵ Polyp biopsy will show smooth muscle arborization. When possible, those who meet clinical criteria for PJS should undergo genetic testing for a STK11 gene mutation. PJS may occur due to de novo mutations in patients with no family history.⁶

Long-term management involves surveillance for polyps and cancer

Screening guidelines for polyps vary. Some suggest starting screening at age 8 to 10 years with esophagogastroduodenoscopy or capsule endoscopy and if negative, colonoscopy at age 18. Others suggest starting screening at 4 to 5 years of age.⁵ The recommendation is to remove polyps if technically feasible.³ Surveillance for Sertoli cell tumors (sex cord stromal tumors) should be done before puberty, and evaluation of other organs at risk of malignancy should begin by the end of adolescence.

The pigmented macules do not require treatment. Macules on the lips may disappear with time, while those on the buccal mucosa persist. The lip lesions can be lightened with chemical peels or laser.

Our patient underwent laparotomy, which revealed a grossly dilated and gangrenous small bowel segment. Intussusception was not present and was thought to have spontaneously reduced. Resection and anastomosis of the affected small bowel was performed. The patient’s postoperative course was uneventful, and her diarrhea and abdominal pain resolved. We recommended follow-up in her home city with primary care and a GI specialist and explained the need for surveillance of her condition.

CORRESPONDENCE
Josette R. McMichael, MD, Department of Dermatology, Emory University, 1525 Clifton Road NE, 1st Floor, Atlanta, GA 30322; [email protected]

A 15-year-old girl was brought to the Family Medicine Clinic in Somaliland, Africa, for evaluation of intermittent abdominal pain and watery diarrhea of 12 years’ duration. Over the previous 2 months, her symptoms had worsened and included vomiting and weight loss. She denied fever, melena, or hematemesis.

Physical examination revealed a thin female with a normal abdominal exam and numerous hyperpigmented macules on the lips, buccal mucosa, fingers, and toes (FIGURE 1). Her family reported that the black spots on her lips had been there since birth. There was no known family history of similar symptoms or black spots.

Her hemoglobin was 10 g/dL (reference range, 12–15 g/dL). A probable diagnosis was discussed with the family, and they elected to travel to India for further evaluation due to limited diagnostic resources in their location. In India, computed tomography (CT) and ultrasonography showed duodenojejunal intussusception. Upper gastrointestinal (GI) endoscopy revealed multiple polyps from the lower stomach to the jejunum of the small bowel; colonoscopy was normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Our patient was given a diagnosis of Peutz-Jeghers syndrome (PJS) based on the characteristic pigmented mucocutaneous macules and numerous polyps in the stomach and small bowel. PJS is an autosomal dominant syndrome characterized by mucocutaneous pigmentation, polyposis of the GI tract, and increased cancer risk. The prevalence is approximately 1 in 100,000.¹ Genetic testing for the STK11 gene mutation, which is found in 70% of familial cases and 30% to 67% of sporadic cases, is not required for diagnosis.¹

What you’ll see. The bluish brown to black spots of PJS often are apparent at birth or in early infancy. They are most common on the lips, buccal mucosa, perioral region, palms, and soles.

When PeutzJeghers syndrome is suspected, the entire GI tract should be investigated.

The polyps may cause bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction.² Intussusception is the most frequent cause of morbidity in childhood for PJS patients.^3,4 Recurrent attacks of abdominal pain likely result from recurring transient episodes of incomplete intussusception. The polyps usually are benign, but patients are at increased risk of GI and non-GI malignancies such as breast, pancreas, lung, and reproductive tract cancers.¹ Most cancers associated with PJS occur during adulthood.²

Other possible causes of hyperpigmentation

PJS can be differentiated from other causes of hyperpigmentation by clinical presentation and/or genetic testing.

Laugier-Hunziker syndrome manifests with macular hyperpigmentation of the lips and buccal mucosa and pigmented bands on the nails in young or middle-aged adults. It is not associated with intestinal polyps.

Continue to: Cronkhite-Canada syndrome

Cronkhite-Canada syndrome consists of acral and oral pigmented macules and GI polyps as well as generalized darkening of the skin, extensive alopecia, loss of taste, and nail dystrophy.

Familial lentiginosis syndromes such as Noonan syndrome and NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, ephelides) have other systemic signs such as cardiac abnormalities, and the pigmentation is not as clearly perioral.

Albright syndrome manifests with oral pigmented macules but also is associated with precocious puberty and polyostotic fibrous dysplasia.

Addison disease may cause multiple hyperpigmented macules but has other systemic involvement; adrenocorticotropic hormone levels are elevated.

Juvenile polyposis syndrome manifests with GI polyps but is not associated with mucosal pigmentation.

Continue to: Use these 4 criteria to make the diagnosis

Use these 4 criteria to make the diagnosis

The diagnosis of PJS is made using the following criteria: (1) two or more histologically confirmed PJS polyps, (2) any number of PJS polyps and a family history of PJS, (3) characteristic mucocutaneous pigmentation and a family history of PJS, or (4) any number of PJS polyps and characteristic mucocutaneous pigmentation.²

When PJS is suspected, the entire GI tract should be investigated. The hamartomatous polyps may be found from the stomach to the anal canal, but the small bowel most commonly is involved. The polyps may occur in early childhood, with one study of 14 children reporting a median age of 4.5 years.⁵ Polyp biopsy will show smooth muscle arborization. When possible, those who meet clinical criteria for PJS should undergo genetic testing for a STK11 gene mutation. PJS may occur due to de novo mutations in patients with no family history.⁶

Long-term management involves surveillance for polyps and cancer

Screening guidelines for polyps vary. Some suggest starting screening at age 8 to 10 years with esophagogastroduodenoscopy or capsule endoscopy and if negative, colonoscopy at age 18. Others suggest starting screening at 4 to 5 years of age.⁵ The recommendation is to remove polyps if technically feasible.³ Surveillance for Sertoli cell tumors (sex cord stromal tumors) should be done before puberty, and evaluation of other organs at risk of malignancy should begin by the end of adolescence.

The pigmented macules do not require treatment. Macules on the lips may disappear with time, while those on the buccal mucosa persist. The lip lesions can be lightened with chemical peels or laser.

Our patient underwent laparotomy, which revealed a grossly dilated and gangrenous small bowel segment. Intussusception was not present and was thought to have spontaneously reduced. Resection and anastomosis of the affected small bowel was performed. The patient’s postoperative course was uneventful, and her diarrhea and abdominal pain resolved. We recommended follow-up in her home city with primary care and a GI specialist and explained the need for surveillance of her condition.

CORRESPONDENCE
Josette R. McMichael, MD, Department of Dermatology, Emory University, 1525 Clifton Road NE, 1st Floor, Atlanta, GA 30322; [email protected]

Like most family medicine residencies, our teaching nursing home was struck with a COVID-19 outbreak. Within 10 days, I was the sole physician responsible for 15 patients with varying degrees of illness, quarantined behind the fire doors of a wing of a Memory Support Unit. My daily work there over the course of the next month prompted me to reflect on some of the core principles of family medicine, and health care, that are vital to effective patient care during a pandemic. My experience provided the following reminders:

Work as a team. Gowned, gloved, and masked behind the fire doors, our world shrank to our patients and a 4-person team comprised of a nurse, 2 nursing assistants, and me. For the first time in the 10+ years I’ve worked at that facility, I actually asked for and memorized the names of everyone I was working with that day. Without an intercom or other telecommunications system, it became important for me to be able to call for my team members by name for immediate help. We had to depend on one another to make sure all patients were hydrated and fed, to avert falls whenever possible, to intervene early when dementia-­associated behaviors were escalating, and to recognize when patients were crashing.

I began asking for the names of everyone I was working with that day and I observed, first-hand, the great finesse that nurses display in their efforts to de-escalate disruptive behaviors.

We also had to depend on each other to ensure that our personal protective equipment remained properly placed, to combat the psychological sense of isolation that quarantine environments engender, and to placate a gnawing undercurrent of unease while working around a potentially deadly pathogen.

Develop clinical routines. Having listened to other medical directors whose nursing homes were affected by the pandemic earlier than we were, and hearing about potentially avoidable complications, we developed clinical routines. This began with identifying any patients with diabetes whose poor appetites while acutely ill could send them into hypoglycemia. We devised a daily clinical report sheet that included vital signs, date of positive COVID-19 test, global clinical status, and advance directives. Unlike the usual mode of working almost in parallel, I began my workday with a “sign-out” from the nurse, then started examining each patient.

Under the strain of this unusual environment and novel circumstances, we communicated more and more often. This allowed us to quickly recognize and communicate emerging changes in the clinical status of a patient by sharing our observations of subtle, nonspecific “sub-threshold” indicators.

Clarify the goals of care. Since most of the patients in the COVID-19 unit were under the long-term care of other attending physicians, it was important for me to understand the wishes of the patient or surrogate decision maker, should life-threatening complications occur. While all affected patients were long-term residents of a memory support unit, some had full-code advance directives. I quickly realized that what was first necessary was to develop rapport and trust with the families who didn’t know me, then discuss goals of care, and finally assure that the advance directives were in congruence with their stated goals. What helped families gain trust in me was knowing that I was seeing their loved one daily, that I was committed to helping the patient survive this infection, and that I was willing to come back to the facility if a crisis occurred—even at night, if necessary.

Appreciate the daily work of team members. One of my greatest worries was dehydration. When elders were acutely ill and eating and drinking poorly, I would assist with feeding and offering liquids. I quickly came to appreciate how complex and subtle this seemingly mundane task can be. Learning the proper pace and portion size, even choosing the right conversation topic and tone, could make the difference between a patient “shutting down” and refusing all nourishment and successfully drinking a 360-cc cup of a high-nutrient shake.

Continue to: In the disrupted routines...

In the disrupted routines and altered physical environments of the COVID-19 unit, the psychological and behavioral complications of dementia intensified for some patients. I observed first-hand the great patience, kindness, and finesse that nurses and nursing assistants display in their efforts to de-escalate and prevent disruptive behaviors.

Empathize with (and appreciate) families. Families tearfully reminded me that they had been suffering from the absence of contact with their loved ones for months; COVID-19 added to that trauma for many of them. They talked about the missed graduations, birthdays, and other precious times together that were lost because of the quarantine.

Families also prevented me from making mistakes. When I ordered nitrofurantoin for a patient with a urinary tract infection, her son called me and respectfully requested I “just check and make sure” it would not cause a problem, given her G6PD deficiency. He prevented me from prescribing an antibiotic contraindicated in that condition.

Bring forward the lessons learned. The COVID-19 outbreak has passed through our nursing home—at least for now. I perceive a subtle shift in how we continue to interact with one another. Behind the masks, we make a little more eye contact; we more often address each other by name; and we acknowledge a greater mutual respect.

The shared experience of COVID-19 has brought us all a little closer together, and in the end, our patients have benefitted.

Like most family medicine residencies, our teaching nursing home was struck with a COVID-19 outbreak. Within 10 days, I was the sole physician responsible for 15 patients with varying degrees of illness, quarantined behind the fire doors of a wing of a Memory Support Unit. My daily work there over the course of the next month prompted me to reflect on some of the core principles of family medicine, and health care, that are vital to effective patient care during a pandemic. My experience provided the following reminders:

Work as a team. Gowned, gloved, and masked behind the fire doors, our world shrank to our patients and a 4-person team comprised of a nurse, 2 nursing assistants, and me. For the first time in the 10+ years I’ve worked at that facility, I actually asked for and memorized the names of everyone I was working with that day. Without an intercom or other telecommunications system, it became important for me to be able to call for my team members by name for immediate help. We had to depend on one another to make sure all patients were hydrated and fed, to avert falls whenever possible, to intervene early when dementia-­associated behaviors were escalating, and to recognize when patients were crashing.

I began asking for the names of everyone I was working with that day and I observed, first-hand, the great finesse that nurses display in their efforts to de-escalate disruptive behaviors.

We also had to depend on each other to ensure that our personal protective equipment remained properly placed, to combat the psychological sense of isolation that quarantine environments engender, and to placate a gnawing undercurrent of unease while working around a potentially deadly pathogen.

Develop clinical routines. Having listened to other medical directors whose nursing homes were affected by the pandemic earlier than we were, and hearing about potentially avoidable complications, we developed clinical routines. This began with identifying any patients with diabetes whose poor appetites while acutely ill could send them into hypoglycemia. We devised a daily clinical report sheet that included vital signs, date of positive COVID-19 test, global clinical status, and advance directives. Unlike the usual mode of working almost in parallel, I began my workday with a “sign-out” from the nurse, then started examining each patient.

Under the strain of this unusual environment and novel circumstances, we communicated more and more often. This allowed us to quickly recognize and communicate emerging changes in the clinical status of a patient by sharing our observations of subtle, nonspecific “sub-threshold” indicators.

Clarify the goals of care. Since most of the patients in the COVID-19 unit were under the long-term care of other attending physicians, it was important for me to understand the wishes of the patient or surrogate decision maker, should life-threatening complications occur. While all affected patients were long-term residents of a memory support unit, some had full-code advance directives. I quickly realized that what was first necessary was to develop rapport and trust with the families who didn’t know me, then discuss goals of care, and finally assure that the advance directives were in congruence with their stated goals. What helped families gain trust in me was knowing that I was seeing their loved one daily, that I was committed to helping the patient survive this infection, and that I was willing to come back to the facility if a crisis occurred—even at night, if necessary.

Appreciate the daily work of team members. One of my greatest worries was dehydration. When elders were acutely ill and eating and drinking poorly, I would assist with feeding and offering liquids. I quickly came to appreciate how complex and subtle this seemingly mundane task can be. Learning the proper pace and portion size, even choosing the right conversation topic and tone, could make the difference between a patient “shutting down” and refusing all nourishment and successfully drinking a 360-cc cup of a high-nutrient shake.

Continue to: In the disrupted routines...

In the disrupted routines and altered physical environments of the COVID-19 unit, the psychological and behavioral complications of dementia intensified for some patients. I observed first-hand the great patience, kindness, and finesse that nurses and nursing assistants display in their efforts to de-escalate and prevent disruptive behaviors.

Empathize with (and appreciate) families. Families tearfully reminded me that they had been suffering from the absence of contact with their loved ones for months; COVID-19 added to that trauma for many of them. They talked about the missed graduations, birthdays, and other precious times together that were lost because of the quarantine.

Families also prevented me from making mistakes. When I ordered nitrofurantoin for a patient with a urinary tract infection, her son called me and respectfully requested I “just check and make sure” it would not cause a problem, given her G6PD deficiency. He prevented me from prescribing an antibiotic contraindicated in that condition.

Bring forward the lessons learned. The COVID-19 outbreak has passed through our nursing home—at least for now. I perceive a subtle shift in how we continue to interact with one another. Behind the masks, we make a little more eye contact; we more often address each other by name; and we acknowledge a greater mutual respect.

The shared experience of COVID-19 has brought us all a little closer together, and in the end, our patients have benefitted.

Like most family medicine residencies, our teaching nursing home was struck with a COVID-19 outbreak. Within 10 days, I was the sole physician responsible for 15 patients with varying degrees of illness, quarantined behind the fire doors of a wing of a Memory Support Unit. My daily work there over the course of the next month prompted me to reflect on some of the core principles of family medicine, and health care, that are vital to effective patient care during a pandemic. My experience provided the following reminders:

Work as a team. Gowned, gloved, and masked behind the fire doors, our world shrank to our patients and a 4-person team comprised of a nurse, 2 nursing assistants, and me. For the first time in the 10+ years I’ve worked at that facility, I actually asked for and memorized the names of everyone I was working with that day. Without an intercom or other telecommunications system, it became important for me to be able to call for my team members by name for immediate help. We had to depend on one another to make sure all patients were hydrated and fed, to avert falls whenever possible, to intervene early when dementia-­associated behaviors were escalating, and to recognize when patients were crashing.

I began asking for the names of everyone I was working with that day and I observed, first-hand, the great finesse that nurses display in their efforts to de-escalate disruptive behaviors.

We also had to depend on each other to ensure that our personal protective equipment remained properly placed, to combat the psychological sense of isolation that quarantine environments engender, and to placate a gnawing undercurrent of unease while working around a potentially deadly pathogen.

Develop clinical routines. Having listened to other medical directors whose nursing homes were affected by the pandemic earlier than we were, and hearing about potentially avoidable complications, we developed clinical routines. This began with identifying any patients with diabetes whose poor appetites while acutely ill could send them into hypoglycemia. We devised a daily clinical report sheet that included vital signs, date of positive COVID-19 test, global clinical status, and advance directives. Unlike the usual mode of working almost in parallel, I began my workday with a “sign-out” from the nurse, then started examining each patient.

Under the strain of this unusual environment and novel circumstances, we communicated more and more often. This allowed us to quickly recognize and communicate emerging changes in the clinical status of a patient by sharing our observations of subtle, nonspecific “sub-threshold” indicators.

Clarify the goals of care. Since most of the patients in the COVID-19 unit were under the long-term care of other attending physicians, it was important for me to understand the wishes of the patient or surrogate decision maker, should life-threatening complications occur. While all affected patients were long-term residents of a memory support unit, some had full-code advance directives. I quickly realized that what was first necessary was to develop rapport and trust with the families who didn’t know me, then discuss goals of care, and finally assure that the advance directives were in congruence with their stated goals. What helped families gain trust in me was knowing that I was seeing their loved one daily, that I was committed to helping the patient survive this infection, and that I was willing to come back to the facility if a crisis occurred—even at night, if necessary.

Appreciate the daily work of team members. One of my greatest worries was dehydration. When elders were acutely ill and eating and drinking poorly, I would assist with feeding and offering liquids. I quickly came to appreciate how complex and subtle this seemingly mundane task can be. Learning the proper pace and portion size, even choosing the right conversation topic and tone, could make the difference between a patient “shutting down” and refusing all nourishment and successfully drinking a 360-cc cup of a high-nutrient shake.

Continue to: In the disrupted routines...

In the disrupted routines and altered physical environments of the COVID-19 unit, the psychological and behavioral complications of dementia intensified for some patients. I observed first-hand the great patience, kindness, and finesse that nurses and nursing assistants display in their efforts to de-escalate and prevent disruptive behaviors.

Empathize with (and appreciate) families. Families tearfully reminded me that they had been suffering from the absence of contact with their loved ones for months; COVID-19 added to that trauma for many of them. They talked about the missed graduations, birthdays, and other precious times together that were lost because of the quarantine.

Families also prevented me from making mistakes. When I ordered nitrofurantoin for a patient with a urinary tract infection, her son called me and respectfully requested I “just check and make sure” it would not cause a problem, given her G6PD deficiency. He prevented me from prescribing an antibiotic contraindicated in that condition.

Bring forward the lessons learned. The COVID-19 outbreak has passed through our nursing home—at least for now. I perceive a subtle shift in how we continue to interact with one another. Behind the masks, we make a little more eye contact; we more often address each other by name; and we acknowledge a greater mutual respect.

The shared experience of COVID-19 has brought us all a little closer together, and in the end, our patients have benefitted.

THE CASE

A 45-year-old man was admitted to the hospital with a fever and generalized rash. For the previous 2 weeks, he had been treated at a skilled nursing facility with IV vancomycin and cefepime for left calcaneal osteomyelitis. He reported that the rash was pruritic and started 2 days prior to hospital admission.

His past medical history was significant for type 2 diabetes mellitus and polysubstance drug abuse. Medical and travel history were otherwise unremarkable. The patient was taking the following medications at the time of presentation: hydrocodone-acetaminophen, cyclobenzaprine, melatonin, and metformin.

Initial vital signs included a temperature of 102.9°F; respiratory rate, 22 breaths/min; heart rate, 97 beats/min; and blood pressure, 89/50 mm Hg. Physical exam was notable for left anterior cervical and axillary lymphadenopathy. The patient had no facial edema, but he did have a diffuse, morbilliform rash on his bilateral upper and lower extremities, encompassing about 54% of his body surface area (FIGURE 1).

Laboratory studies revealed a white blood cell count of 4.7/mcL, with 3.4% eosinophils and 10.9% monocytes; an erythrocyte sedimentation rate of 60 mm/h; and a C-reactive protein level of 1 mg/dL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both elevated (AST: 95 U/L [normal range, 8 - 48 U/L]; ALT: 115 U/L [normal range: 7 - 55 U/L]). A chest x-ray was obtained and showed new lung infiltrates (FIGURE 2).

Linezolid and meropenem were initiated for a presumed health care–associated pneumonia, and a sepsis work-up was initiated.

THE DIAGNOSIS

The patient’s rash and pruritus worsened after meropenem was introduced. A hepatitis panel was nonreactive except for prior hepatitis A exposure. Ultrasound of the liver and spleen was normal. Investigation of pneumonia pathogens including Legionella, Streptococcus, Mycoplasma, and Chlamydia psittaci did not reveal any causative agents. A skin biopsy revealed perivascular neutrophilic dermatitis with dyskeratosis.

The patient was diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome based on his fever, worsening morbilliform rash, lymphadenopathy, and elevated liver transaminase levels. Although he did not have marked eosinophilia, atypical lymphocytes were present. Serologies for human herpesvirus (HHV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) were all unremarkable.

Continue to: During discussions...

During discussions with an infectious disease specialist, it was concluded that the patient’s DRESS syndrome was likely secondary to beta-lactam antibiotics. The patient had been receiving cefepime prior to hospitalization. Meropenem was discontinued and aztreonam was started, with continued linezolid. This patient did not have a reactivation of a herpesvirus (HHV-6, HHV-7, EBV, or CMV), which has been previously reported in cases of DRESS syndrome.

DISCUSSION

DRESS syndrome is a challenging diagnosis to make due to the multiplicity of presenting symptoms. Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings.¹ Accurate diagnosis reduces fatal disease outcomes, which are estimated to occur in 5%-10% of cases.^1,2

Causative agents. DRESS syndrome typically occurs 2 to 6 weeks after the introduction of the causative agent, commonly an aromatic anticonvulsant or antibiotic.³ The incidence of DRESS syndrome in patients using carbamazepine and phenytoin is estimated to be 1 to 5 per 10,000 patients. The incidence of DRESS syndrome in patients using antibiotics is unknown. Frequently, the inducing antibiotic is a beta-lactam, as in this case.^4,5

The pathogenesis of DRESS syndrome is not well understood, although there appears to be an immune-mediated reaction that occurs in certain patients after viral reactivation, particularly with herpesviruses. In vitro studies have demonstrated that the culprit drug is able to induce viral reactivation leading to T-lymphocyte response and systemic inflammation, which occurs in multiple organs.^6,7 Reported long-term sequelae of DRESS syndrome include immune-mediated diseases such as thyroiditis and type 1 diabetes. In addition, it is hypothesized that there is a genetic predisposition involving human leukocyte antigens that increases the likelihood that individuals will develop DRESS syndrome.^5,8

Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings of DRESS syndrome.

Diagnosis. The Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) was developed to assist in the diagnosis of DRESS syndrome.⁹ Patients should be assessed for 11 criteria (outlined in the TABLE⁹), with points applied for the presence, absence, or unknown status of each. A total score of > 5 is consistent with definitive diagnosis of DRESS syndrome, while a score of > 2 indicates probable DRESS syndrome. Additionally, a skin biopsy may be contributory by revealing a dense infiltrate of eosinophils or lymphocytes in the papillary dermis, but this is not needed to make the diagnosis.^10,11

Continue to: Treatment

Treatment is aimed at stopping the causative agent and starting moderate- to high-dose systemic corticosteroids (from 0.5 to 2 mg/kg/d). If symptoms continue to progress, cyclosporine can be used. ­N-acetylcysteine may also be beneficial due to its ability to neutralize drug metabolites that can stimulate T-cell response.⁷ There has not been sufficient evidence to suggest that antiviral medication should be initiated.^1,7

Our patient was treated with 2 mg/kg/d of prednisone, along with triamcinolone cream, diphenhydramine, and ­N-acetylcysteine. His rash improved dramatically during his hospital stay and at the subsequent 1-month follow-up was completely resolved.

THE TAKEAWAY

DRESS syndrome should be suspected in patients presenting with fever, rash, lymphadenopathy, pulmonary infiltrates, and liver involvement after initiation of drugs commonly associated with this syndrome. Our case reinforces previous clinical evidence that beta-lactam antibiotics are a common cause of DRESS syndrome; patients taking these medications should be closely monitored. Cross-reactions are frequent, and it is imperative that patients avoid related drugs to prevent recurrence. Although glucocorticoids are the mainstay of treatment, further studies are needed to assess the benefits of N-acetylcysteine.

CORRESPONDENCE
W. Jacob Cobb, MD, JPS Health Network, 1500 South Main Street, Fort Worth, TX, 76104; [email protected]

THE CASE

A 45-year-old man was admitted to the hospital with a fever and generalized rash. For the previous 2 weeks, he had been treated at a skilled nursing facility with IV vancomycin and cefepime for left calcaneal osteomyelitis. He reported that the rash was pruritic and started 2 days prior to hospital admission.

His past medical history was significant for type 2 diabetes mellitus and polysubstance drug abuse. Medical and travel history were otherwise unremarkable. The patient was taking the following medications at the time of presentation: hydrocodone-acetaminophen, cyclobenzaprine, melatonin, and metformin.

Initial vital signs included a temperature of 102.9°F; respiratory rate, 22 breaths/min; heart rate, 97 beats/min; and blood pressure, 89/50 mm Hg. Physical exam was notable for left anterior cervical and axillary lymphadenopathy. The patient had no facial edema, but he did have a diffuse, morbilliform rash on his bilateral upper and lower extremities, encompassing about 54% of his body surface area (FIGURE 1).

Laboratory studies revealed a white blood cell count of 4.7/mcL, with 3.4% eosinophils and 10.9% monocytes; an erythrocyte sedimentation rate of 60 mm/h; and a C-reactive protein level of 1 mg/dL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both elevated (AST: 95 U/L [normal range, 8 - 48 U/L]; ALT: 115 U/L [normal range: 7 - 55 U/L]). A chest x-ray was obtained and showed new lung infiltrates (FIGURE 2).

Linezolid and meropenem were initiated for a presumed health care–associated pneumonia, and a sepsis work-up was initiated.

THE DIAGNOSIS

The patient’s rash and pruritus worsened after meropenem was introduced. A hepatitis panel was nonreactive except for prior hepatitis A exposure. Ultrasound of the liver and spleen was normal. Investigation of pneumonia pathogens including Legionella, Streptococcus, Mycoplasma, and Chlamydia psittaci did not reveal any causative agents. A skin biopsy revealed perivascular neutrophilic dermatitis with dyskeratosis.

The patient was diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome based on his fever, worsening morbilliform rash, lymphadenopathy, and elevated liver transaminase levels. Although he did not have marked eosinophilia, atypical lymphocytes were present. Serologies for human herpesvirus (HHV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) were all unremarkable.

Continue to: During discussions...

During discussions with an infectious disease specialist, it was concluded that the patient’s DRESS syndrome was likely secondary to beta-lactam antibiotics. The patient had been receiving cefepime prior to hospitalization. Meropenem was discontinued and aztreonam was started, with continued linezolid. This patient did not have a reactivation of a herpesvirus (HHV-6, HHV-7, EBV, or CMV), which has been previously reported in cases of DRESS syndrome.

DISCUSSION

DRESS syndrome is a challenging diagnosis to make due to the multiplicity of presenting symptoms. Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings.¹ Accurate diagnosis reduces fatal disease outcomes, which are estimated to occur in 5%-10% of cases.^1,2

Causative agents. DRESS syndrome typically occurs 2 to 6 weeks after the introduction of the causative agent, commonly an aromatic anticonvulsant or antibiotic.³ The incidence of DRESS syndrome in patients using carbamazepine and phenytoin is estimated to be 1 to 5 per 10,000 patients. The incidence of DRESS syndrome in patients using antibiotics is unknown. Frequently, the inducing antibiotic is a beta-lactam, as in this case.^4,5

The pathogenesis of DRESS syndrome is not well understood, although there appears to be an immune-mediated reaction that occurs in certain patients after viral reactivation, particularly with herpesviruses. In vitro studies have demonstrated that the culprit drug is able to induce viral reactivation leading to T-lymphocyte response and systemic inflammation, which occurs in multiple organs.^6,7 Reported long-term sequelae of DRESS syndrome include immune-mediated diseases such as thyroiditis and type 1 diabetes. In addition, it is hypothesized that there is a genetic predisposition involving human leukocyte antigens that increases the likelihood that individuals will develop DRESS syndrome.^5,8

Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings of DRESS syndrome.

Diagnosis. The Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) was developed to assist in the diagnosis of DRESS syndrome.⁹ Patients should be assessed for 11 criteria (outlined in the TABLE⁹), with points applied for the presence, absence, or unknown status of each. A total score of > 5 is consistent with definitive diagnosis of DRESS syndrome, while a score of > 2 indicates probable DRESS syndrome. Additionally, a skin biopsy may be contributory by revealing a dense infiltrate of eosinophils or lymphocytes in the papillary dermis, but this is not needed to make the diagnosis.^10,11

Continue to: Treatment

Treatment is aimed at stopping the causative agent and starting moderate- to high-dose systemic corticosteroids (from 0.5 to 2 mg/kg/d). If symptoms continue to progress, cyclosporine can be used. ­N-acetylcysteine may also be beneficial due to its ability to neutralize drug metabolites that can stimulate T-cell response.⁷ There has not been sufficient evidence to suggest that antiviral medication should be initiated.^1,7

Our patient was treated with 2 mg/kg/d of prednisone, along with triamcinolone cream, diphenhydramine, and ­N-acetylcysteine. His rash improved dramatically during his hospital stay and at the subsequent 1-month follow-up was completely resolved.

THE TAKEAWAY

DRESS syndrome should be suspected in patients presenting with fever, rash, lymphadenopathy, pulmonary infiltrates, and liver involvement after initiation of drugs commonly associated with this syndrome. Our case reinforces previous clinical evidence that beta-lactam antibiotics are a common cause of DRESS syndrome; patients taking these medications should be closely monitored. Cross-reactions are frequent, and it is imperative that patients avoid related drugs to prevent recurrence. Although glucocorticoids are the mainstay of treatment, further studies are needed to assess the benefits of N-acetylcysteine.

CORRESPONDENCE
W. Jacob Cobb, MD, JPS Health Network, 1500 South Main Street, Fort Worth, TX, 76104; [email protected]

THE CASE

A 45-year-old man was admitted to the hospital with a fever and generalized rash. For the previous 2 weeks, he had been treated at a skilled nursing facility with IV vancomycin and cefepime for left calcaneal osteomyelitis. He reported that the rash was pruritic and started 2 days prior to hospital admission.

His past medical history was significant for type 2 diabetes mellitus and polysubstance drug abuse. Medical and travel history were otherwise unremarkable. The patient was taking the following medications at the time of presentation: hydrocodone-acetaminophen, cyclobenzaprine, melatonin, and metformin.

Initial vital signs included a temperature of 102.9°F; respiratory rate, 22 breaths/min; heart rate, 97 beats/min; and blood pressure, 89/50 mm Hg. Physical exam was notable for left anterior cervical and axillary lymphadenopathy. The patient had no facial edema, but he did have a diffuse, morbilliform rash on his bilateral upper and lower extremities, encompassing about 54% of his body surface area (FIGURE 1).

Laboratory studies revealed a white blood cell count of 4.7/mcL, with 3.4% eosinophils and 10.9% monocytes; an erythrocyte sedimentation rate of 60 mm/h; and a C-reactive protein level of 1 mg/dL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both elevated (AST: 95 U/L [normal range, 8 - 48 U/L]; ALT: 115 U/L [normal range: 7 - 55 U/L]). A chest x-ray was obtained and showed new lung infiltrates (FIGURE 2).

Linezolid and meropenem were initiated for a presumed health care–associated pneumonia, and a sepsis work-up was initiated.

THE DIAGNOSIS

The patient’s rash and pruritus worsened after meropenem was introduced. A hepatitis panel was nonreactive except for prior hepatitis A exposure. Ultrasound of the liver and spleen was normal. Investigation of pneumonia pathogens including Legionella, Streptococcus, Mycoplasma, and Chlamydia psittaci did not reveal any causative agents. A skin biopsy revealed perivascular neutrophilic dermatitis with dyskeratosis.

The patient was diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome based on his fever, worsening morbilliform rash, lymphadenopathy, and elevated liver transaminase levels. Although he did not have marked eosinophilia, atypical lymphocytes were present. Serologies for human herpesvirus (HHV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) were all unremarkable.

Continue to: During discussions...

During discussions with an infectious disease specialist, it was concluded that the patient’s DRESS syndrome was likely secondary to beta-lactam antibiotics. The patient had been receiving cefepime prior to hospitalization. Meropenem was discontinued and aztreonam was started, with continued linezolid. This patient did not have a reactivation of a herpesvirus (HHV-6, HHV-7, EBV, or CMV), which has been previously reported in cases of DRESS syndrome.

DISCUSSION

DRESS syndrome is a challenging diagnosis to make due to the multiplicity of presenting symptoms. Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings.¹ Accurate diagnosis reduces fatal disease outcomes, which are estimated to occur in 5%-10% of cases.^1,2

Causative agents. DRESS syndrome typically occurs 2 to 6 weeks after the introduction of the causative agent, commonly an aromatic anticonvulsant or antibiotic.³ The incidence of DRESS syndrome in patients using carbamazepine and phenytoin is estimated to be 1 to 5 per 10,000 patients. The incidence of DRESS syndrome in patients using antibiotics is unknown. Frequently, the inducing antibiotic is a beta-lactam, as in this case.^4,5

The pathogenesis of DRESS syndrome is not well understood, although there appears to be an immune-mediated reaction that occurs in certain patients after viral reactivation, particularly with herpesviruses. In vitro studies have demonstrated that the culprit drug is able to induce viral reactivation leading to T-lymphocyte response and systemic inflammation, which occurs in multiple organs.^6,7 Reported long-term sequelae of DRESS syndrome include immune-mediated diseases such as thyroiditis and type 1 diabetes. In addition, it is hypothesized that there is a genetic predisposition involving human leukocyte antigens that increases the likelihood that individuals will develop DRESS syndrome.^5,8

Skin rash, lymphadenopathy, hepatic involvement, and hypereosinophilia are characteristic findings of DRESS syndrome.

Diagnosis. The Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) was developed to assist in the diagnosis of DRESS syndrome.⁹ Patients should be assessed for 11 criteria (outlined in the TABLE⁹), with points applied for the presence, absence, or unknown status of each. A total score of > 5 is consistent with definitive diagnosis of DRESS syndrome, while a score of > 2 indicates probable DRESS syndrome. Additionally, a skin biopsy may be contributory by revealing a dense infiltrate of eosinophils or lymphocytes in the papillary dermis, but this is not needed to make the diagnosis.^10,11

Continue to: Treatment

Treatment is aimed at stopping the causative agent and starting moderate- to high-dose systemic corticosteroids (from 0.5 to 2 mg/kg/d). If symptoms continue to progress, cyclosporine can be used. ­N-acetylcysteine may also be beneficial due to its ability to neutralize drug metabolites that can stimulate T-cell response.⁷ There has not been sufficient evidence to suggest that antiviral medication should be initiated.^1,7

Our patient was treated with 2 mg/kg/d of prednisone, along with triamcinolone cream, diphenhydramine, and ­N-acetylcysteine. His rash improved dramatically during his hospital stay and at the subsequent 1-month follow-up was completely resolved.

THE TAKEAWAY

DRESS syndrome should be suspected in patients presenting with fever, rash, lymphadenopathy, pulmonary infiltrates, and liver involvement after initiation of drugs commonly associated with this syndrome. Our case reinforces previous clinical evidence that beta-lactam antibiotics are a common cause of DRESS syndrome; patients taking these medications should be closely monitored. Cross-reactions are frequent, and it is imperative that patients avoid related drugs to prevent recurrence. Although glucocorticoids are the mainstay of treatment, further studies are needed to assess the benefits of N-acetylcysteine.

CORRESPONDENCE
W. Jacob Cobb, MD, JPS Health Network, 1500 South Main Street, Fort Worth, TX, 76104; [email protected]

Bipolar disorder is a prevalent disorder in the primary care setting.^1,2 Primary care providers therefore commonly encounter bipolar depression (BD; a major depressive episode in the context of bipolar disorder), which might be (1) an emerging depressive episode in previously undiagnosed bipolar disorder or (2) a recurrent episode during the course of chronic bipolar illness.^3,4

A primary care–based collaborative model has been identified as a potential strategy for effective management of chronic mental health conditions such as bipolar disorder.^5,6 However, this collaborative treatment model isn’t widely available; many patients with bipolar disorder are, in fact, treated solely by their primary care provider.

Two years ago in this journal,⁷ we addressed how to precisely identify an episode of BD and differentiate it from major depressive disorder (MDD; also known as unipolar depression). In this review, in addition to advancing clinical knowledge of BD, we provide:

• an overview of treatment options for BD (in contrast to the treatment of unipolar depression)
• the pharmacotherapeutic know-how to initiate and maintain treatment for uncomplicated episodes of BD.

We do not discuss management of manic, hypomanic, and mixed episodes of bipolar disorder.

How to identify bipolar depression

Understanding the (sometimes) unclear distinction between bipolar I and bipolar II disorders in an individual patient is key to formulating a therapeutic regimen for BD.

Bipolar I disorder consists of manic episodes, alternating (more often than not) with depressive episodes. Bipolar I usually manifests first with a depressive episode.

Bipolar II disorder manifests with depressive episodes and hypomanic episodes (but never manic episodes).

Continue to: Depressive episodes in the bipolar disorders

Depressive episodes in the bipolar disorders. Bipolar depression can be seen in the settings of both bipolar I and II disorders. When a patient presents with a manic episode, a history of depressive episodes is common (although not essential) to diagnose bipolar I; alternatively, a history of hypomania (but no prior mania) and depression is needed to make the diagnosis of bipolar II. The natural history of the bipolar disorders is therefore alternating manic and almost always depressive episodes (bipolar I) and alternating hypomanic and always depressive episodes (bipolar II).⁸

Failure to adequately treat bipolar depressive episodes can have serious consequences, including a worsening course of illness, alcohol and substance use disorder, and suicide.

Symptoms of hypomanic episodes are similar to what are seen in manic episodes, but are of shorter duration (≥ 4 days [episodes of mania are at least of 1 week’s duration]), lower intensity (no psychotic symptoms), and not associated with significant functional impairment or hospitalization. Table 1⁷ further describes the differentiating features of bipolar I and bipolar II. A history of an unequivocal manic or hypomanic episode makes the diagnosis of BD relatively easy. However, an unclear history of manic or hypomanic symptoms or episodes frequently leads to misdiagnosis or underdiagnosis of BD.

In both bipolar I and II, it is depressive symptoms and episodes that place the greatest burden on patients across the lifespan: They are the most commonly experienced features of the bipolar disorders^9,10 and lead to significant distress and functional impairment¹¹; in fact, patients with bipolar disorder spend 3 (or more) times as long in depressive episodes as in manic or hypomanic episodes.^12,13 In addition, subthreshold depressive symptoms occur commonly between major mood episodes.

Failure to identify and adequately treat depressive episodes of the bipolar disorders can have serious consequences: Patients are at risk of a worsening course of illness, alcohol use disorder, substance use disorder, chronic disability, mixed states, rapid cycling of mood episodes, and suicide.

Guidelines for treating bipolar depression

Despite the similarity in presenting symptoms and signs of depressive episodes in bipolar disorders and MDD, treating episodes of BD is significantly different than treating MDD. Antidepressant monotherapy, a mainstay of treatment for MDD, has limited utility in BD (especially depressive episodes of bipolar I) because of its limited efficacy and potential to destabilize mood, lead to rapid cycling, and induce mania or hypomania. Treatment options for BD include pharmacotherapy (the primary modality), psychological intervention (a useful adjunct, described later), and electroconvulsive therapy (ECT; highly worth considering in severe or treatment-resistant cases).

Continue to: For this article...

For this article, we searched PubMed and Google Scholar for guidelines for the management of bipolar disorders in adults that were published between July 2013 (when the US Food and Drug Administration [FDA] approved lurasidone for the treatment of BD) and March 2019. Related guideline-­referenced articles and clinical trials were also reviewed.

Our search identified 6 guidelines issued during the search period, developed by the:

• Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD),¹⁴
• British Association for Psychopharmacology (BAP),¹⁵
• Japanese Society of Mood Disorders (JSMD),¹⁶
• National Institute for Health and Care Excellence (NICE),¹⁷
• International College of Neuropsychopharmacology (CINP),¹⁸ and
• Royal Australian and New Zealand College of Psychiatrists.¹⁹

How to manage an episode of bipolar depression

First-line pharmacotherapeutic agents for the management of BD in acute bipolar I are listed and described in Table 2.^4-19 Compared to the number of studies and reports on the management of BD in bipolar I, few studies have been conducted that specifically examine the treatment of BD in acute bipolar II. In practice, evidence from the treatment of BD in bipolar I has been extrapolated to the treatment of bipolar II depression. CANMAT–ISBD guidelines recommend quetiapine as the only first-line therapy for BD in bipolar II; JSMD, CINP, and NICE guidelines do not make distinct recommendations for treating BD in bipolar II.

Top recommended medications for bipolar depression are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/ fluoxetine.

Patients who have BD can present de novo (ie, not taking any medication for bipolar disorder) or with a breakthrough episode while on maintenance medication(s). In either case, monotherapy for BD is preferred, although combinations of medications (Table 2^14-19) can be more effective in some cases. Treatment guidelines overlap to a high degree, especially in regard to first-line treatments, but there is variation, especially beyond first-line therapeutics.²⁰

The top recommended medications for BD are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/fluoxetine. FDA-approved agents for treating acute BD specifically include quetiapine, lurasidone, and combined olanzapine/fluoxetine. Guidelines generally recommend a first step of adjusting the dosage of medications in any established regimen before changing or adding other agents. If clinical improvement is not seen using any recommended medications, psychiatric referral is recommended. See Table 3^21,22 for dosing and titration guidance and highlights of both common and rare but serious adverse effects.

Continue to: Recommendations, best options for acute bipolar depression

Start with lithium, lamotrigine, quetiapine, or lurasidone as the first-line medication at the dosages given in Table 3.^21,22 Olanzapine alone, or in combination with fluoxetine, can be used when it has been determined that the medications listed above are ineffective.

Note that lithium requires regular blood monitoring (Table 3^21,22). However, lithium has the advantage of strong supporting evidence of benefit in all mood episodes of bipolar disorders (depressive, manic, hypomanic), as well as maintenance, prevention of recurrence, and anti-suicidal properties.

Also of note: Lurasidone is much more costly than other recommended medications because it is available only by brand name in the United States; the other agents are available as generics. Consider generic equivalents of the recommended agents when cost is an important factor, in part because of the impact that cost has on medication adherence for some patients.

Last, olanzapine should be used later in the treatment algorithm, unless rapid control of symptoms is needed or other first-line medications are ineffective or not tolerated—given the higher propensity of the drug to produce weight gain and cause metabolic problems, including obesity and hyperglycemia.

The importance of maintenance therapy

Almost all patients with BD require maintenance treatment to prevent subsequent episodes, reduce residual symptoms, and restore functioning and quality of life. Maintenance therapy is formulated on the basis of efficacy and tolerability in the individual patient.

Continue to: As a general rule...

Lithium has strong supporting evidence of benefit in mood episodes of all bipolar disorders.

As a general rule, the strongest evidence for preventing recurrent BD episodes favors lithium—and most guidelines therefore support lithium as first-line maintenance therapy. It is important to note, however, that if a medication (or medications) successfully aborted an acute BD episode in a given patient, that agent (or agents) should be continued for maintenance purposes to prevent or minimize future episodes—generally, at the same dosage. First-line pharmacotherapeutic agents for the maintenance of bipolar disorder, and thus to prevent subsequent episodes of BD, are listed in Table 4.^14-19

℞ antidepressantsin bipolar depression?

The use of antidepressants to treat BD remains a topic of ongoing deliberation. Antidepressant treatment of BD has historically raised concern for depressive relapse due to ineffectiveness and the ability of antidepressants to increase (1) the frequency of manic and hypomanic episodes²³ and (2) mood instability in the form of induction of mixed states or rapid cycling. Among most authorities, the recommendation against using antidepressants for BD in both bipolar I and II is the same; however, limited evidence allows the use of antidepressant monotherapy in select cases of BD episodes in bipolar II,^24,25 although not bipolar I.

The consensus in the field is that medications with mood-stabilizing effects should be considered as monotherapy before adding an antidepressant (if an antidepressant is to be added) to treat BD in bipolar II.²⁶ In other words, if an antidepressant is to be used at all, it should be combined with a mood stabilizer or atypical antipsychotic^15,27 and should probably not be used long term. The efficacy of antidepressants in treating BD in bipolar II should be assessed periodically at follow-up.

Nonpharmaceutical treatment options

Although pharmacotherapy is the mainstay of treatment of BD, adjunctive psychotherapy can be useful for treating acute BD episodes that occur during the maintenance phase of the disorder. Psychoeducation (ie, education on psychiatric illness and the importance of medication adherence), alone or in combination with interpersonal and social rhythm therapy (IPSRT), family-focused therapy (FFT), and cognitive behavioral therapy (CBT) can add to the overall efficacy of pharmacotherapy by lowering the risk of relapse and enhancing psychosocial functioning.²⁸

IPSRT is supported by what is known as the instability model, which specifies that 3 interconnected pathways trigger recurrences of a bipolar episode: stressful life events, medication nonadherence, and social-rhythm disruption. IPSRT also uses principles of interpersonal psychotherapy that are applied in treating MDD, “arguing that improvement in interpersonal relationships can ameliorate affective symptoms and prevent their return.”^29,30

Continue to: FFT

FFT focuses on communication styles between patients and their spouses and families. The goal is to improve relationship functioning. FFT is delivered to the patient and the family.

Attention to social factors. For psychotherapy to provide adequate results as an adjunct to pharmacotherapy, social stressors (eg, homelessness and financial concerns) might also need to be considered and addressed through social services or a social work consult.

NICE guidelines recommend psychological intervention (in particular, with CBT and FFT) for acute BD. CANMAT–ISBD guidelines recommend either adjunctive psychoeducation, CBT, or FFT during the maintenance phase. Again, medication is the mainstay of treatment for BD in bipolar disorders; psychotherapy has an adjunctive role—unlike the approach to treatment of MDD, in which psychotherapy can be used alone in cases of mild, or even moderate, severity.

Referral for specialty care

In the primary care setting, providers might choose to manage BD by initiating first-line pharmacotherapeutic agents or continuing established treatment regimens with necessary dosage adjustments. These patients should be monitored closely until symptoms remit.

However, it is important for the primary care provider to identify patients who need psychiatric referral. Complex presentations, severe symptoms, and poor treatment response might warrant evaluation and management by a psychiatrist. Furthermore, patients with comorbid psychotic features, catatonia, or severely debilitating depression (with or without suicidality) need referral to the emergency department.

Continue to: Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT). Patients might also need referral to Psychiatry for ECT, which is recommended by ­CANMAT–ISBD and JSMD guidelines as a second-line option; by the Royal Australian and New Zealand College of Psychiatrists as a third-line option; and by BAP for cases that are resistant to conventional treatment, with or without a high risk of suicide; in pregnancy; and in life-threatening situations.^15,31,32

Telemedicine. There is a considerable shortage of mental health care professionals.^33,34 The fact that nearly all (96%) counties in the United States have an unmet need for prescribers of mental health services (mainly psychiatrists) makes it crucial that primary care physicians be knowledgeable and prepared to manage BD—often with infrequent psychiatry consultation or, even, without psychiatry consultation. For primary care facilities that lack access to psychiatric services, telemedicine can be used as a consultative resource.

Limited evidence allows the use of antidepressant monotherapy in select cases of bipolar depressive episodes in bipolar II, although not in bipolar I.

Psychiatric consultation using telemedicine technologies has provided significant cost savings for medical centers and decreased the likelihood of hospital admission,³⁵ thereby alleviating health care costs and improving care, as shown in a rural Kansas county study.³⁶ Furthermore, the burden on emergency departments in several states has been significantly reduced with psychiatric consultations via interactive telemedicine technologies.³⁷

ACKNOWLEDGEMENT
Mark Yassa, BS, provided editing assistance.

CORRESPONDENCE
Nagy Youssef, MD, PhD, Medical College of Georgia at Augusta University, Department of Psychiatry and Health Behavior, 997 St. Sebastian Way, Augusta, GA 30912; [email protected].

Bipolar disorder is a prevalent disorder in the primary care setting.^1,2 Primary care providers therefore commonly encounter bipolar depression (BD; a major depressive episode in the context of bipolar disorder), which might be (1) an emerging depressive episode in previously undiagnosed bipolar disorder or (2) a recurrent episode during the course of chronic bipolar illness.^3,4

A primary care–based collaborative model has been identified as a potential strategy for effective management of chronic mental health conditions such as bipolar disorder.^5,6 However, this collaborative treatment model isn’t widely available; many patients with bipolar disorder are, in fact, treated solely by their primary care provider.

Two years ago in this journal,⁷ we addressed how to precisely identify an episode of BD and differentiate it from major depressive disorder (MDD; also known as unipolar depression). In this review, in addition to advancing clinical knowledge of BD, we provide:

• an overview of treatment options for BD (in contrast to the treatment of unipolar depression)
• the pharmacotherapeutic know-how to initiate and maintain treatment for uncomplicated episodes of BD.

We do not discuss management of manic, hypomanic, and mixed episodes of bipolar disorder.

How to identify bipolar depression

Understanding the (sometimes) unclear distinction between bipolar I and bipolar II disorders in an individual patient is key to formulating a therapeutic regimen for BD.

Bipolar I disorder consists of manic episodes, alternating (more often than not) with depressive episodes. Bipolar I usually manifests first with a depressive episode.

Bipolar II disorder manifests with depressive episodes and hypomanic episodes (but never manic episodes).

Continue to: Depressive episodes in the bipolar disorders

Depressive episodes in the bipolar disorders. Bipolar depression can be seen in the settings of both bipolar I and II disorders. When a patient presents with a manic episode, a history of depressive episodes is common (although not essential) to diagnose bipolar I; alternatively, a history of hypomania (but no prior mania) and depression is needed to make the diagnosis of bipolar II. The natural history of the bipolar disorders is therefore alternating manic and almost always depressive episodes (bipolar I) and alternating hypomanic and always depressive episodes (bipolar II).⁸

Failure to adequately treat bipolar depressive episodes can have serious consequences, including a worsening course of illness, alcohol and substance use disorder, and suicide.

Symptoms of hypomanic episodes are similar to what are seen in manic episodes, but are of shorter duration (≥ 4 days [episodes of mania are at least of 1 week’s duration]), lower intensity (no psychotic symptoms), and not associated with significant functional impairment or hospitalization. Table 1⁷ further describes the differentiating features of bipolar I and bipolar II. A history of an unequivocal manic or hypomanic episode makes the diagnosis of BD relatively easy. However, an unclear history of manic or hypomanic symptoms or episodes frequently leads to misdiagnosis or underdiagnosis of BD.

In both bipolar I and II, it is depressive symptoms and episodes that place the greatest burden on patients across the lifespan: They are the most commonly experienced features of the bipolar disorders^9,10 and lead to significant distress and functional impairment¹¹; in fact, patients with bipolar disorder spend 3 (or more) times as long in depressive episodes as in manic or hypomanic episodes.^12,13 In addition, subthreshold depressive symptoms occur commonly between major mood episodes.

Failure to identify and adequately treat depressive episodes of the bipolar disorders can have serious consequences: Patients are at risk of a worsening course of illness, alcohol use disorder, substance use disorder, chronic disability, mixed states, rapid cycling of mood episodes, and suicide.

Guidelines for treating bipolar depression

Despite the similarity in presenting symptoms and signs of depressive episodes in bipolar disorders and MDD, treating episodes of BD is significantly different than treating MDD. Antidepressant monotherapy, a mainstay of treatment for MDD, has limited utility in BD (especially depressive episodes of bipolar I) because of its limited efficacy and potential to destabilize mood, lead to rapid cycling, and induce mania or hypomania. Treatment options for BD include pharmacotherapy (the primary modality), psychological intervention (a useful adjunct, described later), and electroconvulsive therapy (ECT; highly worth considering in severe or treatment-resistant cases).

Continue to: For this article...

For this article, we searched PubMed and Google Scholar for guidelines for the management of bipolar disorders in adults that were published between July 2013 (when the US Food and Drug Administration [FDA] approved lurasidone for the treatment of BD) and March 2019. Related guideline-­referenced articles and clinical trials were also reviewed.

Our search identified 6 guidelines issued during the search period, developed by the:

• Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD),¹⁴
• British Association for Psychopharmacology (BAP),¹⁵
• Japanese Society of Mood Disorders (JSMD),¹⁶
• National Institute for Health and Care Excellence (NICE),¹⁷
• International College of Neuropsychopharmacology (CINP),¹⁸ and
• Royal Australian and New Zealand College of Psychiatrists.¹⁹

How to manage an episode of bipolar depression

First-line pharmacotherapeutic agents for the management of BD in acute bipolar I are listed and described in Table 2.^4-19 Compared to the number of studies and reports on the management of BD in bipolar I, few studies have been conducted that specifically examine the treatment of BD in acute bipolar II. In practice, evidence from the treatment of BD in bipolar I has been extrapolated to the treatment of bipolar II depression. CANMAT–ISBD guidelines recommend quetiapine as the only first-line therapy for BD in bipolar II; JSMD, CINP, and NICE guidelines do not make distinct recommendations for treating BD in bipolar II.

Top recommended medications for bipolar depression are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/ fluoxetine.

Patients who have BD can present de novo (ie, not taking any medication for bipolar disorder) or with a breakthrough episode while on maintenance medication(s). In either case, monotherapy for BD is preferred, although combinations of medications (Table 2^14-19) can be more effective in some cases. Treatment guidelines overlap to a high degree, especially in regard to first-line treatments, but there is variation, especially beyond first-line therapeutics.²⁰

The top recommended medications for BD are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/fluoxetine. FDA-approved agents for treating acute BD specifically include quetiapine, lurasidone, and combined olanzapine/fluoxetine. Guidelines generally recommend a first step of adjusting the dosage of medications in any established regimen before changing or adding other agents. If clinical improvement is not seen using any recommended medications, psychiatric referral is recommended. See Table 3^21,22 for dosing and titration guidance and highlights of both common and rare but serious adverse effects.

Continue to: Recommendations, best options for acute bipolar depression

Start with lithium, lamotrigine, quetiapine, or lurasidone as the first-line medication at the dosages given in Table 3.^21,22 Olanzapine alone, or in combination with fluoxetine, can be used when it has been determined that the medications listed above are ineffective.

Note that lithium requires regular blood monitoring (Table 3^21,22). However, lithium has the advantage of strong supporting evidence of benefit in all mood episodes of bipolar disorders (depressive, manic, hypomanic), as well as maintenance, prevention of recurrence, and anti-suicidal properties.

Also of note: Lurasidone is much more costly than other recommended medications because it is available only by brand name in the United States; the other agents are available as generics. Consider generic equivalents of the recommended agents when cost is an important factor, in part because of the impact that cost has on medication adherence for some patients.

Last, olanzapine should be used later in the treatment algorithm, unless rapid control of symptoms is needed or other first-line medications are ineffective or not tolerated—given the higher propensity of the drug to produce weight gain and cause metabolic problems, including obesity and hyperglycemia.

The importance of maintenance therapy

Almost all patients with BD require maintenance treatment to prevent subsequent episodes, reduce residual symptoms, and restore functioning and quality of life. Maintenance therapy is formulated on the basis of efficacy and tolerability in the individual patient.

Continue to: As a general rule...

Lithium has strong supporting evidence of benefit in mood episodes of all bipolar disorders.

As a general rule, the strongest evidence for preventing recurrent BD episodes favors lithium—and most guidelines therefore support lithium as first-line maintenance therapy. It is important to note, however, that if a medication (or medications) successfully aborted an acute BD episode in a given patient, that agent (or agents) should be continued for maintenance purposes to prevent or minimize future episodes—generally, at the same dosage. First-line pharmacotherapeutic agents for the maintenance of bipolar disorder, and thus to prevent subsequent episodes of BD, are listed in Table 4.^14-19

℞ antidepressantsin bipolar depression?

The use of antidepressants to treat BD remains a topic of ongoing deliberation. Antidepressant treatment of BD has historically raised concern for depressive relapse due to ineffectiveness and the ability of antidepressants to increase (1) the frequency of manic and hypomanic episodes²³ and (2) mood instability in the form of induction of mixed states or rapid cycling. Among most authorities, the recommendation against using antidepressants for BD in both bipolar I and II is the same; however, limited evidence allows the use of antidepressant monotherapy in select cases of BD episodes in bipolar II,^24,25 although not bipolar I.

The consensus in the field is that medications with mood-stabilizing effects should be considered as monotherapy before adding an antidepressant (if an antidepressant is to be added) to treat BD in bipolar II.²⁶ In other words, if an antidepressant is to be used at all, it should be combined with a mood stabilizer or atypical antipsychotic^15,27 and should probably not be used long term. The efficacy of antidepressants in treating BD in bipolar II should be assessed periodically at follow-up.

Nonpharmaceutical treatment options

Although pharmacotherapy is the mainstay of treatment of BD, adjunctive psychotherapy can be useful for treating acute BD episodes that occur during the maintenance phase of the disorder. Psychoeducation (ie, education on psychiatric illness and the importance of medication adherence), alone or in combination with interpersonal and social rhythm therapy (IPSRT), family-focused therapy (FFT), and cognitive behavioral therapy (CBT) can add to the overall efficacy of pharmacotherapy by lowering the risk of relapse and enhancing psychosocial functioning.²⁸

IPSRT is supported by what is known as the instability model, which specifies that 3 interconnected pathways trigger recurrences of a bipolar episode: stressful life events, medication nonadherence, and social-rhythm disruption. IPSRT also uses principles of interpersonal psychotherapy that are applied in treating MDD, “arguing that improvement in interpersonal relationships can ameliorate affective symptoms and prevent their return.”^29,30

Continue to: FFT

FFT focuses on communication styles between patients and their spouses and families. The goal is to improve relationship functioning. FFT is delivered to the patient and the family.

Attention to social factors. For psychotherapy to provide adequate results as an adjunct to pharmacotherapy, social stressors (eg, homelessness and financial concerns) might also need to be considered and addressed through social services or a social work consult.

NICE guidelines recommend psychological intervention (in particular, with CBT and FFT) for acute BD. CANMAT–ISBD guidelines recommend either adjunctive psychoeducation, CBT, or FFT during the maintenance phase. Again, medication is the mainstay of treatment for BD in bipolar disorders; psychotherapy has an adjunctive role—unlike the approach to treatment of MDD, in which psychotherapy can be used alone in cases of mild, or even moderate, severity.

Referral for specialty care

In the primary care setting, providers might choose to manage BD by initiating first-line pharmacotherapeutic agents or continuing established treatment regimens with necessary dosage adjustments. These patients should be monitored closely until symptoms remit.

However, it is important for the primary care provider to identify patients who need psychiatric referral. Complex presentations, severe symptoms, and poor treatment response might warrant evaluation and management by a psychiatrist. Furthermore, patients with comorbid psychotic features, catatonia, or severely debilitating depression (with or without suicidality) need referral to the emergency department.

Continue to: Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT). Patients might also need referral to Psychiatry for ECT, which is recommended by ­CANMAT–ISBD and JSMD guidelines as a second-line option; by the Royal Australian and New Zealand College of Psychiatrists as a third-line option; and by BAP for cases that are resistant to conventional treatment, with or without a high risk of suicide; in pregnancy; and in life-threatening situations.^15,31,32

Telemedicine. There is a considerable shortage of mental health care professionals.^33,34 The fact that nearly all (96%) counties in the United States have an unmet need for prescribers of mental health services (mainly psychiatrists) makes it crucial that primary care physicians be knowledgeable and prepared to manage BD—often with infrequent psychiatry consultation or, even, without psychiatry consultation. For primary care facilities that lack access to psychiatric services, telemedicine can be used as a consultative resource.

Limited evidence allows the use of antidepressant monotherapy in select cases of bipolar depressive episodes in bipolar II, although not in bipolar I.

Psychiatric consultation using telemedicine technologies has provided significant cost savings for medical centers and decreased the likelihood of hospital admission,³⁵ thereby alleviating health care costs and improving care, as shown in a rural Kansas county study.³⁶ Furthermore, the burden on emergency departments in several states has been significantly reduced with psychiatric consultations via interactive telemedicine technologies.³⁷

ACKNOWLEDGEMENT
Mark Yassa, BS, provided editing assistance.

CORRESPONDENCE
Nagy Youssef, MD, PhD, Medical College of Georgia at Augusta University, Department of Psychiatry and Health Behavior, 997 St. Sebastian Way, Augusta, GA 30912; [email protected].

Bipolar disorder is a prevalent disorder in the primary care setting.^1,2 Primary care providers therefore commonly encounter bipolar depression (BD; a major depressive episode in the context of bipolar disorder), which might be (1) an emerging depressive episode in previously undiagnosed bipolar disorder or (2) a recurrent episode during the course of chronic bipolar illness.^3,4

A primary care–based collaborative model has been identified as a potential strategy for effective management of chronic mental health conditions such as bipolar disorder.^5,6 However, this collaborative treatment model isn’t widely available; many patients with bipolar disorder are, in fact, treated solely by their primary care provider.

Two years ago in this journal,⁷ we addressed how to precisely identify an episode of BD and differentiate it from major depressive disorder (MDD; also known as unipolar depression). In this review, in addition to advancing clinical knowledge of BD, we provide:

• an overview of treatment options for BD (in contrast to the treatment of unipolar depression)
• the pharmacotherapeutic know-how to initiate and maintain treatment for uncomplicated episodes of BD.

We do not discuss management of manic, hypomanic, and mixed episodes of bipolar disorder.

How to identify bipolar depression

Understanding the (sometimes) unclear distinction between bipolar I and bipolar II disorders in an individual patient is key to formulating a therapeutic regimen for BD.

Bipolar I disorder consists of manic episodes, alternating (more often than not) with depressive episodes. Bipolar I usually manifests first with a depressive episode.

Bipolar II disorder manifests with depressive episodes and hypomanic episodes (but never manic episodes).

Continue to: Depressive episodes in the bipolar disorders

Depressive episodes in the bipolar disorders. Bipolar depression can be seen in the settings of both bipolar I and II disorders. When a patient presents with a manic episode, a history of depressive episodes is common (although not essential) to diagnose bipolar I; alternatively, a history of hypomania (but no prior mania) and depression is needed to make the diagnosis of bipolar II. The natural history of the bipolar disorders is therefore alternating manic and almost always depressive episodes (bipolar I) and alternating hypomanic and always depressive episodes (bipolar II).⁸

Failure to adequately treat bipolar depressive episodes can have serious consequences, including a worsening course of illness, alcohol and substance use disorder, and suicide.

Symptoms of hypomanic episodes are similar to what are seen in manic episodes, but are of shorter duration (≥ 4 days [episodes of mania are at least of 1 week’s duration]), lower intensity (no psychotic symptoms), and not associated with significant functional impairment or hospitalization. Table 1⁷ further describes the differentiating features of bipolar I and bipolar II. A history of an unequivocal manic or hypomanic episode makes the diagnosis of BD relatively easy. However, an unclear history of manic or hypomanic symptoms or episodes frequently leads to misdiagnosis or underdiagnosis of BD.

In both bipolar I and II, it is depressive symptoms and episodes that place the greatest burden on patients across the lifespan: They are the most commonly experienced features of the bipolar disorders^9,10 and lead to significant distress and functional impairment¹¹; in fact, patients with bipolar disorder spend 3 (or more) times as long in depressive episodes as in manic or hypomanic episodes.^12,13 In addition, subthreshold depressive symptoms occur commonly between major mood episodes.

Failure to identify and adequately treat depressive episodes of the bipolar disorders can have serious consequences: Patients are at risk of a worsening course of illness, alcohol use disorder, substance use disorder, chronic disability, mixed states, rapid cycling of mood episodes, and suicide.

Guidelines for treating bipolar depression

Despite the similarity in presenting symptoms and signs of depressive episodes in bipolar disorders and MDD, treating episodes of BD is significantly different than treating MDD. Antidepressant monotherapy, a mainstay of treatment for MDD, has limited utility in BD (especially depressive episodes of bipolar I) because of its limited efficacy and potential to destabilize mood, lead to rapid cycling, and induce mania or hypomania. Treatment options for BD include pharmacotherapy (the primary modality), psychological intervention (a useful adjunct, described later), and electroconvulsive therapy (ECT; highly worth considering in severe or treatment-resistant cases).

Continue to: For this article...

For this article, we searched PubMed and Google Scholar for guidelines for the management of bipolar disorders in adults that were published between July 2013 (when the US Food and Drug Administration [FDA] approved lurasidone for the treatment of BD) and March 2019. Related guideline-­referenced articles and clinical trials were also reviewed.

Our search identified 6 guidelines issued during the search period, developed by the:

• Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD),¹⁴
• British Association for Psychopharmacology (BAP),¹⁵
• Japanese Society of Mood Disorders (JSMD),¹⁶
• National Institute for Health and Care Excellence (NICE),¹⁷
• International College of Neuropsychopharmacology (CINP),¹⁸ and
• Royal Australian and New Zealand College of Psychiatrists.¹⁹

How to manage an episode of bipolar depression

First-line pharmacotherapeutic agents for the management of BD in acute bipolar I are listed and described in Table 2.^4-19 Compared to the number of studies and reports on the management of BD in bipolar I, few studies have been conducted that specifically examine the treatment of BD in acute bipolar II. In practice, evidence from the treatment of BD in bipolar I has been extrapolated to the treatment of bipolar II depression. CANMAT–ISBD guidelines recommend quetiapine as the only first-line therapy for BD in bipolar II; JSMD, CINP, and NICE guidelines do not make distinct recommendations for treating BD in bipolar II.

Top recommended medications for bipolar depression are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/ fluoxetine.

Patients who have BD can present de novo (ie, not taking any medication for bipolar disorder) or with a breakthrough episode while on maintenance medication(s). In either case, monotherapy for BD is preferred, although combinations of medications (Table 2^14-19) can be more effective in some cases. Treatment guidelines overlap to a high degree, especially in regard to first-line treatments, but there is variation, especially beyond first-line therapeutics.²⁰

The top recommended medications for BD are lithium, quetiapine, olanzapine, lamotrigine, and combined olanzapine/fluoxetine. FDA-approved agents for treating acute BD specifically include quetiapine, lurasidone, and combined olanzapine/fluoxetine. Guidelines generally recommend a first step of adjusting the dosage of medications in any established regimen before changing or adding other agents. If clinical improvement is not seen using any recommended medications, psychiatric referral is recommended. See Table 3^21,22 for dosing and titration guidance and highlights of both common and rare but serious adverse effects.

Continue to: Recommendations, best options for acute bipolar depression

Start with lithium, lamotrigine, quetiapine, or lurasidone as the first-line medication at the dosages given in Table 3.^21,22 Olanzapine alone, or in combination with fluoxetine, can be used when it has been determined that the medications listed above are ineffective.

Note that lithium requires regular blood monitoring (Table 3^21,22). However, lithium has the advantage of strong supporting evidence of benefit in all mood episodes of bipolar disorders (depressive, manic, hypomanic), as well as maintenance, prevention of recurrence, and anti-suicidal properties.

Also of note: Lurasidone is much more costly than other recommended medications because it is available only by brand name in the United States; the other agents are available as generics. Consider generic equivalents of the recommended agents when cost is an important factor, in part because of the impact that cost has on medication adherence for some patients.

Last, olanzapine should be used later in the treatment algorithm, unless rapid control of symptoms is needed or other first-line medications are ineffective or not tolerated—given the higher propensity of the drug to produce weight gain and cause metabolic problems, including obesity and hyperglycemia.

The importance of maintenance therapy

Almost all patients with BD require maintenance treatment to prevent subsequent episodes, reduce residual symptoms, and restore functioning and quality of life. Maintenance therapy is formulated on the basis of efficacy and tolerability in the individual patient.

Continue to: As a general rule...

Lithium has strong supporting evidence of benefit in mood episodes of all bipolar disorders.

As a general rule, the strongest evidence for preventing recurrent BD episodes favors lithium—and most guidelines therefore support lithium as first-line maintenance therapy. It is important to note, however, that if a medication (or medications) successfully aborted an acute BD episode in a given patient, that agent (or agents) should be continued for maintenance purposes to prevent or minimize future episodes—generally, at the same dosage. First-line pharmacotherapeutic agents for the maintenance of bipolar disorder, and thus to prevent subsequent episodes of BD, are listed in Table 4.^14-19

℞ antidepressantsin bipolar depression?

The use of antidepressants to treat BD remains a topic of ongoing deliberation. Antidepressant treatment of BD has historically raised concern for depressive relapse due to ineffectiveness and the ability of antidepressants to increase (1) the frequency of manic and hypomanic episodes²³ and (2) mood instability in the form of induction of mixed states or rapid cycling. Among most authorities, the recommendation against using antidepressants for BD in both bipolar I and II is the same; however, limited evidence allows the use of antidepressant monotherapy in select cases of BD episodes in bipolar II,^24,25 although not bipolar I.

The consensus in the field is that medications with mood-stabilizing effects should be considered as monotherapy before adding an antidepressant (if an antidepressant is to be added) to treat BD in bipolar II.²⁶ In other words, if an antidepressant is to be used at all, it should be combined with a mood stabilizer or atypical antipsychotic^15,27 and should probably not be used long term. The efficacy of antidepressants in treating BD in bipolar II should be assessed periodically at follow-up.

Nonpharmaceutical treatment options

Although pharmacotherapy is the mainstay of treatment of BD, adjunctive psychotherapy can be useful for treating acute BD episodes that occur during the maintenance phase of the disorder. Psychoeducation (ie, education on psychiatric illness and the importance of medication adherence), alone or in combination with interpersonal and social rhythm therapy (IPSRT), family-focused therapy (FFT), and cognitive behavioral therapy (CBT) can add to the overall efficacy of pharmacotherapy by lowering the risk of relapse and enhancing psychosocial functioning.²⁸

IPSRT is supported by what is known as the instability model, which specifies that 3 interconnected pathways trigger recurrences of a bipolar episode: stressful life events, medication nonadherence, and social-rhythm disruption. IPSRT also uses principles of interpersonal psychotherapy that are applied in treating MDD, “arguing that improvement in interpersonal relationships can ameliorate affective symptoms and prevent their return.”^29,30

Continue to: FFT

FFT focuses on communication styles between patients and their spouses and families. The goal is to improve relationship functioning. FFT is delivered to the patient and the family.

Attention to social factors. For psychotherapy to provide adequate results as an adjunct to pharmacotherapy, social stressors (eg, homelessness and financial concerns) might also need to be considered and addressed through social services or a social work consult.

NICE guidelines recommend psychological intervention (in particular, with CBT and FFT) for acute BD. CANMAT–ISBD guidelines recommend either adjunctive psychoeducation, CBT, or FFT during the maintenance phase. Again, medication is the mainstay of treatment for BD in bipolar disorders; psychotherapy has an adjunctive role—unlike the approach to treatment of MDD, in which psychotherapy can be used alone in cases of mild, or even moderate, severity.

Referral for specialty care

In the primary care setting, providers might choose to manage BD by initiating first-line pharmacotherapeutic agents or continuing established treatment regimens with necessary dosage adjustments. These patients should be monitored closely until symptoms remit.

However, it is important for the primary care provider to identify patients who need psychiatric referral. Complex presentations, severe symptoms, and poor treatment response might warrant evaluation and management by a psychiatrist. Furthermore, patients with comorbid psychotic features, catatonia, or severely debilitating depression (with or without suicidality) need referral to the emergency department.

Continue to: Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT). Patients might also need referral to Psychiatry for ECT, which is recommended by ­CANMAT–ISBD and JSMD guidelines as a second-line option; by the Royal Australian and New Zealand College of Psychiatrists as a third-line option; and by BAP for cases that are resistant to conventional treatment, with or without a high risk of suicide; in pregnancy; and in life-threatening situations.^15,31,32

Telemedicine. There is a considerable shortage of mental health care professionals.^33,34 The fact that nearly all (96%) counties in the United States have an unmet need for prescribers of mental health services (mainly psychiatrists) makes it crucial that primary care physicians be knowledgeable and prepared to manage BD—often with infrequent psychiatry consultation or, even, without psychiatry consultation. For primary care facilities that lack access to psychiatric services, telemedicine can be used as a consultative resource.

Limited evidence allows the use of antidepressant monotherapy in select cases of bipolar depressive episodes in bipolar II, although not in bipolar I.

Psychiatric consultation using telemedicine technologies has provided significant cost savings for medical centers and decreased the likelihood of hospital admission,³⁵ thereby alleviating health care costs and improving care, as shown in a rural Kansas county study.³⁶ Furthermore, the burden on emergency departments in several states has been significantly reduced with psychiatric consultations via interactive telemedicine technologies.³⁷

ACKNOWLEDGEMENT
Mark Yassa, BS, provided editing assistance.

CORRESPONDENCE
Nagy Youssef, MD, PhD, Medical College of Georgia at Augusta University, Department of Psychiatry and Health Behavior, 997 St. Sebastian Way, Augusta, GA 30912; [email protected].

Food allergy is a complex condition that has become a growing concern for parents and an increasing public health problem in the United States. Food allergy affects social interactions, school attendance, and quality of life, especially when associated with comorbid atopic conditions such as asthma, atopic dermatitis, and allergic rhinitis.^1,2 It is the major cause of anaphylaxis in children, accounting for as many as 81% of cases.³ Societal costs of food allergy are great and are spread broadly across the health care system and the family. (See “What is the cost of food allergy?”².)

What a food allergy is—and isn’t

The National Institute of Allergy and Infectious Diseases ­(NIAID) defines food allergy as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.”⁴ An adverse reaction to food or a food component that lacks an identified immunologic pathophysiology is not considered food allergy but is classified as food intolerance.⁴

The CDC estimates that 4% to 6% of children in the United States have a food allergy. Almost 40% of food-allergic children have a history of severe food-induced reactions.

Food allergy is caused by either immunoglobulin E (IgE)-mediated or non-IgE-mediated immunologic dysfunction. IgE antibodies can trigger an intense inflammatory response to certain allergens. Non-IgE-mediated food allergies are less common and not well understood.

© Joe Gorman

This article focuses only on the diagnosis and management of IgE-mediated food allergy.

The culprits

More than 170 foods have been reported to cause an IgE-­mediated reaction. Table 1^5-8 lists the 8 foods that most commonly cause allergic reactions in the United States and that account for > 50% of allergies to food.⁹ Studies vary in their methodology for estimating the prevalence of allergy to individual foods, but cow’s milk and peanuts appear to be the most common, each affecting as many as 2% to 2.5% of children.^7,8 In general, allergies to cow’s milk and to eggs are more prevalent in very young and preschool children, whereas allergies to peanuts, tree nuts, fish, and shellfish are more prevalent in older children.¹⁰ Labels on all packaged foods regulated by the US Food and Drug Administration must declare if the product contains even a trace of these 8 allergens.

How common is food allergy?

The Centers for Disease Control and Prevention (CDC) estimates that 4% to 6% of children in the United States have a food allergy.^11,12 Almost 40% of food-allergic children have a history of severe food-induced reactions.¹³ Other developed countries cite similar estimates of overall prevalence.^14,15

However, many estimates of the prevalence of food allergy are derived from self-reports, without objective data.⁹ Accurate evaluation of the prevalence of food allergy is challenging because of many factors, including differences in study methodology and the definition of allergy, geographic variation, racial and ethnic variations, and dietary exposure. Parents and children often confuse nonallergic food reactions, such as food intolerance, with food allergy. Precise determination of the prevalence and natural history of food allergy at the population level requires confirmatory oral food challenges of a representative sample of infants and young children with presumed food allergy.¹⁶

Continue to: The CDC concludes that the prevalence...

The CDC concludes that the prevalence of food allergy in children younger than 18 years increased by 18% from 1997 through 2007.^17,18 The cause of this increase is unclear but likely multifactorial; hypotheses include an increase in associated atopic conditions, delayed introduction of allergenic foods, and living in an overly sterile environment with reduced exposure to microbes.¹⁹ A recent population-based study of food allergy among children in Olmsted County, Minnesota, found that the incidence of food allergy increased between 2002 and 2007, stabilized subsequently, and appears to be declining among children 1 to 4 years of age, following a peak in 2006-2007.¹⁹

What are the risk factors?

Proposed risk factors for food allergy include demographics, genetics, a history of atopic disease, and environmental factors. Food allergy might be more common in boys than in girls, and in African Americans and Asians than in Whites.^12,16 A child is 7 times more likely to be allergic to peanuts if a parent or sibling has peanut allergy.²⁰ Infants and children with eczema or asthma are more likely to develop food allergy; the severity of eczema correlates with risk.^12,20 Improvements in hygiene in Western societies have decreased the spread of infection, but this has been accompanied by a rise in atopic disease. In countries where health standards are poor and exposure to pathogens is greater, the prevalence of allergy is low.²¹

A child is 7 times more likely to be allergic to peanuts if a parent or sibling has peanut allergy.

Conversely, increased microbial exposure might help protect against atopy via a pathway in which T-helper cells prevent pro-allergic immune development and keep harmless environmental exposures from becoming allergens.²² Attendance at daycare and exposure to farm animals early in life reduces the likelihood of atopic disease.^16,21 The presence of a dog in the home lessens the probability of egg allergy in infants.²³ Food allergy is less common in younger siblings than in first-born children, possibly due to ­younger siblings’ increased exposure to infection and alterations in the gut microbiome.^23,24

Diagnosis: Established by presentation, positive testing

Onset of symptoms after exposure to a suspected food allergen almost always occurs within 2 hours and, typically, resolves within several hours. Symptoms should occur consistently after ingestion of the food allergen. Subsequent exposures can trigger more severe symptoms, depending on the amount, route, and duration of exposure to the allergen.²⁵ Reactions typically follow ingestion or cutaneous exposures; inhalation rarely triggers a response.²⁶ IgE-mediated release of histamine and other mediators from mast cells and basophils triggers reactions that typically involve one or more organ systems (Table 2).²⁵

Cutaneous symptoms are the most common manifestations of food allergy, occurring in 70% to 80% of childhood reactions. Gastrointestinal and oral or respiratory symptoms occur in, respectively, 40% to 50% and 25% of allergic reactions to food. Cardiovascular symptoms develop in fewer than 10% of allergic reactions.²⁶

Continue to: Anaphylaxis

Anaphylaxis is a serious allergic reaction that develops rapidly and can cause death; diagnosis is based on specific criteria (Table 3).²⁷ Data for rates of anaphylaxis due to food allergy are limited. The incidence of fatal reaction due to food allergy is estimated to be 1 in every 800,000 children annually.³

Clinical suspicion. Food allergy should be suspected in infants and children who present with anaphylaxis or other symptoms (Table 2²⁵) that occur within minutes to hours of ingesting food.⁴ Parental and self-reports alone are insufficient to diagnose food allergy. NIAID guidelines recommend that patient reports of food allergy be confirmed, because multiple studies demonstrate that 50% to 90% of presumed food allergies are not true allergy.⁴ Health care providers must obtain a detailed medical history and pertinent family history, plus perform a physical exam and allergy sensitivity testing. Methods to help diagnose food allergies include skin-prick tests, allergen-specific serum IgE tests, and oral food challenges.⁴

General principles and utility of testing

Before ordering tests, it’s important to distinguish between food sensitization and food allergy and to inform the families of children with suspected food allergy about the limitations of skin-prick tests and serum IgE tests. A child with IgE antibodies specific to a food or with a positive skin-prick test, but without symptoms upon ingestion of the food, is merely sensitized; food allergy indicates the appearance of symptoms following exposure to a specific food, in addition to the detection of specific IgE antibodies or a positive skin-prick test to that same food.²⁸

Skin-prick testing. Skin-prick tests can be performed at any age. The procedure involves pricking or scratching the surface of the skin, usually the volar aspect of the forearm or the back, with a commercial extract. Testing should be performed by a physician or other provider who is properly trained in the technique and in interpreting results. The extract contains specific allergenic proteins that activate mast cells, resulting in a characteristic wheal-and-flare response that is typically measured 15 to 20 minutes after application. Some medications, such as H₁- and H₂-receptor blockers and tricyclic antidepressants, can interfere with results and need to be held for 3 to 5 days before testing.

A positive skin-prick test result is defined as a wheal ≥ 3 mm larger in diameter than the negative control. The larger the size of the wheal, the higher the likelihood of a reaction to the tested food.²⁹ Patients who exhibit dermatographism might experience a wheal-and-flare response from the action of the skin-prick test, rather than from food-specific IgE antibodies. A negative skin-prick test has > 90% negative predictive value, so the test can rule out suspected food allergy.³⁰ However, the skin-prick test alone cannot be used to diagnose food allergy because it has a high false-positive rate.

Continue to: Allergen-specific serum IgE testing

Allergen-specific serum IgE ­testing. Measurement of food-specific serum IgE levels is routinely available and requires only a blood specimen. The test can be used in patients with skin disease, and results are not affected by concurrent medications. The presence of food-specific IgE indicates that the patient is sensitized to that allergen and might react upon exposure; children with a higher level of antibody are more likely to react.²⁹

Food-specific serum IgE tests are sensitive but nonspecific for food allergy.³¹ Broad food-allergy test panels often yield false-positive results that can lead to unnecessary dietary elimination, resulting in years of inconvenience, nutrition problems, and needless health care expense.³²

It is appropriate to order tests of specific serum IgE to foods ingested within the 2 to 3–hour window before onset of symptoms to avoid broad food allergy test panels. Like skin-prick testing, positive allergen-specific serum IgE tests alone cannot diagnose food allergy.

Oral food challenge. The double-blind, placebo-controlled oral food challenge is the gold standard for the diagnosis of food allergy. Because this test is time-consuming and technically difficult, single-blind or open food challenges are more common. Oral food challenges should be performed only by a physician or other provider who can identify and treat anaphylaxis.

The presence of a dog in the home lessens the probability of egg allergy in infants.

The oral challenge starts with a very low dose of suspected food allergen, which is gradually increased every 15 to 30 minutes as vital signs are monitored carefully. Patients are observed for an allergic reaction for 1 hour after the final dose.

Continue to: A retrospective study...

A retrospective study showed that, whereas 19% of patients reacted during an open food challenge, only 2% required epinephrine.³³ Another study showed that 89% of children whose serum IgE testing was positive for specific foods were able to reintroduce those foods into the diet after a reassuring oral food challenge.³⁴

Other diagnostic tests. The basophil activation assay, measurement of total serum IgE, atopy patch tests, and intradermal tests have been used, but are not recommended, for making the diagnosis of food allergy.⁴

How can food allergy be managed?

Medical options are few. No approved treatment exists for food allergy. However, it’s important to appropriately manage acute reactions and reduce the risk of subsequent reactions.¹ Parents or other caregivers can give an H₁ antihistamine, such as diphenhydramine, to infants and children with acute non-life-threatening symptoms. More severe symptoms require rapid administration of epinephrine.¹ Auto-injectable epinephrine should be prescribed for parents and caregivers to use as needed for emergency treatment of anaphylaxis.

Team approach. A multidisciplinary approach to managing food allergy—involving physicians, school nurses, dietitians, and teachers, and using educational materials—is ideal. This strategy expands knowledge about food allergies, enhances correct administration of epinephrine, and reduces allergic reactions.¹

Avoidance of food allergens can be challenging. Parents and caregivers should be taught to interpret the list of ingredients on food packages. Self-recognition of allergic reactions reduces the likelihood of a subsequent severe allergic reaction.³⁵

Continue to: Importance of individualized care

Importance of individualized care. Health care providers should develop personalized management plans for their patients.¹ (A good place to start is with the “Food Allergy & Anaphylaxis Emergency Care Plan”^a developed by Food Allergy Research & Education [FARE]). Keep in mind that children with multiple food allergies consume less calcium and protein, and tend to be shorter⁴; therefore, it’s wise to closely monitor growth in these children and consider referral to a dietitian who is familiar with food allergy.

Potential of immunotherapy. Current research focuses on immunotherapy to induce tolerance to food allergens and protect against life-threatening allergic reactions. The goal of immunotherapy is to lessen adverse reactions to allergenic food proteins; the strategy is to have patients repeatedly ingest small but gradually increasing doses of the food allergen over many months.³⁶ Although immunotherapy has successfully allowed some patients to consume larger quantities of a food without having an allergic reaction, it is unknown whether immunotherapy provides permanent resolution of food allergy. In addition, immunotherapy often causes serious systemic and local reactions.^1,36,37

Is prevention possible?

Maternal diet during pregnancy and lactation does not affect development of food allergy in infants.^38,39 Breastfeeding might prevent development of atopic disease, but evidence is insufficient to determine whether breastfeeding reduces the likelihood of food allergy.³⁹ In nonbreastfed infants at high risk of food allergy, extensively or partially hydrolyzed formula might help protect against food allergy, compared to standard cow’s milk formula.^9,39 Feeding with soy formula rather than cow’s milk formula does not help prevent food allergy.^39,40 Pregnant and breastfeeding women should not restrict their diet as a means of preventing food allergy.³⁹

Diet in infancy. Over the years, physicians have debated the proper timing of the introduction of solid foods into the diet of infants. Traditional teaching advocated delaying introduction of potentially allergenic foods to reduce the risk of food allergy; however, this guideline was based on inconsistent evidence,⁴¹ and the strategy did not reduce the incidence of food allergy. The prevalence of food allergy is lower in developing countries where caregivers introduce foods to infants at an earlier age.²⁰

Multiple studies demonstrate that 50% to 90% of presumed food allergies are not true allergy.

A recent large clinical trial indicates that early introduction of peanut-containing foods can help prevent peanut allergy. The study randomized 4- to 11-month-old infants with severe eczema, egg allergy, or both, to eat or avoid peanut products until 5 years of age. Infants assigned to eat peanuts were 81% less likely to develop peanut allergy than infants in the avoidance group. Absolute risk reduction was 14% (number need to treat = 7).⁴² Another study showed a nonsignificant (20%) lower relative risk of food allergy in breastfed infants who were fed potentially allergenic foods starting at 3 months of age, compared to being exclusively breastfed.⁴³

Continue to: Based on these data...

Based on these data,^42,43 NIAID instituted recommendations in 2017 aimed at preventing peanut allergy⁴⁴:

• In healthy infants without known food allergy and those with mild or moderate eczema, caregivers can introduce peanut-containing foods at home with other solid foods.Parents who are anxious about a possible allergic reaction can introduce peanut products in a physician’s office.
• Infants at high risk of peanut allergy (those with severe eczema or egg allergy, or both) should undergo peanut-specific IgE or skin-prick testing:
  • Negative test: indicates low risk of a reaction to peanuts; the infant should start consuming peanut-containing foods at 4 to 6 months of age, at home or in a physician’s office, depending on the parents’ preference
  • Positive test: Referral to an allergist is recommended.

Do children outgrow food allergy?

Approximately 85% of children who have an allergy to milk, egg, soy, or wheat outgrow their allergy; however, only 15% to 20% who have an allergy to peanuts, tree nuts, fish, or shellfish eventually tolerate these foods. The time to resolution of food allergy varies with the food, and might not occur until adolescence.⁴ No test reliably predicts which children develop tolerance to any given food. A decrease in the food-specific serum IgE level or a decrease in the size of the wheal on skin-prick testing might portend the onset of tolerance to the food.⁴

CORRESPONDENCE
Catherine M. Bettcher, MD, FAAFP, Briarwood Family Medicine, 1801 Briarwood Circle, Building #10, Ann Arbor, MI 48108; [email protected].

Food allergy is a complex condition that has become a growing concern for parents and an increasing public health problem in the United States. Food allergy affects social interactions, school attendance, and quality of life, especially when associated with comorbid atopic conditions such as asthma, atopic dermatitis, and allergic rhinitis.^1,2 It is the major cause of anaphylaxis in children, accounting for as many as 81% of cases.³ Societal costs of food allergy are great and are spread broadly across the health care system and the family. (See “What is the cost of food allergy?”².)

What a food allergy is—and isn’t

The National Institute of Allergy and Infectious Diseases ­(NIAID) defines food allergy as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.”⁴ An adverse reaction to food or a food component that lacks an identified immunologic pathophysiology is not considered food allergy but is classified as food intolerance.⁴

The CDC estimates that 4% to 6% of children in the United States have a food allergy. Almost 40% of food-allergic children have a history of severe food-induced reactions.

Food allergy is caused by either immunoglobulin E (IgE)-mediated or non-IgE-mediated immunologic dysfunction. IgE antibodies can trigger an intense inflammatory response to certain allergens. Non-IgE-mediated food allergies are less common and not well understood.

© Joe Gorman

This article focuses only on the diagnosis and management of IgE-mediated food allergy.

The culprits

More than 170 foods have been reported to cause an IgE-­mediated reaction. Table 1^5-8 lists the 8 foods that most commonly cause allergic reactions in the United States and that account for > 50% of allergies to food.⁹ Studies vary in their methodology for estimating the prevalence of allergy to individual foods, but cow’s milk and peanuts appear to be the most common, each affecting as many as 2% to 2.5% of children.^7,8 In general, allergies to cow’s milk and to eggs are more prevalent in very young and preschool children, whereas allergies to peanuts, tree nuts, fish, and shellfish are more prevalent in older children.¹⁰ Labels on all packaged foods regulated by the US Food and Drug Administration must declare if the product contains even a trace of these 8 allergens.

How common is food allergy?

The Centers for Disease Control and Prevention (CDC) estimates that 4% to 6% of children in the United States have a food allergy.^11,12 Almost 40% of food-allergic children have a history of severe food-induced reactions.¹³ Other developed countries cite similar estimates of overall prevalence.^14,15

However, many estimates of the prevalence of food allergy are derived from self-reports, without objective data.⁹ Accurate evaluation of the prevalence of food allergy is challenging because of many factors, including differences in study methodology and the definition of allergy, geographic variation, racial and ethnic variations, and dietary exposure. Parents and children often confuse nonallergic food reactions, such as food intolerance, with food allergy. Precise determination of the prevalence and natural history of food allergy at the population level requires confirmatory oral food challenges of a representative sample of infants and young children with presumed food allergy.¹⁶

Continue to: The CDC concludes that the prevalence...

The CDC concludes that the prevalence of food allergy in children younger than 18 years increased by 18% from 1997 through 2007.^17,18 The cause of this increase is unclear but likely multifactorial; hypotheses include an increase in associated atopic conditions, delayed introduction of allergenic foods, and living in an overly sterile environment with reduced exposure to microbes.¹⁹ A recent population-based study of food allergy among children in Olmsted County, Minnesota, found that the incidence of food allergy increased between 2002 and 2007, stabilized subsequently, and appears to be declining among children 1 to 4 years of age, following a peak in 2006-2007.¹⁹

What are the risk factors?

Proposed risk factors for food allergy include demographics, genetics, a history of atopic disease, and environmental factors. Food allergy might be more common in boys than in girls, and in African Americans and Asians than in Whites.^12,16 A child is 7 times more likely to be allergic to peanuts if a parent or sibling has peanut allergy.²⁰ Infants and children with eczema or asthma are more likely to develop food allergy; the severity of eczema correlates with risk.^12,20 Improvements in hygiene in Western societies have decreased the spread of infection, but this has been accompanied by a rise in atopic disease. In countries where health standards are poor and exposure to pathogens is greater, the prevalence of allergy is low.²¹

A child is 7 times more likely to be allergic to peanuts if a parent or sibling has peanut allergy.

Conversely, increased microbial exposure might help protect against atopy via a pathway in which T-helper cells prevent pro-allergic immune development and keep harmless environmental exposures from becoming allergens.²² Attendance at daycare and exposure to farm animals early in life reduces the likelihood of atopic disease.^16,21 The presence of a dog in the home lessens the probability of egg allergy in infants.²³ Food allergy is less common in younger siblings than in first-born children, possibly due to ­younger siblings’ increased exposure to infection and alterations in the gut microbiome.^23,24

Diagnosis: Established by presentation, positive testing

Onset of symptoms after exposure to a suspected food allergen almost always occurs within 2 hours and, typically, resolves within several hours. Symptoms should occur consistently after ingestion of the food allergen. Subsequent exposures can trigger more severe symptoms, depending on the amount, route, and duration of exposure to the allergen.²⁵ Reactions typically follow ingestion or cutaneous exposures; inhalation rarely triggers a response.²⁶ IgE-mediated release of histamine and other mediators from mast cells and basophils triggers reactions that typically involve one or more organ systems (Table 2).²⁵

Cutaneous symptoms are the most common manifestations of food allergy, occurring in 70% to 80% of childhood reactions. Gastrointestinal and oral or respiratory symptoms occur in, respectively, 40% to 50% and 25% of allergic reactions to food. Cardiovascular symptoms develop in fewer than 10% of allergic reactions.²⁶

Continue to: Anaphylaxis

Anaphylaxis is a serious allergic reaction that develops rapidly and can cause death; diagnosis is based on specific criteria (Table 3).²⁷ Data for rates of anaphylaxis due to food allergy are limited. The incidence of fatal reaction due to food allergy is estimated to be 1 in every 800,000 children annually.³

Clinical suspicion. Food allergy should be suspected in infants and children who present with anaphylaxis or other symptoms (Table 2²⁵) that occur within minutes to hours of ingesting food.⁴ Parental and self-reports alone are insufficient to diagnose food allergy. NIAID guidelines recommend that patient reports of food allergy be confirmed, because multiple studies demonstrate that 50% to 90% of presumed food allergies are not true allergy.⁴ Health care providers must obtain a detailed medical history and pertinent family history, plus perform a physical exam and allergy sensitivity testing. Methods to help diagnose food allergies include skin-prick tests, allergen-specific serum IgE tests, and oral food challenges.⁴

General principles and utility of testing

Before ordering tests, it’s important to distinguish between food sensitization and food allergy and to inform the families of children with suspected food allergy about the limitations of skin-prick tests and serum IgE tests. A child with IgE antibodies specific to a food or with a positive skin-prick test, but without symptoms upon ingestion of the food, is merely sensitized; food allergy indicates the appearance of symptoms following exposure to a specific food, in addition to the detection of specific IgE antibodies or a positive skin-prick test to that same food.²⁸

Skin-prick testing. Skin-prick tests can be performed at any age. The procedure involves pricking or scratching the surface of the skin, usually the volar aspect of the forearm or the back, with a commercial extract. Testing should be performed by a physician or other provider who is properly trained in the technique and in interpreting results. The extract contains specific allergenic proteins that activate mast cells, resulting in a characteristic wheal-and-flare response that is typically measured 15 to 20 minutes after application. Some medications, such as H₁- and H₂-receptor blockers and tricyclic antidepressants, can interfere with results and need to be held for 3 to 5 days before testing.

A positive skin-prick test result is defined as a wheal ≥ 3 mm larger in diameter than the negative control. The larger the size of the wheal, the higher the likelihood of a reaction to the tested food.²⁹ Patients who exhibit dermatographism might experience a wheal-and-flare response from the action of the skin-prick test, rather than from food-specific IgE antibodies. A negative skin-prick test has > 90% negative predictive value, so the test can rule out suspected food allergy.³⁰ However, the skin-prick test alone cannot be used to diagnose food allergy because it has a high false-positive rate.

Continue to: Allergen-specific serum IgE testing

Allergen-specific serum IgE ­testing. Measurement of food-specific serum IgE levels is routinely available and requires only a blood specimen. The test can be used in patients with skin disease, and results are not affected by concurrent medications. The presence of food-specific IgE indicates that the patient is sensitized to that allergen and might react upon exposure; children with a higher level of antibody are more likely to react.²⁹

Food-specific serum IgE tests are sensitive but nonspecific for food allergy.³¹ Broad food-allergy test panels often yield false-positive results that can lead to unnecessary dietary elimination, resulting in years of inconvenience, nutrition problems, and needless health care expense.³²

It is appropriate to order tests of specific serum IgE to foods ingested within the 2 to 3–hour window before onset of symptoms to avoid broad food allergy test panels. Like skin-prick testing, positive allergen-specific serum IgE tests alone cannot diagnose food allergy.

Oral food challenge. The double-blind, placebo-controlled oral food challenge is the gold standard for the diagnosis of food allergy. Because this test is time-consuming and technically difficult, single-blind or open food challenges are more common. Oral food challenges should be performed only by a physician or other provider who can identify and treat anaphylaxis.

The presence of a dog in the home lessens the probability of egg allergy in infants.

The oral challenge starts with a very low dose of suspected food allergen, which is gradually increased every 15 to 30 minutes as vital signs are monitored carefully. Patients are observed for an allergic reaction for 1 hour after the final dose.

Continue to: A retrospective study...

A retrospective study showed that, whereas 19% of patients reacted during an open food challenge, only 2% required epinephrine.³³ Another study showed that 89% of children whose serum IgE testing was positive for specific foods were able to reintroduce those foods into the diet after a reassuring oral food challenge.³⁴

Other diagnostic tests. The basophil activation assay, measurement of total serum IgE, atopy patch tests, and intradermal tests have been used, but are not recommended, for making the diagnosis of food allergy.⁴

How can food allergy be managed?

Medical options are few. No approved treatment exists for food allergy. However, it’s important to appropriately manage acute reactions and reduce the risk of subsequent reactions.¹ Parents or other caregivers can give an H₁ antihistamine, such as diphenhydramine, to infants and children with acute non-life-threatening symptoms. More severe symptoms require rapid administration of epinephrine.¹ Auto-injectable epinephrine should be prescribed for parents and caregivers to use as needed for emergency treatment of anaphylaxis.

Team approach. A multidisciplinary approach to managing food allergy—involving physicians, school nurses, dietitians, and teachers, and using educational materials—is ideal. This strategy expands knowledge about food allergies, enhances correct administration of epinephrine, and reduces allergic reactions.¹

Avoidance of food allergens can be challenging. Parents and caregivers should be taught to interpret the list of ingredients on food packages. Self-recognition of allergic reactions reduces the likelihood of a subsequent severe allergic reaction.³⁵

Continue to: Importance of individualized care

Importance of individualized care. Health care providers should develop personalized management plans for their patients.¹ (A good place to start is with the “Food Allergy & Anaphylaxis Emergency Care Plan”^a developed by Food Allergy Research & Education [FARE]). Keep in mind that children with multiple food allergies consume less calcium and protein, and tend to be shorter⁴; therefore, it’s wise to closely monitor growth in these children and consider referral to a dietitian who is familiar with food allergy.

Potential of immunotherapy. Current research focuses on immunotherapy to induce tolerance to food allergens and protect against life-threatening allergic reactions. The goal of immunotherapy is to lessen adverse reactions to allergenic food proteins; the strategy is to have patients repeatedly ingest small but gradually increasing doses of the food allergen over many months.³⁶ Although immunotherapy has successfully allowed some patients to consume larger quantities of a food without having an allergic reaction, it is unknown whether immunotherapy provides permanent resolution of food allergy. In addition, immunotherapy often causes serious systemic and local reactions.^1,36,37

Is prevention possible?

Maternal diet during pregnancy and lactation does not affect development of food allergy in infants.^38,39 Breastfeeding might prevent development of atopic disease, but evidence is insufficient to determine whether breastfeeding reduces the likelihood of food allergy.³⁹ In nonbreastfed infants at high risk of food allergy, extensively or partially hydrolyzed formula might help protect against food allergy, compared to standard cow’s milk formula.^9,39 Feeding with soy formula rather than cow’s milk formula does not help prevent food allergy.^39,40 Pregnant and breastfeeding women should not restrict their diet as a means of preventing food allergy.³⁹

Diet in infancy. Over the years, physicians have debated the proper timing of the introduction of solid foods into the diet of infants. Traditional teaching advocated delaying introduction of potentially allergenic foods to reduce the risk of food allergy; however, this guideline was based on inconsistent evidence,⁴¹ and the strategy did not reduce the incidence of food allergy. The prevalence of food allergy is lower in developing countries where caregivers introduce foods to infants at an earlier age.²⁰

Multiple studies demonstrate that 50% to 90% of presumed food allergies are not true allergy.

A recent large clinical trial indicates that early introduction of peanut-containing foods can help prevent peanut allergy. The study randomized 4- to 11-month-old infants with severe eczema, egg allergy, or both, to eat or avoid peanut products until 5 years of age. Infants assigned to eat peanuts were 81% less likely to develop peanut allergy than infants in the avoidance group. Absolute risk reduction was 14% (number need to treat = 7).⁴² Another study showed a nonsignificant (20%) lower relative risk of food allergy in breastfed infants who were fed potentially allergenic foods starting at 3 months of age, compared to being exclusively breastfed.⁴³

Continue to: Based on these data...

Based on these data,^42,43 NIAID instituted recommendations in 2017 aimed at preventing peanut allergy⁴⁴:

• In healthy infants without known food allergy and those with mild or moderate eczema, caregivers can introduce peanut-containing foods at home with other solid foods.Parents who are anxious about a possible allergic reaction can introduce peanut products in a physician’s office.
• Infants at high risk of peanut allergy (those with severe eczema or egg allergy, or both) should undergo peanut-specific IgE or skin-prick testing:
  • Negative test: indicates low risk of a reaction to peanuts; the infant should start consuming peanut-containing foods at 4 to 6 months of age, at home or in a physician’s office, depending on the parents’ preference
  • Positive test: Referral to an allergist is recommended.

Do children outgrow food allergy?

Approximately 85% of children who have an allergy to milk, egg, soy, or wheat outgrow their allergy; however, only 15% to 20% who have an allergy to peanuts, tree nuts, fish, or shellfish eventually tolerate these foods. The time to resolution of food allergy varies with the food, and might not occur until adolescence.⁴ No test reliably predicts which children develop tolerance to any given food. A decrease in the food-specific serum IgE level or a decrease in the size of the wheal on skin-prick testing might portend the onset of tolerance to the food.⁴

CORRESPONDENCE
Catherine M. Bettcher, MD, FAAFP, Briarwood Family Medicine, 1801 Briarwood Circle, Building #10, Ann Arbor, MI 48108; [email protected].

Food allergy is a complex condition that has become a growing concern for parents and an increasing public health problem in the United States. Food allergy affects social interactions, school attendance, and quality of life, especially when associated with comorbid atopic conditions such as asthma, atopic dermatitis, and allergic rhinitis.^1,2 It is the major cause of anaphylaxis in children, accounting for as many as 81% of cases.³ Societal costs of food allergy are great and are spread broadly across the health care system and the family. (See “What is the cost of food allergy?”².)

What a food allergy is—and isn’t

The National Institute of Allergy and Infectious Diseases ­(NIAID) defines food allergy as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.”⁴ An adverse reaction to food or a food component that lacks an identified immunologic pathophysiology is not considered food allergy but is classified as food intolerance.⁴

The CDC estimates that 4% to 6% of children in the United States have a food allergy. Almost 40% of food-allergic children have a history of severe food-induced reactions.

Food allergy is caused by either immunoglobulin E (IgE)-mediated or non-IgE-mediated immunologic dysfunction. IgE antibodies can trigger an intense inflammatory response to certain allergens. Non-IgE-mediated food allergies are less common and not well understood.

© Joe Gorman

This article focuses only on the diagnosis and management of IgE-mediated food allergy.

The culprits

More than 170 foods have been reported to cause an IgE-­mediated reaction. Table 1^5-8 lists the 8 foods that most commonly cause allergic reactions in the United States and that account for > 50% of allergies to food.⁹ Studies vary in their methodology for estimating the prevalence of allergy to individual foods, but cow’s milk and peanuts appear to be the most common, each affecting as many as 2% to 2.5% of children.^7,8 In general, allergies to cow’s milk and to eggs are more prevalent in very young and preschool children, whereas allergies to peanuts, tree nuts, fish, and shellfish are more prevalent in older children.¹⁰ Labels on all packaged foods regulated by the US Food and Drug Administration must declare if the product contains even a trace of these 8 allergens.

How common is food allergy?

The Centers for Disease Control and Prevention (CDC) estimates that 4% to 6% of children in the United States have a food allergy.^11,12 Almost 40% of food-allergic children have a history of severe food-induced reactions.¹³ Other developed countries cite similar estimates of overall prevalence.^14,15

However, many estimates of the prevalence of food allergy are derived from self-reports, without objective data.⁹ Accurate evaluation of the prevalence of food allergy is challenging because of many factors, including differences in study methodology and the definition of allergy, geographic variation, racial and ethnic variations, and dietary exposure. Parents and children often confuse nonallergic food reactions, such as food intolerance, with food allergy. Precise determination of the prevalence and natural history of food allergy at the population level requires confirmatory oral food challenges of a representative sample of infants and young children with presumed food allergy.¹⁶

Continue to: The CDC concludes that the prevalence...

The CDC concludes that the prevalence of food allergy in children younger than 18 years increased by 18% from 1997 through 2007.^17,18 The cause of this increase is unclear but likely multifactorial; hypotheses include an increase in associated atopic conditions, delayed introduction of allergenic foods, and living in an overly sterile environment with reduced exposure to microbes.¹⁹ A recent population-based study of food allergy among children in Olmsted County, Minnesota, found that the incidence of food allergy increased between 2002 and 2007, stabilized subsequently, and appears to be declining among children 1 to 4 years of age, following a peak in 2006-2007.¹⁹

What are the risk factors?

Proposed risk factors for food allergy include demographics, genetics, a history of atopic disease, and environmental factors. Food allergy might be more common in boys than in girls, and in African Americans and Asians than in Whites.^12,16 A child is 7 times more likely to be allergic to peanuts if a parent or sibling has peanut allergy.²⁰ Infants and children with eczema or asthma are more likely to develop food allergy; the severity of eczema correlates with risk.^12,20 Improvements in hygiene in Western societies have decreased the spread of infection, but this has been accompanied by a rise in atopic disease. In countries where health standards are poor and exposure to pathogens is greater, the prevalence of allergy is low.²¹

A child is 7 times more likely to be allergic to peanuts if a parent or sibling has peanut allergy.

Conversely, increased microbial exposure might help protect against atopy via a pathway in which T-helper cells prevent pro-allergic immune development and keep harmless environmental exposures from becoming allergens.²² Attendance at daycare and exposure to farm animals early in life reduces the likelihood of atopic disease.^16,21 The presence of a dog in the home lessens the probability of egg allergy in infants.²³ Food allergy is less common in younger siblings than in first-born children, possibly due to ­younger siblings’ increased exposure to infection and alterations in the gut microbiome.^23,24

Diagnosis: Established by presentation, positive testing

Onset of symptoms after exposure to a suspected food allergen almost always occurs within 2 hours and, typically, resolves within several hours. Symptoms should occur consistently after ingestion of the food allergen. Subsequent exposures can trigger more severe symptoms, depending on the amount, route, and duration of exposure to the allergen.²⁵ Reactions typically follow ingestion or cutaneous exposures; inhalation rarely triggers a response.²⁶ IgE-mediated release of histamine and other mediators from mast cells and basophils triggers reactions that typically involve one or more organ systems (Table 2).²⁵

Cutaneous symptoms are the most common manifestations of food allergy, occurring in 70% to 80% of childhood reactions. Gastrointestinal and oral or respiratory symptoms occur in, respectively, 40% to 50% and 25% of allergic reactions to food. Cardiovascular symptoms develop in fewer than 10% of allergic reactions.²⁶

Continue to: Anaphylaxis

Anaphylaxis is a serious allergic reaction that develops rapidly and can cause death; diagnosis is based on specific criteria (Table 3).²⁷ Data for rates of anaphylaxis due to food allergy are limited. The incidence of fatal reaction due to food allergy is estimated to be 1 in every 800,000 children annually.³

Clinical suspicion. Food allergy should be suspected in infants and children who present with anaphylaxis or other symptoms (Table 2²⁵) that occur within minutes to hours of ingesting food.⁴ Parental and self-reports alone are insufficient to diagnose food allergy. NIAID guidelines recommend that patient reports of food allergy be confirmed, because multiple studies demonstrate that 50% to 90% of presumed food allergies are not true allergy.⁴ Health care providers must obtain a detailed medical history and pertinent family history, plus perform a physical exam and allergy sensitivity testing. Methods to help diagnose food allergies include skin-prick tests, allergen-specific serum IgE tests, and oral food challenges.⁴

General principles and utility of testing

Before ordering tests, it’s important to distinguish between food sensitization and food allergy and to inform the families of children with suspected food allergy about the limitations of skin-prick tests and serum IgE tests. A child with IgE antibodies specific to a food or with a positive skin-prick test, but without symptoms upon ingestion of the food, is merely sensitized; food allergy indicates the appearance of symptoms following exposure to a specific food, in addition to the detection of specific IgE antibodies or a positive skin-prick test to that same food.²⁸

Skin-prick testing. Skin-prick tests can be performed at any age. The procedure involves pricking or scratching the surface of the skin, usually the volar aspect of the forearm or the back, with a commercial extract. Testing should be performed by a physician or other provider who is properly trained in the technique and in interpreting results. The extract contains specific allergenic proteins that activate mast cells, resulting in a characteristic wheal-and-flare response that is typically measured 15 to 20 minutes after application. Some medications, such as H₁- and H₂-receptor blockers and tricyclic antidepressants, can interfere with results and need to be held for 3 to 5 days before testing.

A positive skin-prick test result is defined as a wheal ≥ 3 mm larger in diameter than the negative control. The larger the size of the wheal, the higher the likelihood of a reaction to the tested food.²⁹ Patients who exhibit dermatographism might experience a wheal-and-flare response from the action of the skin-prick test, rather than from food-specific IgE antibodies. A negative skin-prick test has > 90% negative predictive value, so the test can rule out suspected food allergy.³⁰ However, the skin-prick test alone cannot be used to diagnose food allergy because it has a high false-positive rate.

Continue to: Allergen-specific serum IgE testing

Allergen-specific serum IgE ­testing. Measurement of food-specific serum IgE levels is routinely available and requires only a blood specimen. The test can be used in patients with skin disease, and results are not affected by concurrent medications. The presence of food-specific IgE indicates that the patient is sensitized to that allergen and might react upon exposure; children with a higher level of antibody are more likely to react.²⁹

Food-specific serum IgE tests are sensitive but nonspecific for food allergy.³¹ Broad food-allergy test panels often yield false-positive results that can lead to unnecessary dietary elimination, resulting in years of inconvenience, nutrition problems, and needless health care expense.³²

It is appropriate to order tests of specific serum IgE to foods ingested within the 2 to 3–hour window before onset of symptoms to avoid broad food allergy test panels. Like skin-prick testing, positive allergen-specific serum IgE tests alone cannot diagnose food allergy.

Oral food challenge. The double-blind, placebo-controlled oral food challenge is the gold standard for the diagnosis of food allergy. Because this test is time-consuming and technically difficult, single-blind or open food challenges are more common. Oral food challenges should be performed only by a physician or other provider who can identify and treat anaphylaxis.

The presence of a dog in the home lessens the probability of egg allergy in infants.

The oral challenge starts with a very low dose of suspected food allergen, which is gradually increased every 15 to 30 minutes as vital signs are monitored carefully. Patients are observed for an allergic reaction for 1 hour after the final dose.

Continue to: A retrospective study...

A retrospective study showed that, whereas 19% of patients reacted during an open food challenge, only 2% required epinephrine.³³ Another study showed that 89% of children whose serum IgE testing was positive for specific foods were able to reintroduce those foods into the diet after a reassuring oral food challenge.³⁴

Other diagnostic tests. The basophil activation assay, measurement of total serum IgE, atopy patch tests, and intradermal tests have been used, but are not recommended, for making the diagnosis of food allergy.⁴

How can food allergy be managed?

Medical options are few. No approved treatment exists for food allergy. However, it’s important to appropriately manage acute reactions and reduce the risk of subsequent reactions.¹ Parents or other caregivers can give an H₁ antihistamine, such as diphenhydramine, to infants and children with acute non-life-threatening symptoms. More severe symptoms require rapid administration of epinephrine.¹ Auto-injectable epinephrine should be prescribed for parents and caregivers to use as needed for emergency treatment of anaphylaxis.

Team approach. A multidisciplinary approach to managing food allergy—involving physicians, school nurses, dietitians, and teachers, and using educational materials—is ideal. This strategy expands knowledge about food allergies, enhances correct administration of epinephrine, and reduces allergic reactions.¹

Avoidance of food allergens can be challenging. Parents and caregivers should be taught to interpret the list of ingredients on food packages. Self-recognition of allergic reactions reduces the likelihood of a subsequent severe allergic reaction.³⁵

Continue to: Importance of individualized care

Importance of individualized care. Health care providers should develop personalized management plans for their patients.¹ (A good place to start is with the “Food Allergy & Anaphylaxis Emergency Care Plan”^a developed by Food Allergy Research & Education [FARE]). Keep in mind that children with multiple food allergies consume less calcium and protein, and tend to be shorter⁴; therefore, it’s wise to closely monitor growth in these children and consider referral to a dietitian who is familiar with food allergy.

Potential of immunotherapy. Current research focuses on immunotherapy to induce tolerance to food allergens and protect against life-threatening allergic reactions. The goal of immunotherapy is to lessen adverse reactions to allergenic food proteins; the strategy is to have patients repeatedly ingest small but gradually increasing doses of the food allergen over many months.³⁶ Although immunotherapy has successfully allowed some patients to consume larger quantities of a food without having an allergic reaction, it is unknown whether immunotherapy provides permanent resolution of food allergy. In addition, immunotherapy often causes serious systemic and local reactions.^1,36,37

Is prevention possible?

Maternal diet during pregnancy and lactation does not affect development of food allergy in infants.^38,39 Breastfeeding might prevent development of atopic disease, but evidence is insufficient to determine whether breastfeeding reduces the likelihood of food allergy.³⁹ In nonbreastfed infants at high risk of food allergy, extensively or partially hydrolyzed formula might help protect against food allergy, compared to standard cow’s milk formula.^9,39 Feeding with soy formula rather than cow’s milk formula does not help prevent food allergy.^39,40 Pregnant and breastfeeding women should not restrict their diet as a means of preventing food allergy.³⁹

Diet in infancy. Over the years, physicians have debated the proper timing of the introduction of solid foods into the diet of infants. Traditional teaching advocated delaying introduction of potentially allergenic foods to reduce the risk of food allergy; however, this guideline was based on inconsistent evidence,⁴¹ and the strategy did not reduce the incidence of food allergy. The prevalence of food allergy is lower in developing countries where caregivers introduce foods to infants at an earlier age.²⁰

Multiple studies demonstrate that 50% to 90% of presumed food allergies are not true allergy.

A recent large clinical trial indicates that early introduction of peanut-containing foods can help prevent peanut allergy. The study randomized 4- to 11-month-old infants with severe eczema, egg allergy, or both, to eat or avoid peanut products until 5 years of age. Infants assigned to eat peanuts were 81% less likely to develop peanut allergy than infants in the avoidance group. Absolute risk reduction was 14% (number need to treat = 7).⁴² Another study showed a nonsignificant (20%) lower relative risk of food allergy in breastfed infants who were fed potentially allergenic foods starting at 3 months of age, compared to being exclusively breastfed.⁴³

Continue to: Based on these data...

Based on these data,^42,43 NIAID instituted recommendations in 2017 aimed at preventing peanut allergy⁴⁴:

• In healthy infants without known food allergy and those with mild or moderate eczema, caregivers can introduce peanut-containing foods at home with other solid foods.Parents who are anxious about a possible allergic reaction can introduce peanut products in a physician’s office.
• Infants at high risk of peanut allergy (those with severe eczema or egg allergy, or both) should undergo peanut-specific IgE or skin-prick testing:
  • Negative test: indicates low risk of a reaction to peanuts; the infant should start consuming peanut-containing foods at 4 to 6 months of age, at home or in a physician’s office, depending on the parents’ preference
  • Positive test: Referral to an allergist is recommended.

Do children outgrow food allergy?

Approximately 85% of children who have an allergy to milk, egg, soy, or wheat outgrow their allergy; however, only 15% to 20% who have an allergy to peanuts, tree nuts, fish, or shellfish eventually tolerate these foods. The time to resolution of food allergy varies with the food, and might not occur until adolescence.⁴ No test reliably predicts which children develop tolerance to any given food. A decrease in the food-specific serum IgE level or a decrease in the size of the wheal on skin-prick testing might portend the onset of tolerance to the food.⁴

CORRESPONDENCE
Catherine M. Bettcher, MD, FAAFP, Briarwood Family Medicine, 1801 Briarwood Circle, Building #10, Ann Arbor, MI 48108; [email protected].

Wernicke-Korsakoff syndrome is a cluster of symptoms attributed to a disorder of vitamin B1 (thiamine) deficiency, manifesting as a combined presentation of alcohol-induced Wernicke encephalopathy (WE) and Korsakoff syndrome (KS).¹ While there is consensus on the characteristic presentation and symptoms of WE, there is a lack of agreement on the exact definition of KS. The classic triad describing WE consists of ataxia, ophthalmoplegia, and confusion; however, reports now suggest that a majority of patients exhibit only 1 or 2 of the elements of the triad. KS is often seen as a condition of chronic thiamine deficiency manifesting as memory impairment alongside a cognitive and behavioral decline, with no clear consensus on the sequence of appearance of symptoms. The typical relationship is thought to be a progression of WE to KS if untreated.

From a mental health perspective, WE presents with delirium and confusion whereas KS manifests with irreversible dementia and a cognitive deterioration. Though it is commonly taught that KS-induced memory loss is permanent due to neuronal damage (classically identified as damage to the mammillary bodies - though other structures have been implicated as well), more recent research suggest otherwise.² A review published in 2018, for example, gathered several case reports and case series that suggest significant improvement in memory and cognition attributed to behavioral and pharmacologic interventions, indicating this as an area deserving of further study.³ About 20% of patients diagnosed with WE by autopsy exhibited none of the classical triad symptoms prior to death.⁴ Hence, these conditions are surmised to be significantly underdiagnosed and misdiagnosed.

Though consensus regarding the appropriate treatment regimen is lacking for WE, a common protocol consists of high-dose parenteral thiamine for 4 to 7 days.⁵ This is usually followed by daily oral thiamine repletion until the patient either achieves complete abstinence from alcohol (ideal) or decreases consumption. The goal is to allow thiamine stores to replete and maintain at minimum required body levels moving forward. In this case report, we highlight the utilization of a long-term, unconventional intramuscular (IM) thiamine repletion regimen to ensure maintenance of a patient’s mental status, highlighting discrepancies in our understanding of the mechanisms at play in WE and its treatment.

Case Presentation

A 65-year-old male patient with a more than 3-decade history of daily hard liquor intake, multiple psychiatric hospitalizations for WE, and a prior suicide attempt, presented to the emergency department (ED) with increased frequency of falls, poor oral intake, confabulation, and diminished verbal communication. A chart review revealed memory impairment alongside the diagnoses of schizoaffective disorder and WE, and confusion that was responsive to thiamine administration as well as a history of hypertension, hyperlipidemia, osteoarthritis, and urinary retention secondary to benign prostatic hyperplasia (BPH).

On examination the patient was found to be disoriented with a clouded sensorium. While the history of heavy daily alcohol use was clear in the chart and confirmed by other sources, it appeared unlikely that the patient had been using alcohol in the preceding month due to restricted access in his most recent living environment (a shared apartment with daily nursing assistance). He reported no lightheadedness, dizziness, palpitations, numbness, tingling, or any head trauma. He also negated the presence of active mood symptoms, auditory or visual hallucinations or suicidal ideation (SI)

The patient was admitted to the Internal Medicine Service and received a workup for the causes of delirium, including consideration of normal pressure hydrocephalus (NPH) and other neurologic conditions. Laboratory tests including a comprehensive metabolic panel, thyroid stimulating hormone, urinalysis, urine toxicology screen, and vitamin B12 and folate levels were in normal ranges. Although brain imaging revealed enlarged ventricles, NPH was considered unlikely because of the absence of ophthalmologic abnormalities, like gaze nystagmus, and urinary incontinence; conversely, there was some presence of urinary retention attributed to BPH and required an admission a few months prior. Moreover, magnetic resonance images showed that the ventricles were enlarged slightly out of proportion to the sulci, which can be seen with predominantly central volume loss compared with the pattern typically seen in NPH.

In light of concern for WE and the patient's history, treatment with IV thiamine and IV fluids was initiated and the Liaison Psychiatry Service was consulted for cognitive disability and treatment of his mood. Administration of IV thiamine rapidly restored his sensorium, but he became abruptly disorganized as the IV regimen graduated to an oral thiamine dose of 200 mg 3 times daily. Simultaneously, as medical stabilization was achieved, the patient was transferred to the inpatient psychiatry unit to address the nonresolving cognitive impairment and behavioral disorganization. This specifically involved newly emerging, impulsive, self-harming behaviors like throwing himself on the ground and banging his head on the floor. Such behaviors along with paucity of speech and decreased oral intake, ultimately warranted constant observation, which led to a decrease in self-harming activity. All this behavior was noted even though the patient was adherent to oral administration of thiamine. Throughout this time, the patient underwent several transfers back and forth between the Psychiatry and Internal Medicine services due to ongoing concern for the possibility of delirium or WE. However, the Neurology and Internal Medicine services did not feel that WE would explain the patient’s mental and behavioral status, in part due to his ongoing adherence with daily oral thiamine dosing that was not associated with improvement in mental status.

Recollecting the patient’s improvement with the parenteral thiamine regimen (IV and IM), the psychiatry unit tried a thiamine regimen of 200 mg IM and 100 mg oral 2 times daily. After about 2 weeks on this regimen, the patient subsequently achieved remarkable improvement in his cognitive and behavioral status, with resolution of selfharming behaviors. The patient was noted to be calmer, more linear, and more oriented, though he remained incompletely oriented throughout his hospitalization. As improvement in sensorium was established and the patient’s hospital stay prolonged (Figure), his mood symptoms began manifesting as guilt, low energy, decreased appetite, withdrawal, and passive SI. This was followed by a trial of lithium that was discontinued due to elevated creatine levels. As the patient continued to report depression, a multidrug regimen of divalproex, fluoxetine, and quetiapine was administered, which lead to remarkable improvement.

At this time, it was concluded that the stores of thiamine in the patient’s body may have been replenished, the alcohol intake completely ceased and that he needed to be weaned off of thiamine. The next step taken was reduction of the twice daily 200 mg IM thiamine dose to a once daily regimen, and oral thiamine was put on hold. Over the next 48 hours, the patient became less verbal, more withdrawn, incontinent of urine, and delirious. The twice daily IM 200 mg thiamine was restarted, but this time the patient demonstrated very slow improvement. After 2 weeks, the IM thiamine 200 mg was increased to 3 times daily, and the patient showed marked improvement in recall, mood, and effect.

Several attempts were made to reduce the IM thiamine burden on the patient and/ or transition to an exclusively oral regimen. However, he rapidly decompensated within hours of each attempt to taper the IM dose and required immediate reinstation. On the IM thiamine regimen, he eventually appeared to reach a stable cognitive and affective baseline marked by incomplete orientation but pleasant affect, he reported no mood complaints, behavioral stability, and an ability to comply with care needs and have simple conversations. Some speech content remained disorganized particularly if engaged beyond simple exchanges.

The patient was discharged to a skilled nursing facility after a month of 3 times daily IM administration of thiamine. Within the next 24 hours, the patient returned to the ED with the originally reported symptoms of ataxia, agitation, and confusion. On inquiry, it was revealed that the ordered vials of IM thiamine for injection had not arrived with him at the nursing facility and he had missed 2 doses. The blood laboratory results, scans, and all other parameters were otherwise found to be normal and the patient was adherent to his prescribed antipsychotics and antidepressants. As anticipated, restoration of the IM thiamine regimen revived his baseline within hours. While confusion and delirium resolved completely with treatment, the memory impairments persisted. This patient has been administered a 3 times daily IM dose of 200 mg thiamine for more than 2 years with a stable cognitive clinical picture.

Discussion

According to data from the 2016 National Survey on Drug Use and Health, 16 million individuals in the US aged ≥ 12 years reported heavy alcohol use, which is defined as binge drinking on ≥ 5 days in the past month.6,7 Thiamine deficiency is an alcoholrelated disorder that is frequently encountered in hospital settings. This deficiency can also occur in the context of malabsorption, malnutrition, a prolonged course of vomiting, and bariatric surgery.^8,9

The deficiency in thiamine, which is sometimes known as WE, manifests rarely with all 3 of the classic triad of gait disturbances, abnormal eye movements, and mental status changes, with only 16.5% of patients displaying all of the triad.⁴ Moreover, there may be additional symptoms not listed in this triad, such as memory impairment, bilateral sixth nerve palsy, ptosis, hypotension, and hypothermia.^10.11 This inconsistent presentation makes the diagnosis challenging and therefore requires a higher threshold for suspicion. If undiagnosed and/or untreated, WE can lead to chronic thiamine deficiency causing permanent brain damage in the guise of KS. This further increases the importance of timely diagnosis and treatment.

Our case highlights the utilization of an unconventional thiamine regimen that appeared to be temporally associated with mental status improvement. The patient’s clouded sensorium and confusion could not be attributed to metabolic, encephalopathic, or infectious pathologies due to the absence of supportive laboratory evidence. He responded to IV and IM doses of thiamine, but repeated attempts to taper the IM doses with the objective of transitioning to oral thiamine supplementation were followed by immediate decompensations in mental status. This was atypical of WE as the patient seemed adequately replete with thiamine, and missing a few doses should not be enough to deplete his stores. Thus, reflecting a unique case of thiamine-dependent chronically set WE when even a single missed dose of thiamine adversely affected the patient’s cognitive baseline. Interesting to note is this patient’s memory issue, as evident by clinical examination and dating back at least 5 years as per chart review. This premature amnestic component of his presentation indicates a likely parallel running KS component of his presentation. Conversely, the patient’s long history of alcohol use disorder, prior episodes of WE, and ideal response achieved only on parenteral thiamine repletion further supported the diagnosis of WE and our impression of the scenario.

Even though this patient had prior episodes of WE, there remained diagnostic uncertainty regarding his altered mental status for some time before the nonoral thiamine repletion treatment was implemented. Particularly in this admission, the patient’s mental status frequently waxed and waned and there was the additional confusion of whether a potential psychiatric etiology contributed to some of the elements of his presentation, such as his impulsive self-harm behaviors. This behavior led to recurrent transfers among the Psychiatry Service, Internal Medicine Service, and the ED.

The patient’s presentation did not reflect the classical triad of WE, and while this is consistent with the majority of clinical manifestations, various services were reluctant to attribute his symptoms to WE. Once the threshold of suspicion of thiamine deficiency was lowered and the deficit treated more aggressively, the patient seemed to improve tremendously. Presence of memory problems and confabulation, both of which this patient exhibited, are suggestive of KS and are not expected to recover with treatment, yet for this patient there did seem to be some improvement—though not complete resolution. This is consistent with newer evidence suggesting that some recovery from the deficits seen in KS is possible.³

Once diagnosed, the treatment objective is the replenishment of thiamine stores and optimization of the metabolic scenario of the body to prevent recurrence. For acute WE symptoms, many regimens call for 250 to 500 mg of IV thiamine supplementation 2 to 3 times daily for 3 to 5 days. High dose IV thiamine (≥ 500 mg daily) has been proposed to be efficacious and free of considerable adverse effects.¹² A study conducted at the University of North Carolina described thiamine prescribing practices in a large academic hospital, analyzing data with the objective of assessing outcomes of ordering high-dose IV thiamine (HDIV, ≥ 200 mg IV twice daily) to patients with encephalopathy. ¹³ The researchers concluded that HDIV, even though rarely prescribed, was associated with decreased inpatient mortality in bivariable models. However, in multivariable analyses this decrease was found to be clinically insignificant. Our patient benefitted from both IV and IM delivery.

Ideally, after the initial IV thiamine dose, oral administration of thiamine 250 to 1,000 mg is continued until a reduction, if not abstinence, from alcohol use is achieved.⁵ Many patients are discharged on an oral maintenance dose of thiamine 100 mg. Oral thiamine is poorly absorbed and less effective in both prophylaxis and treatment of newly diagnosed WE; therefore, it is typically used only after IM or IV replenishment. It remains unclear why this patient required IM thiamine multiple times per day to maintain his mental status, and why he would present with selfinjurious behaviors after missing doses. The patient’s response can be attributed to late-onset defects in oral thiamine absorption at the carrier protein level of the brush border and basolateral membranes of his jejunum; however, an invasive procedure like a jejunal biopsy to establish the definitive etiology was neither necessary nor practical once treatment response was observed. ¹⁴ Other possible explanations include rapid thiamine metabolism, poor gastrointestinal absorption and a late-onset deficit in the thiamine diffusion mechanisms, and active transport systems (thiamine utilization depends on active transport in low availability states and passive transport when readily available). The nature of these mechanisms deserves further study. Less data have been reported on the administration and utility of IM thiamine for chronic WE; hence, our case report is one of the first illustrating the role of this method for sustained repletion.

Conclusions

This case presented a clinical dilemma because the conventional treatment regimen for WE didn’t yield the desired outcome until the mode and duration of thiamine administration were adjusted. It illustrates the utility of a sustained intensive thiamine regimen irrespective of sobriety status, as opposed to the traditional regimen of parenteral (primarily IV) thiamine for 3 to 7 days, followed by oral repletion until the patient achieves sustained abstinence. In this patient’s case, access to nursing care postdischarge facilitated his continued adherence to IM thiamine therapy.

The longitudinal time course of this case suggests a relationship between this route of administration and improvement in symptom burden and indicates that this patient may have a long-term need for IM thiamine to maintain his baseline mental status. Of great benefit in such patients would be the availability of a long-acting IM thiamine therapy. Risk of overdose is unlikely due to the water solubility of B group vitamins.

This case report highlights the importance of setting a high clinical suspicion for WE due to its ever-increasing incidence in these times. We also wish to direct researchers to consider other out-of-the-box treatment options in case of failure of the conventional regime. In documenting this patient report, we invite more medical providers to investigate and explore other therapeutic options for WE treatment with the aim of decreasing both morbidity and mortality secondary to the condition.

Wernicke-Korsakoff syndrome is a cluster of symptoms attributed to a disorder of vitamin B1 (thiamine) deficiency, manifesting as a combined presentation of alcohol-induced Wernicke encephalopathy (WE) and Korsakoff syndrome (KS).¹ While there is consensus on the characteristic presentation and symptoms of WE, there is a lack of agreement on the exact definition of KS. The classic triad describing WE consists of ataxia, ophthalmoplegia, and confusion; however, reports now suggest that a majority of patients exhibit only 1 or 2 of the elements of the triad. KS is often seen as a condition of chronic thiamine deficiency manifesting as memory impairment alongside a cognitive and behavioral decline, with no clear consensus on the sequence of appearance of symptoms. The typical relationship is thought to be a progression of WE to KS if untreated.

From a mental health perspective, WE presents with delirium and confusion whereas KS manifests with irreversible dementia and a cognitive deterioration. Though it is commonly taught that KS-induced memory loss is permanent due to neuronal damage (classically identified as damage to the mammillary bodies - though other structures have been implicated as well), more recent research suggest otherwise.² A review published in 2018, for example, gathered several case reports and case series that suggest significant improvement in memory and cognition attributed to behavioral and pharmacologic interventions, indicating this as an area deserving of further study.³ About 20% of patients diagnosed with WE by autopsy exhibited none of the classical triad symptoms prior to death.⁴ Hence, these conditions are surmised to be significantly underdiagnosed and misdiagnosed.

Though consensus regarding the appropriate treatment regimen is lacking for WE, a common protocol consists of high-dose parenteral thiamine for 4 to 7 days.⁵ This is usually followed by daily oral thiamine repletion until the patient either achieves complete abstinence from alcohol (ideal) or decreases consumption. The goal is to allow thiamine stores to replete and maintain at minimum required body levels moving forward. In this case report, we highlight the utilization of a long-term, unconventional intramuscular (IM) thiamine repletion regimen to ensure maintenance of a patient’s mental status, highlighting discrepancies in our understanding of the mechanisms at play in WE and its treatment.

Case Presentation

A 65-year-old male patient with a more than 3-decade history of daily hard liquor intake, multiple psychiatric hospitalizations for WE, and a prior suicide attempt, presented to the emergency department (ED) with increased frequency of falls, poor oral intake, confabulation, and diminished verbal communication. A chart review revealed memory impairment alongside the diagnoses of schizoaffective disorder and WE, and confusion that was responsive to thiamine administration as well as a history of hypertension, hyperlipidemia, osteoarthritis, and urinary retention secondary to benign prostatic hyperplasia (BPH).

On examination the patient was found to be disoriented with a clouded sensorium. While the history of heavy daily alcohol use was clear in the chart and confirmed by other sources, it appeared unlikely that the patient had been using alcohol in the preceding month due to restricted access in his most recent living environment (a shared apartment with daily nursing assistance). He reported no lightheadedness, dizziness, palpitations, numbness, tingling, or any head trauma. He also negated the presence of active mood symptoms, auditory or visual hallucinations or suicidal ideation (SI)

The patient was admitted to the Internal Medicine Service and received a workup for the causes of delirium, including consideration of normal pressure hydrocephalus (NPH) and other neurologic conditions. Laboratory tests including a comprehensive metabolic panel, thyroid stimulating hormone, urinalysis, urine toxicology screen, and vitamin B12 and folate levels were in normal ranges. Although brain imaging revealed enlarged ventricles, NPH was considered unlikely because of the absence of ophthalmologic abnormalities, like gaze nystagmus, and urinary incontinence; conversely, there was some presence of urinary retention attributed to BPH and required an admission a few months prior. Moreover, magnetic resonance images showed that the ventricles were enlarged slightly out of proportion to the sulci, which can be seen with predominantly central volume loss compared with the pattern typically seen in NPH.

In light of concern for WE and the patient's history, treatment with IV thiamine and IV fluids was initiated and the Liaison Psychiatry Service was consulted for cognitive disability and treatment of his mood. Administration of IV thiamine rapidly restored his sensorium, but he became abruptly disorganized as the IV regimen graduated to an oral thiamine dose of 200 mg 3 times daily. Simultaneously, as medical stabilization was achieved, the patient was transferred to the inpatient psychiatry unit to address the nonresolving cognitive impairment and behavioral disorganization. This specifically involved newly emerging, impulsive, self-harming behaviors like throwing himself on the ground and banging his head on the floor. Such behaviors along with paucity of speech and decreased oral intake, ultimately warranted constant observation, which led to a decrease in self-harming activity. All this behavior was noted even though the patient was adherent to oral administration of thiamine. Throughout this time, the patient underwent several transfers back and forth between the Psychiatry and Internal Medicine services due to ongoing concern for the possibility of delirium or WE. However, the Neurology and Internal Medicine services did not feel that WE would explain the patient’s mental and behavioral status, in part due to his ongoing adherence with daily oral thiamine dosing that was not associated with improvement in mental status.

Recollecting the patient’s improvement with the parenteral thiamine regimen (IV and IM), the psychiatry unit tried a thiamine regimen of 200 mg IM and 100 mg oral 2 times daily. After about 2 weeks on this regimen, the patient subsequently achieved remarkable improvement in his cognitive and behavioral status, with resolution of selfharming behaviors. The patient was noted to be calmer, more linear, and more oriented, though he remained incompletely oriented throughout his hospitalization. As improvement in sensorium was established and the patient’s hospital stay prolonged (Figure), his mood symptoms began manifesting as guilt, low energy, decreased appetite, withdrawal, and passive SI. This was followed by a trial of lithium that was discontinued due to elevated creatine levels. As the patient continued to report depression, a multidrug regimen of divalproex, fluoxetine, and quetiapine was administered, which lead to remarkable improvement.

At this time, it was concluded that the stores of thiamine in the patient’s body may have been replenished, the alcohol intake completely ceased and that he needed to be weaned off of thiamine. The next step taken was reduction of the twice daily 200 mg IM thiamine dose to a once daily regimen, and oral thiamine was put on hold. Over the next 48 hours, the patient became less verbal, more withdrawn, incontinent of urine, and delirious. The twice daily IM 200 mg thiamine was restarted, but this time the patient demonstrated very slow improvement. After 2 weeks, the IM thiamine 200 mg was increased to 3 times daily, and the patient showed marked improvement in recall, mood, and effect.

Several attempts were made to reduce the IM thiamine burden on the patient and/ or transition to an exclusively oral regimen. However, he rapidly decompensated within hours of each attempt to taper the IM dose and required immediate reinstation. On the IM thiamine regimen, he eventually appeared to reach a stable cognitive and affective baseline marked by incomplete orientation but pleasant affect, he reported no mood complaints, behavioral stability, and an ability to comply with care needs and have simple conversations. Some speech content remained disorganized particularly if engaged beyond simple exchanges.

The patient was discharged to a skilled nursing facility after a month of 3 times daily IM administration of thiamine. Within the next 24 hours, the patient returned to the ED with the originally reported symptoms of ataxia, agitation, and confusion. On inquiry, it was revealed that the ordered vials of IM thiamine for injection had not arrived with him at the nursing facility and he had missed 2 doses. The blood laboratory results, scans, and all other parameters were otherwise found to be normal and the patient was adherent to his prescribed antipsychotics and antidepressants. As anticipated, restoration of the IM thiamine regimen revived his baseline within hours. While confusion and delirium resolved completely with treatment, the memory impairments persisted. This patient has been administered a 3 times daily IM dose of 200 mg thiamine for more than 2 years with a stable cognitive clinical picture.

Discussion

According to data from the 2016 National Survey on Drug Use and Health, 16 million individuals in the US aged ≥ 12 years reported heavy alcohol use, which is defined as binge drinking on ≥ 5 days in the past month.6,7 Thiamine deficiency is an alcoholrelated disorder that is frequently encountered in hospital settings. This deficiency can also occur in the context of malabsorption, malnutrition, a prolonged course of vomiting, and bariatric surgery.^8,9

The deficiency in thiamine, which is sometimes known as WE, manifests rarely with all 3 of the classic triad of gait disturbances, abnormal eye movements, and mental status changes, with only 16.5% of patients displaying all of the triad.⁴ Moreover, there may be additional symptoms not listed in this triad, such as memory impairment, bilateral sixth nerve palsy, ptosis, hypotension, and hypothermia.^10.11 This inconsistent presentation makes the diagnosis challenging and therefore requires a higher threshold for suspicion. If undiagnosed and/or untreated, WE can lead to chronic thiamine deficiency causing permanent brain damage in the guise of KS. This further increases the importance of timely diagnosis and treatment.

Our case highlights the utilization of an unconventional thiamine regimen that appeared to be temporally associated with mental status improvement. The patient’s clouded sensorium and confusion could not be attributed to metabolic, encephalopathic, or infectious pathologies due to the absence of supportive laboratory evidence. He responded to IV and IM doses of thiamine, but repeated attempts to taper the IM doses with the objective of transitioning to oral thiamine supplementation were followed by immediate decompensations in mental status. This was atypical of WE as the patient seemed adequately replete with thiamine, and missing a few doses should not be enough to deplete his stores. Thus, reflecting a unique case of thiamine-dependent chronically set WE when even a single missed dose of thiamine adversely affected the patient’s cognitive baseline. Interesting to note is this patient’s memory issue, as evident by clinical examination and dating back at least 5 years as per chart review. This premature amnestic component of his presentation indicates a likely parallel running KS component of his presentation. Conversely, the patient’s long history of alcohol use disorder, prior episodes of WE, and ideal response achieved only on parenteral thiamine repletion further supported the diagnosis of WE and our impression of the scenario.

Even though this patient had prior episodes of WE, there remained diagnostic uncertainty regarding his altered mental status for some time before the nonoral thiamine repletion treatment was implemented. Particularly in this admission, the patient’s mental status frequently waxed and waned and there was the additional confusion of whether a potential psychiatric etiology contributed to some of the elements of his presentation, such as his impulsive self-harm behaviors. This behavior led to recurrent transfers among the Psychiatry Service, Internal Medicine Service, and the ED.

The patient’s presentation did not reflect the classical triad of WE, and while this is consistent with the majority of clinical manifestations, various services were reluctant to attribute his symptoms to WE. Once the threshold of suspicion of thiamine deficiency was lowered and the deficit treated more aggressively, the patient seemed to improve tremendously. Presence of memory problems and confabulation, both of which this patient exhibited, are suggestive of KS and are not expected to recover with treatment, yet for this patient there did seem to be some improvement—though not complete resolution. This is consistent with newer evidence suggesting that some recovery from the deficits seen in KS is possible.³

Once diagnosed, the treatment objective is the replenishment of thiamine stores and optimization of the metabolic scenario of the body to prevent recurrence. For acute WE symptoms, many regimens call for 250 to 500 mg of IV thiamine supplementation 2 to 3 times daily for 3 to 5 days. High dose IV thiamine (≥ 500 mg daily) has been proposed to be efficacious and free of considerable adverse effects.¹² A study conducted at the University of North Carolina described thiamine prescribing practices in a large academic hospital, analyzing data with the objective of assessing outcomes of ordering high-dose IV thiamine (HDIV, ≥ 200 mg IV twice daily) to patients with encephalopathy. ¹³ The researchers concluded that HDIV, even though rarely prescribed, was associated with decreased inpatient mortality in bivariable models. However, in multivariable analyses this decrease was found to be clinically insignificant. Our patient benefitted from both IV and IM delivery.

Ideally, after the initial IV thiamine dose, oral administration of thiamine 250 to 1,000 mg is continued until a reduction, if not abstinence, from alcohol use is achieved.⁵ Many patients are discharged on an oral maintenance dose of thiamine 100 mg. Oral thiamine is poorly absorbed and less effective in both prophylaxis and treatment of newly diagnosed WE; therefore, it is typically used only after IM or IV replenishment. It remains unclear why this patient required IM thiamine multiple times per day to maintain his mental status, and why he would present with selfinjurious behaviors after missing doses. The patient’s response can be attributed to late-onset defects in oral thiamine absorption at the carrier protein level of the brush border and basolateral membranes of his jejunum; however, an invasive procedure like a jejunal biopsy to establish the definitive etiology was neither necessary nor practical once treatment response was observed. ¹⁴ Other possible explanations include rapid thiamine metabolism, poor gastrointestinal absorption and a late-onset deficit in the thiamine diffusion mechanisms, and active transport systems (thiamine utilization depends on active transport in low availability states and passive transport when readily available). The nature of these mechanisms deserves further study. Less data have been reported on the administration and utility of IM thiamine for chronic WE; hence, our case report is one of the first illustrating the role of this method for sustained repletion.

Conclusions

This case presented a clinical dilemma because the conventional treatment regimen for WE didn’t yield the desired outcome until the mode and duration of thiamine administration were adjusted. It illustrates the utility of a sustained intensive thiamine regimen irrespective of sobriety status, as opposed to the traditional regimen of parenteral (primarily IV) thiamine for 3 to 7 days, followed by oral repletion until the patient achieves sustained abstinence. In this patient’s case, access to nursing care postdischarge facilitated his continued adherence to IM thiamine therapy.

The longitudinal time course of this case suggests a relationship between this route of administration and improvement in symptom burden and indicates that this patient may have a long-term need for IM thiamine to maintain his baseline mental status. Of great benefit in such patients would be the availability of a long-acting IM thiamine therapy. Risk of overdose is unlikely due to the water solubility of B group vitamins.

This case report highlights the importance of setting a high clinical suspicion for WE due to its ever-increasing incidence in these times. We also wish to direct researchers to consider other out-of-the-box treatment options in case of failure of the conventional regime. In documenting this patient report, we invite more medical providers to investigate and explore other therapeutic options for WE treatment with the aim of decreasing both morbidity and mortality secondary to the condition.

Wernicke-Korsakoff syndrome is a cluster of symptoms attributed to a disorder of vitamin B1 (thiamine) deficiency, manifesting as a combined presentation of alcohol-induced Wernicke encephalopathy (WE) and Korsakoff syndrome (KS).¹ While there is consensus on the characteristic presentation and symptoms of WE, there is a lack of agreement on the exact definition of KS. The classic triad describing WE consists of ataxia, ophthalmoplegia, and confusion; however, reports now suggest that a majority of patients exhibit only 1 or 2 of the elements of the triad. KS is often seen as a condition of chronic thiamine deficiency manifesting as memory impairment alongside a cognitive and behavioral decline, with no clear consensus on the sequence of appearance of symptoms. The typical relationship is thought to be a progression of WE to KS if untreated.

From a mental health perspective, WE presents with delirium and confusion whereas KS manifests with irreversible dementia and a cognitive deterioration. Though it is commonly taught that KS-induced memory loss is permanent due to neuronal damage (classically identified as damage to the mammillary bodies - though other structures have been implicated as well), more recent research suggest otherwise.² A review published in 2018, for example, gathered several case reports and case series that suggest significant improvement in memory and cognition attributed to behavioral and pharmacologic interventions, indicating this as an area deserving of further study.³ About 20% of patients diagnosed with WE by autopsy exhibited none of the classical triad symptoms prior to death.⁴ Hence, these conditions are surmised to be significantly underdiagnosed and misdiagnosed.

Though consensus regarding the appropriate treatment regimen is lacking for WE, a common protocol consists of high-dose parenteral thiamine for 4 to 7 days.⁵ This is usually followed by daily oral thiamine repletion until the patient either achieves complete abstinence from alcohol (ideal) or decreases consumption. The goal is to allow thiamine stores to replete and maintain at minimum required body levels moving forward. In this case report, we highlight the utilization of a long-term, unconventional intramuscular (IM) thiamine repletion regimen to ensure maintenance of a patient’s mental status, highlighting discrepancies in our understanding of the mechanisms at play in WE and its treatment.

Case Presentation

A 65-year-old male patient with a more than 3-decade history of daily hard liquor intake, multiple psychiatric hospitalizations for WE, and a prior suicide attempt, presented to the emergency department (ED) with increased frequency of falls, poor oral intake, confabulation, and diminished verbal communication. A chart review revealed memory impairment alongside the diagnoses of schizoaffective disorder and WE, and confusion that was responsive to thiamine administration as well as a history of hypertension, hyperlipidemia, osteoarthritis, and urinary retention secondary to benign prostatic hyperplasia (BPH).

On examination the patient was found to be disoriented with a clouded sensorium. While the history of heavy daily alcohol use was clear in the chart and confirmed by other sources, it appeared unlikely that the patient had been using alcohol in the preceding month due to restricted access in his most recent living environment (a shared apartment with daily nursing assistance). He reported no lightheadedness, dizziness, palpitations, numbness, tingling, or any head trauma. He also negated the presence of active mood symptoms, auditory or visual hallucinations or suicidal ideation (SI)

The patient was admitted to the Internal Medicine Service and received a workup for the causes of delirium, including consideration of normal pressure hydrocephalus (NPH) and other neurologic conditions. Laboratory tests including a comprehensive metabolic panel, thyroid stimulating hormone, urinalysis, urine toxicology screen, and vitamin B12 and folate levels were in normal ranges. Although brain imaging revealed enlarged ventricles, NPH was considered unlikely because of the absence of ophthalmologic abnormalities, like gaze nystagmus, and urinary incontinence; conversely, there was some presence of urinary retention attributed to BPH and required an admission a few months prior. Moreover, magnetic resonance images showed that the ventricles were enlarged slightly out of proportion to the sulci, which can be seen with predominantly central volume loss compared with the pattern typically seen in NPH.

In light of concern for WE and the patient's history, treatment with IV thiamine and IV fluids was initiated and the Liaison Psychiatry Service was consulted for cognitive disability and treatment of his mood. Administration of IV thiamine rapidly restored his sensorium, but he became abruptly disorganized as the IV regimen graduated to an oral thiamine dose of 200 mg 3 times daily. Simultaneously, as medical stabilization was achieved, the patient was transferred to the inpatient psychiatry unit to address the nonresolving cognitive impairment and behavioral disorganization. This specifically involved newly emerging, impulsive, self-harming behaviors like throwing himself on the ground and banging his head on the floor. Such behaviors along with paucity of speech and decreased oral intake, ultimately warranted constant observation, which led to a decrease in self-harming activity. All this behavior was noted even though the patient was adherent to oral administration of thiamine. Throughout this time, the patient underwent several transfers back and forth between the Psychiatry and Internal Medicine services due to ongoing concern for the possibility of delirium or WE. However, the Neurology and Internal Medicine services did not feel that WE would explain the patient’s mental and behavioral status, in part due to his ongoing adherence with daily oral thiamine dosing that was not associated with improvement in mental status.

Recollecting the patient’s improvement with the parenteral thiamine regimen (IV and IM), the psychiatry unit tried a thiamine regimen of 200 mg IM and 100 mg oral 2 times daily. After about 2 weeks on this regimen, the patient subsequently achieved remarkable improvement in his cognitive and behavioral status, with resolution of selfharming behaviors. The patient was noted to be calmer, more linear, and more oriented, though he remained incompletely oriented throughout his hospitalization. As improvement in sensorium was established and the patient’s hospital stay prolonged (Figure), his mood symptoms began manifesting as guilt, low energy, decreased appetite, withdrawal, and passive SI. This was followed by a trial of lithium that was discontinued due to elevated creatine levels. As the patient continued to report depression, a multidrug regimen of divalproex, fluoxetine, and quetiapine was administered, which lead to remarkable improvement.

At this time, it was concluded that the stores of thiamine in the patient’s body may have been replenished, the alcohol intake completely ceased and that he needed to be weaned off of thiamine. The next step taken was reduction of the twice daily 200 mg IM thiamine dose to a once daily regimen, and oral thiamine was put on hold. Over the next 48 hours, the patient became less verbal, more withdrawn, incontinent of urine, and delirious. The twice daily IM 200 mg thiamine was restarted, but this time the patient demonstrated very slow improvement. After 2 weeks, the IM thiamine 200 mg was increased to 3 times daily, and the patient showed marked improvement in recall, mood, and effect.

Several attempts were made to reduce the IM thiamine burden on the patient and/ or transition to an exclusively oral regimen. However, he rapidly decompensated within hours of each attempt to taper the IM dose and required immediate reinstation. On the IM thiamine regimen, he eventually appeared to reach a stable cognitive and affective baseline marked by incomplete orientation but pleasant affect, he reported no mood complaints, behavioral stability, and an ability to comply with care needs and have simple conversations. Some speech content remained disorganized particularly if engaged beyond simple exchanges.

The patient was discharged to a skilled nursing facility after a month of 3 times daily IM administration of thiamine. Within the next 24 hours, the patient returned to the ED with the originally reported symptoms of ataxia, agitation, and confusion. On inquiry, it was revealed that the ordered vials of IM thiamine for injection had not arrived with him at the nursing facility and he had missed 2 doses. The blood laboratory results, scans, and all other parameters were otherwise found to be normal and the patient was adherent to his prescribed antipsychotics and antidepressants. As anticipated, restoration of the IM thiamine regimen revived his baseline within hours. While confusion and delirium resolved completely with treatment, the memory impairments persisted. This patient has been administered a 3 times daily IM dose of 200 mg thiamine for more than 2 years with a stable cognitive clinical picture.

Discussion

According to data from the 2016 National Survey on Drug Use and Health, 16 million individuals in the US aged ≥ 12 years reported heavy alcohol use, which is defined as binge drinking on ≥ 5 days in the past month.6,7 Thiamine deficiency is an alcoholrelated disorder that is frequently encountered in hospital settings. This deficiency can also occur in the context of malabsorption, malnutrition, a prolonged course of vomiting, and bariatric surgery.^8,9

The deficiency in thiamine, which is sometimes known as WE, manifests rarely with all 3 of the classic triad of gait disturbances, abnormal eye movements, and mental status changes, with only 16.5% of patients displaying all of the triad.⁴ Moreover, there may be additional symptoms not listed in this triad, such as memory impairment, bilateral sixth nerve palsy, ptosis, hypotension, and hypothermia.^10.11 This inconsistent presentation makes the diagnosis challenging and therefore requires a higher threshold for suspicion. If undiagnosed and/or untreated, WE can lead to chronic thiamine deficiency causing permanent brain damage in the guise of KS. This further increases the importance of timely diagnosis and treatment.

Our case highlights the utilization of an unconventional thiamine regimen that appeared to be temporally associated with mental status improvement. The patient’s clouded sensorium and confusion could not be attributed to metabolic, encephalopathic, or infectious pathologies due to the absence of supportive laboratory evidence. He responded to IV and IM doses of thiamine, but repeated attempts to taper the IM doses with the objective of transitioning to oral thiamine supplementation were followed by immediate decompensations in mental status. This was atypical of WE as the patient seemed adequately replete with thiamine, and missing a few doses should not be enough to deplete his stores. Thus, reflecting a unique case of thiamine-dependent chronically set WE when even a single missed dose of thiamine adversely affected the patient’s cognitive baseline. Interesting to note is this patient’s memory issue, as evident by clinical examination and dating back at least 5 years as per chart review. This premature amnestic component of his presentation indicates a likely parallel running KS component of his presentation. Conversely, the patient’s long history of alcohol use disorder, prior episodes of WE, and ideal response achieved only on parenteral thiamine repletion further supported the diagnosis of WE and our impression of the scenario.

Even though this patient had prior episodes of WE, there remained diagnostic uncertainty regarding his altered mental status for some time before the nonoral thiamine repletion treatment was implemented. Particularly in this admission, the patient’s mental status frequently waxed and waned and there was the additional confusion of whether a potential psychiatric etiology contributed to some of the elements of his presentation, such as his impulsive self-harm behaviors. This behavior led to recurrent transfers among the Psychiatry Service, Internal Medicine Service, and the ED.

The patient’s presentation did not reflect the classical triad of WE, and while this is consistent with the majority of clinical manifestations, various services were reluctant to attribute his symptoms to WE. Once the threshold of suspicion of thiamine deficiency was lowered and the deficit treated more aggressively, the patient seemed to improve tremendously. Presence of memory problems and confabulation, both of which this patient exhibited, are suggestive of KS and are not expected to recover with treatment, yet for this patient there did seem to be some improvement—though not complete resolution. This is consistent with newer evidence suggesting that some recovery from the deficits seen in KS is possible.³

Once diagnosed, the treatment objective is the replenishment of thiamine stores and optimization of the metabolic scenario of the body to prevent recurrence. For acute WE symptoms, many regimens call for 250 to 500 mg of IV thiamine supplementation 2 to 3 times daily for 3 to 5 days. High dose IV thiamine (≥ 500 mg daily) has been proposed to be efficacious and free of considerable adverse effects.¹² A study conducted at the University of North Carolina described thiamine prescribing practices in a large academic hospital, analyzing data with the objective of assessing outcomes of ordering high-dose IV thiamine (HDIV, ≥ 200 mg IV twice daily) to patients with encephalopathy. ¹³ The researchers concluded that HDIV, even though rarely prescribed, was associated with decreased inpatient mortality in bivariable models. However, in multivariable analyses this decrease was found to be clinically insignificant. Our patient benefitted from both IV and IM delivery.

Ideally, after the initial IV thiamine dose, oral administration of thiamine 250 to 1,000 mg is continued until a reduction, if not abstinence, from alcohol use is achieved.⁵ Many patients are discharged on an oral maintenance dose of thiamine 100 mg. Oral thiamine is poorly absorbed and less effective in both prophylaxis and treatment of newly diagnosed WE; therefore, it is typically used only after IM or IV replenishment. It remains unclear why this patient required IM thiamine multiple times per day to maintain his mental status, and why he would present with selfinjurious behaviors after missing doses. The patient’s response can be attributed to late-onset defects in oral thiamine absorption at the carrier protein level of the brush border and basolateral membranes of his jejunum; however, an invasive procedure like a jejunal biopsy to establish the definitive etiology was neither necessary nor practical once treatment response was observed. ¹⁴ Other possible explanations include rapid thiamine metabolism, poor gastrointestinal absorption and a late-onset deficit in the thiamine diffusion mechanisms, and active transport systems (thiamine utilization depends on active transport in low availability states and passive transport when readily available). The nature of these mechanisms deserves further study. Less data have been reported on the administration and utility of IM thiamine for chronic WE; hence, our case report is one of the first illustrating the role of this method for sustained repletion.

Conclusions

This case presented a clinical dilemma because the conventional treatment regimen for WE didn’t yield the desired outcome until the mode and duration of thiamine administration were adjusted. It illustrates the utility of a sustained intensive thiamine regimen irrespective of sobriety status, as opposed to the traditional regimen of parenteral (primarily IV) thiamine for 3 to 7 days, followed by oral repletion until the patient achieves sustained abstinence. In this patient’s case, access to nursing care postdischarge facilitated his continued adherence to IM thiamine therapy.

The longitudinal time course of this case suggests a relationship between this route of administration and improvement in symptom burden and indicates that this patient may have a long-term need for IM thiamine to maintain his baseline mental status. Of great benefit in such patients would be the availability of a long-acting IM thiamine therapy. Risk of overdose is unlikely due to the water solubility of B group vitamins.

This case report highlights the importance of setting a high clinical suspicion for WE due to its ever-increasing incidence in these times. We also wish to direct researchers to consider other out-of-the-box treatment options in case of failure of the conventional regime. In documenting this patient report, we invite more medical providers to investigate and explore other therapeutic options for WE treatment with the aim of decreasing both morbidity and mortality secondary to the condition.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2), which causes the respiratory disease coronavirus disease-19 (COVID- 19), was first identified as a cluster of cases of pneumonia in Wuhan, Hubei Province of China on December 31, 2019.1 Within a month, the disease had spread significantly, leading the World Health Organization (WHO) to designate COVID-19 a public health emergency of international concern. On March 11, 2020, the WHO declared COVID-19 a global pandemic.² As of August 18, 2020, the virus has infected > 21 million people, with > 750,000 deaths worldwide.3 The spread of COVID-19 has had a dramatic impact on social, economic, and health care issues throughout the world, which has been discussed elsewhere.⁴

Prior to the this century, members of the coronavirus family had minimal impact on human health.5 However, in the past 20 years, outbreaks have highlighted an emerging importance of coronaviruses in morbidity and mortality on a global scale. Although less prevalent than COVID-19, severe acute respiratory syndrome (SARS) in 2002 to 2003 and Middle East respiratory syndrome (MERS) in 2012 likely had higher mortality rates than the current pandemic.⁵ Based on this recent history, it is reasonable to assume that we will continue to see novel diseases with similar significant health and societal implications. The challenges presented to health care providers (HCPs) by such novel viral pathogens are numerous, including methods for rapid diagnosis, prevention, and treatment. In the current study, we focus on diagnosis issues, which were evident with COVID-19 with the time required to develop rapid and effective diagnostic modalities.

We have previously reported the utility of using artificial intelligence (AI) in the histopathologic diagnosis of cancer.^6-8 AI was first described in 1956 and involves the field of computer science in which machines are trained to learn from experience.⁹ Machine learning (ML) is a subset of AI and is achieved by using mathematic models to compute sample datasets.¹⁰ Current ML employs deep learning with neural network algorithms, which can recognize patterns and achieve complex computational tasks often far quicker and with increased precision than can humans.^11-13 In addition to applications in pathology, ML algorithms have both prognostic and diagnostic applications in multiple medical specialties, such as radiology, dermatology, ophthalmology, and cardiology.6 It is predicted that AI will impact almost every aspect of health care in the future.¹⁴

In this article, we examine the potential for AI to diagnose patients with COVID-19 pneumonia using chest radiographs (CXR) alone. This is done using Microsoft CustomVision (www.customvision.ai), a readily available, automated ML platform. Employing AI to both screen and diagnose emerging health emergencies such as COVID-19 has the potential to dramatically change how we approach medical care in the future. In addition, we describe the creation of a publicly available website (interknowlogy-covid-19 .azurewebsites.net) that could augment COVID-19 pneumonia CXR diagnosis.

Methods

For the training dataset, 103 CXR images of COVID-19 were downloaded from GitHub covid-chest-xray dataset^.15 Five hundred images of non-COVID-19 pneumonia and 500 images of the normal lung were downloaded from the Kaggle RSNA Pneumonia Detection Challenge dataset.¹⁶ To balance the dataset, we expanded the COVID-19 dataset to 500 images by slight rotation (probability = 1, max rotation = 5) and zooming (probability = 0.5, percentage area = 0.9) of the original images using the Augmentor Python package.¹⁷

Validation Dataset

For the validation dataset 30 random CXR images were obtained from the US Department of Veterans Affairs (VA) PACS (picture archiving and communication system). This dataset included 10 CXR images from hospitalized patients with COVID-19, 10 CXR pneumonia images from patients without COVID-19, and 10 normal CXRs. COVID-19 diagnoses were confirmed with a positive test result from the Xpert Xpress SARS-CoV-2 polymerase chain reaction (PCR) platform.¹⁸

Microsoft Custom

Vision Microsoft CustomVision is an automated image classification and object detection system that is a part of Microsoft Azure Cognitive Services (azure.microsoft.com). It has a pay-as-you-go model with fees depending on the computing needs and usage. It offers a free trial to users for 2 initial projects. The service is online with an easy-to-follow graphical user interface. No coding skills are necessary.

We created a new classification project in CustomVision and chose a compact general domain for small size and easy export to TensorFlow. js model format. TensorFlow.js is a JavaScript library that enables dynamic download and execution of ML models. After the project was created, we proceeded to upload our image dataset. Each class was uploaded separately and tagged with the appropriate label (covid pneumonia, non-covid pneumonia, or normal lung). The system rejected 16 COVID-19 images as duplicates. The final CustomVision training dataset consisted of 484 images of COVID-19 pneumonia, 500 images of non-COVID-19 pneumonia, and 500 images of normal lungs. Once uploaded, CustomVision self-trains using the dataset upon initiating the program (Figure 1).

Website Creation

CustomVision was used to train the model. It can be used to execute the model continuously, or the model can be compacted and decoupled from CustomVision. In this case, the model was compacted and decoupled for use in an online application. An Angular online application was created with TensorFlow.js. Within a user’s web browser, the model is executed when an image of a CXR is submitted. Confidence values for each classification are returned. In this design, after the initial webpage and model is downloaded, the webpage no longer needs to access any server components and performs all operations in the browser. Although the solution works well on mobile phone browsers and in low bandwidth situations, the quality of predictions may depend on the browser and device used. At no time does an image get submitted to the cloud.

Result

Overall, our trained model showed 92.9% precision and recall. Precision and recall results for each label were 98.9% and 94.8%, respectively for COVID-19 pneumonia; 91.8% and 89%, respectively, for non- COVID-19 pneumonia; and 88.8% and 95%, respectively, for normal lung (Figure 2). Next, we proceeded to validate the training model on the VA data by making individual predictions on 30 images from the VA dataset. Our model performed well with 100% sensitivity (recall), 95% specificity, 97% accuracy, 91% positive predictive value (precision), and 100% negative predictive value (Table).

Discussion

We successfully demonstrated the potential of using AI algorithms in assessing CXRs for COVID-19. We first trained the CustomVision automated image classification and object detection system to differentiate cases of COVID-19 from pneumonia from other etiologies as well as normal lung CXRs. We then tested our model against known patients from the James A. Haley Veterans’ Hospital in Tampa, Florida. The program achieved 100% sensitivity (recall), 95% specificity, 97% accuracy, 91% positive predictive value (precision), and 100% negative predictive value in differentiating the 3 scenarios. Using the trained ML model, we proceeded to create a website that could augment COVID-19 CXR diagnosis.¹⁹ The website works on mobile as well as desktop platforms. A health care provider can take a CXR photo with a mobile phone or upload the image file. The ML algorithm would provide the probability of COVID-19 pneumonia, non-COVID-19 pneumonia, or normal lung diagnosis (Figure 3).

Emerging diseases such as COVID-19 present numerous challenges to HCPs, governments, and businesses, as well as to individual members of society. As evidenced with COVID-19, the time from first recognition of an emerging pathogen to the development of methods for reliable diagnosis and treatment can be months, even with a concerted international effort. The gold standard for diagnosis of COVID-19 is by reverse transcriptase PCR (RT-PCR) technologies; however, early RT-PCR testing produced less than optimal results.^20-22 Even after the development of reliable tests for detection, making test kits readily available to health care providers on an adequate scale presents an additional challenge as evident with COVID-19.

Use of X-ray vs Computed Tomography

The lack of availability of diagnostic RTPCR with COVID-19 initially placed increased reliability on presumptive diagnoses via imaging in some situations.²³ Most of the literature evaluating radiographs of patients with COVID-19 focuses on chest computed tomography (CT) findings, with initial results suggesting CT was more accurate than early RT-PCR methodologies.21,22,24 The Radiological Society of North America Expert consensus statement on chest CT for COVID-19 states that CT findings can even precede positivity on RT-PCR in some cases.²² However, currently it does not recommend the use of CT scanning as a screening tool. Furthermore, the actual sensitivity and specificity of CT interpretation by radiologists for COVID-19 are unknown.²²

Characteristic CT findings include ground-glass opacities (GGOs) and consolidation most commonly in the lung periphery, though a diffuse distribution was found in a minority of patients.^21,23,25-27 Lomoro and colleagues recently summarized the CT findings from several reports that described abnormalities as most often bilateral and peripheral, subpleural, and affecting the lower lobes.26 Not surprisingly, CT appears more sensitive at detecting changes with COVID-19 than does CXR, with reports that a minority of patients exhibited CT changes before changes were visible on CXR.^23,26

We focused our study on the potential of AI in the examination of CXRs in patients with COVID-19, as there are several limitations to the routine use of CT scans with conditions such as COVID-19. Aside from the more considerable time required to obtain CTs, there are issues with contamination of CT suites, sometimes requiring a dedicated COVID-19 CT scanner.^23,28 The time constraints of decontamination or limited utilization of CT suites can delay or disrupt services for patients with and without COVID-19. Because of these factors, CXR may be a better resource to minimize the risk of infection to other patients. Also, accurate assessment of abnormalities on CXR for COVID-19 may identify patients in whom the CXR was performed for other purposes.²³ CXR is more readily available than CT, especially in more remote or underdeveloped areas.²⁸ Finally, as with CT, CXR abnormalities are reported to have appeared before RT-PCR tests became positive for a minority of patients.²³

CXR findings described in patients with COVID-19 are similar to those of CT and include GGOs, consolidation, and hazy increased opacities.^{23,25,26,28,29} Like CT, the majority of patients who received CXR demonstrated greater involvement in the lower zones and peripherally.^{23,25,26,28,29} Most patients showed bilateral involvement. However, while these findings are common in patients with COVID-19, they are not specific and can be seen in other conditions, such as other viral pneumonia, bacterial pneumonia, injury from drug toxicity, inhalation injury, connective tissue disease, and idiopathic conditions.

Application of AI for COVID-19

Applications of AI in interpreting radiographs of various types are numerous, and extensive literature has been written on the topic.³⁰ Using deep learning algorithms, AI has multiple possible roles to augment traditional radiograph interpretation. These include the potential for screening, triaging, and increasing the speed to render diagnoses. It also can provide a rapid “second opinion” to the radiologist to support the final interpretation. In areas with critical shortages of radiologists, AI potentially can be used to render the definitive diagnosis. In COVID- 19, imaging studies have been shown to correlate with disease severity and mortality, and AI could assist in monitoring the course of the disease as it progresses and potentially identify patients at greatest risk.²⁷ Furthermore, early results from PCR have been considered suboptimal, and it is known that patients with COVID-19 can test negative initially even by reliable testing methodologies. As AI technology progresses, interpretation can detect and guide triage and treatment of patients with high suspicions of COVID-19 but negative initial PCR results, or in situations where test availability is limited or results are delayed. There are numerous potential benefits should a rapid diagnostic test as simple as a CXR be able to reliably impact containment and prevention of the spread of contagions such as COVID- 19 early in its course.

Few studies have assessed using AI in the radiologic diagnosis of COVID-19, most of which use CT scanning. Bai and colleagues demonstrated increased accuracy, sensitivity, and specificity in distinguishing chest CTs of COVID-19 patients from other types of pneumonia.^21,31 A separate study demonstrated the utility of using AI to differentiate COVID-19 from community-acquired pneumonia with CT.32 However, the effective utility of AI for CXR interpretation also has been demonstrated.^14,33 Implementation of convolutional neural network layers has allowed for reliable differentiation of viral and bacterial pneumonia with CXR imaging.³⁴ Evidence suggests that there is great potential in the application of AI in the interpretation of radiographs of all types.

Finally, we have developed a publicly available website based on our studies.¹⁸ This website is for research use only as it is based on data from our preliminary investigation. To appear within the website, images must have protected health information removed before uploading. The information on the website, including text, graphics, images, or other material, is for research and may not be appropriate for all circumstances. The website does not provide medical, professional, or licensed advice and is not a substitute for consultation with a HCP. Medical advice should be sought from a qualified HCP for any questions, and the website should not be used for medical diagnosis or treatment.

Limitations

In our preliminary study, we have demonstrated the potential impact AI can have in multiple aspects of patient care for emerging pathogens such as COVID-19 using a test as readily available as a CXR. However, several limitations to this investigation should be mentioned. The study is retrospective in nature with limited sample size and with X-rays from patients with various stages of COVID-19 pneumonia. Also, cases of non-COVID-19 pneumonia are not stratified into different types or etiologies. We intend to demonstrate the potential of AI in differentiating COVID-19 pneumonia from non-COVID-19 pneumonia of any etiology, though future studies should address comparison of COVID-19 cases to more specific types of pneumonias, such as of bacterial or viral origin. Furthermore, the present study does not address any potential effects of additional radiographic findings from coexistent conditions, such as pulmonary edema as seen in congestive heart failure, pleural effusions (which can be seen with COVID-19 pneumonia, though rarely), interstitial lung disease, etc. Future studies are required to address these issues. Ultimately, prospective studies to assess AI-assisted radiographic interpretation in conditions such as COVID-19 are required to demonstrate the impact on diagnosis, treatment, outcome, and patient safety as these technologies are implemented.

Conclusions

We have used a readily available, commercial platform to demonstrate the potential of AI to assist in the successful diagnosis of COVID-19 pneumonia on CXR images. While this technology has numerous applications in radiology, we have focused on the potential impact on future world health crises such as COVID-19. The findings have implications for screening and triage, initial diagnosis, monitoring disease progression, and identifying patients at increased risk of morbidity and mortality. Based on the data, a website was created to demonstrate how such technologies could be shared and distributed to others to combat entities such as COVID-19 moving forward. Our study offers a small window into the potential for how AI will likely dramatically change the practice of medicine in the future.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2), which causes the respiratory disease coronavirus disease-19 (COVID- 19), was first identified as a cluster of cases of pneumonia in Wuhan, Hubei Province of China on December 31, 2019.1 Within a month, the disease had spread significantly, leading the World Health Organization (WHO) to designate COVID-19 a public health emergency of international concern. On March 11, 2020, the WHO declared COVID-19 a global pandemic.² As of August 18, 2020, the virus has infected > 21 million people, with > 750,000 deaths worldwide.3 The spread of COVID-19 has had a dramatic impact on social, economic, and health care issues throughout the world, which has been discussed elsewhere.⁴

Prior to the this century, members of the coronavirus family had minimal impact on human health.5 However, in the past 20 years, outbreaks have highlighted an emerging importance of coronaviruses in morbidity and mortality on a global scale. Although less prevalent than COVID-19, severe acute respiratory syndrome (SARS) in 2002 to 2003 and Middle East respiratory syndrome (MERS) in 2012 likely had higher mortality rates than the current pandemic.⁵ Based on this recent history, it is reasonable to assume that we will continue to see novel diseases with similar significant health and societal implications. The challenges presented to health care providers (HCPs) by such novel viral pathogens are numerous, including methods for rapid diagnosis, prevention, and treatment. In the current study, we focus on diagnosis issues, which were evident with COVID-19 with the time required to develop rapid and effective diagnostic modalities.

We have previously reported the utility of using artificial intelligence (AI) in the histopathologic diagnosis of cancer.^6-8 AI was first described in 1956 and involves the field of computer science in which machines are trained to learn from experience.⁹ Machine learning (ML) is a subset of AI and is achieved by using mathematic models to compute sample datasets.¹⁰ Current ML employs deep learning with neural network algorithms, which can recognize patterns and achieve complex computational tasks often far quicker and with increased precision than can humans.^11-13 In addition to applications in pathology, ML algorithms have both prognostic and diagnostic applications in multiple medical specialties, such as radiology, dermatology, ophthalmology, and cardiology.6 It is predicted that AI will impact almost every aspect of health care in the future.¹⁴

In this article, we examine the potential for AI to diagnose patients with COVID-19 pneumonia using chest radiographs (CXR) alone. This is done using Microsoft CustomVision (www.customvision.ai), a readily available, automated ML platform. Employing AI to both screen and diagnose emerging health emergencies such as COVID-19 has the potential to dramatically change how we approach medical care in the future. In addition, we describe the creation of a publicly available website (interknowlogy-covid-19 .azurewebsites.net) that could augment COVID-19 pneumonia CXR diagnosis.

Methods

For the training dataset, 103 CXR images of COVID-19 were downloaded from GitHub covid-chest-xray dataset^.15 Five hundred images of non-COVID-19 pneumonia and 500 images of the normal lung were downloaded from the Kaggle RSNA Pneumonia Detection Challenge dataset.¹⁶ To balance the dataset, we expanded the COVID-19 dataset to 500 images by slight rotation (probability = 1, max rotation = 5) and zooming (probability = 0.5, percentage area = 0.9) of the original images using the Augmentor Python package.¹⁷

Validation Dataset

For the validation dataset 30 random CXR images were obtained from the US Department of Veterans Affairs (VA) PACS (picture archiving and communication system). This dataset included 10 CXR images from hospitalized patients with COVID-19, 10 CXR pneumonia images from patients without COVID-19, and 10 normal CXRs. COVID-19 diagnoses were confirmed with a positive test result from the Xpert Xpress SARS-CoV-2 polymerase chain reaction (PCR) platform.¹⁸

Microsoft Custom

Vision Microsoft CustomVision is an automated image classification and object detection system that is a part of Microsoft Azure Cognitive Services (azure.microsoft.com). It has a pay-as-you-go model with fees depending on the computing needs and usage. It offers a free trial to users for 2 initial projects. The service is online with an easy-to-follow graphical user interface. No coding skills are necessary.

We created a new classification project in CustomVision and chose a compact general domain for small size and easy export to TensorFlow. js model format. TensorFlow.js is a JavaScript library that enables dynamic download and execution of ML models. After the project was created, we proceeded to upload our image dataset. Each class was uploaded separately and tagged with the appropriate label (covid pneumonia, non-covid pneumonia, or normal lung). The system rejected 16 COVID-19 images as duplicates. The final CustomVision training dataset consisted of 484 images of COVID-19 pneumonia, 500 images of non-COVID-19 pneumonia, and 500 images of normal lungs. Once uploaded, CustomVision self-trains using the dataset upon initiating the program (Figure 1).

Website Creation

CustomVision was used to train the model. It can be used to execute the model continuously, or the model can be compacted and decoupled from CustomVision. In this case, the model was compacted and decoupled for use in an online application. An Angular online application was created with TensorFlow.js. Within a user’s web browser, the model is executed when an image of a CXR is submitted. Confidence values for each classification are returned. In this design, after the initial webpage and model is downloaded, the webpage no longer needs to access any server components and performs all operations in the browser. Although the solution works well on mobile phone browsers and in low bandwidth situations, the quality of predictions may depend on the browser and device used. At no time does an image get submitted to the cloud.

Result

Overall, our trained model showed 92.9% precision and recall. Precision and recall results for each label were 98.9% and 94.8%, respectively for COVID-19 pneumonia; 91.8% and 89%, respectively, for non- COVID-19 pneumonia; and 88.8% and 95%, respectively, for normal lung (Figure 2). Next, we proceeded to validate the training model on the VA data by making individual predictions on 30 images from the VA dataset. Our model performed well with 100% sensitivity (recall), 95% specificity, 97% accuracy, 91% positive predictive value (precision), and 100% negative predictive value (Table).

Discussion

We successfully demonstrated the potential of using AI algorithms in assessing CXRs for COVID-19. We first trained the CustomVision automated image classification and object detection system to differentiate cases of COVID-19 from pneumonia from other etiologies as well as normal lung CXRs. We then tested our model against known patients from the James A. Haley Veterans’ Hospital in Tampa, Florida. The program achieved 100% sensitivity (recall), 95% specificity, 97% accuracy, 91% positive predictive value (precision), and 100% negative predictive value in differentiating the 3 scenarios. Using the trained ML model, we proceeded to create a website that could augment COVID-19 CXR diagnosis.¹⁹ The website works on mobile as well as desktop platforms. A health care provider can take a CXR photo with a mobile phone or upload the image file. The ML algorithm would provide the probability of COVID-19 pneumonia, non-COVID-19 pneumonia, or normal lung diagnosis (Figure 3).

Emerging diseases such as COVID-19 present numerous challenges to HCPs, governments, and businesses, as well as to individual members of society. As evidenced with COVID-19, the time from first recognition of an emerging pathogen to the development of methods for reliable diagnosis and treatment can be months, even with a concerted international effort. The gold standard for diagnosis of COVID-19 is by reverse transcriptase PCR (RT-PCR) technologies; however, early RT-PCR testing produced less than optimal results.^20-22 Even after the development of reliable tests for detection, making test kits readily available to health care providers on an adequate scale presents an additional challenge as evident with COVID-19.

Use of X-ray vs Computed Tomography

The lack of availability of diagnostic RTPCR with COVID-19 initially placed increased reliability on presumptive diagnoses via imaging in some situations.²³ Most of the literature evaluating radiographs of patients with COVID-19 focuses on chest computed tomography (CT) findings, with initial results suggesting CT was more accurate than early RT-PCR methodologies.21,22,24 The Radiological Society of North America Expert consensus statement on chest CT for COVID-19 states that CT findings can even precede positivity on RT-PCR in some cases.²² However, currently it does not recommend the use of CT scanning as a screening tool. Furthermore, the actual sensitivity and specificity of CT interpretation by radiologists for COVID-19 are unknown.²²

Characteristic CT findings include ground-glass opacities (GGOs) and consolidation most commonly in the lung periphery, though a diffuse distribution was found in a minority of patients.^21,23,25-27 Lomoro and colleagues recently summarized the CT findings from several reports that described abnormalities as most often bilateral and peripheral, subpleural, and affecting the lower lobes.26 Not surprisingly, CT appears more sensitive at detecting changes with COVID-19 than does CXR, with reports that a minority of patients exhibited CT changes before changes were visible on CXR.^23,26

We focused our study on the potential of AI in the examination of CXRs in patients with COVID-19, as there are several limitations to the routine use of CT scans with conditions such as COVID-19. Aside from the more considerable time required to obtain CTs, there are issues with contamination of CT suites, sometimes requiring a dedicated COVID-19 CT scanner.^23,28 The time constraints of decontamination or limited utilization of CT suites can delay or disrupt services for patients with and without COVID-19. Because of these factors, CXR may be a better resource to minimize the risk of infection to other patients. Also, accurate assessment of abnormalities on CXR for COVID-19 may identify patients in whom the CXR was performed for other purposes.²³ CXR is more readily available than CT, especially in more remote or underdeveloped areas.²⁸ Finally, as with CT, CXR abnormalities are reported to have appeared before RT-PCR tests became positive for a minority of patients.²³

CXR findings described in patients with COVID-19 are similar to those of CT and include GGOs, consolidation, and hazy increased opacities.^{23,25,26,28,29} Like CT, the majority of patients who received CXR demonstrated greater involvement in the lower zones and peripherally.^{23,25,26,28,29} Most patients showed bilateral involvement. However, while these findings are common in patients with COVID-19, they are not specific and can be seen in other conditions, such as other viral pneumonia, bacterial pneumonia, injury from drug toxicity, inhalation injury, connective tissue disease, and idiopathic conditions.

Application of AI for COVID-19

Applications of AI in interpreting radiographs of various types are numerous, and extensive literature has been written on the topic.³⁰ Using deep learning algorithms, AI has multiple possible roles to augment traditional radiograph interpretation. These include the potential for screening, triaging, and increasing the speed to render diagnoses. It also can provide a rapid “second opinion” to the radiologist to support the final interpretation. In areas with critical shortages of radiologists, AI potentially can be used to render the definitive diagnosis. In COVID- 19, imaging studies have been shown to correlate with disease severity and mortality, and AI could assist in monitoring the course of the disease as it progresses and potentially identify patients at greatest risk.²⁷ Furthermore, early results from PCR have been considered suboptimal, and it is known that patients with COVID-19 can test negative initially even by reliable testing methodologies. As AI technology progresses, interpretation can detect and guide triage and treatment of patients with high suspicions of COVID-19 but negative initial PCR results, or in situations where test availability is limited or results are delayed. There are numerous potential benefits should a rapid diagnostic test as simple as a CXR be able to reliably impact containment and prevention of the spread of contagions such as COVID- 19 early in its course.

Few studies have assessed using AI in the radiologic diagnosis of COVID-19, most of which use CT scanning. Bai and colleagues demonstrated increased accuracy, sensitivity, and specificity in distinguishing chest CTs of COVID-19 patients from other types of pneumonia.^21,31 A separate study demonstrated the utility of using AI to differentiate COVID-19 from community-acquired pneumonia with CT.32 However, the effective utility of AI for CXR interpretation also has been demonstrated.^14,33 Implementation of convolutional neural network layers has allowed for reliable differentiation of viral and bacterial pneumonia with CXR imaging.³⁴ Evidence suggests that there is great potential in the application of AI in the interpretation of radiographs of all types.

Finally, we have developed a publicly available website based on our studies.¹⁸ This website is for research use only as it is based on data from our preliminary investigation. To appear within the website, images must have protected health information removed before uploading. The information on the website, including text, graphics, images, or other material, is for research and may not be appropriate for all circumstances. The website does not provide medical, professional, or licensed advice and is not a substitute for consultation with a HCP. Medical advice should be sought from a qualified HCP for any questions, and the website should not be used for medical diagnosis or treatment.

Limitations

In our preliminary study, we have demonstrated the potential impact AI can have in multiple aspects of patient care for emerging pathogens such as COVID-19 using a test as readily available as a CXR. However, several limitations to this investigation should be mentioned. The study is retrospective in nature with limited sample size and with X-rays from patients with various stages of COVID-19 pneumonia. Also, cases of non-COVID-19 pneumonia are not stratified into different types or etiologies. We intend to demonstrate the potential of AI in differentiating COVID-19 pneumonia from non-COVID-19 pneumonia of any etiology, though future studies should address comparison of COVID-19 cases to more specific types of pneumonias, such as of bacterial or viral origin. Furthermore, the present study does not address any potential effects of additional radiographic findings from coexistent conditions, such as pulmonary edema as seen in congestive heart failure, pleural effusions (which can be seen with COVID-19 pneumonia, though rarely), interstitial lung disease, etc. Future studies are required to address these issues. Ultimately, prospective studies to assess AI-assisted radiographic interpretation in conditions such as COVID-19 are required to demonstrate the impact on diagnosis, treatment, outcome, and patient safety as these technologies are implemented.

Conclusions

We have used a readily available, commercial platform to demonstrate the potential of AI to assist in the successful diagnosis of COVID-19 pneumonia on CXR images. While this technology has numerous applications in radiology, we have focused on the potential impact on future world health crises such as COVID-19. The findings have implications for screening and triage, initial diagnosis, monitoring disease progression, and identifying patients at increased risk of morbidity and mortality. Based on the data, a website was created to demonstrate how such technologies could be shared and distributed to others to combat entities such as COVID-19 moving forward. Our study offers a small window into the potential for how AI will likely dramatically change the practice of medicine in the future.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2), which causes the respiratory disease coronavirus disease-19 (COVID- 19), was first identified as a cluster of cases of pneumonia in Wuhan, Hubei Province of China on December 31, 2019.1 Within a month, the disease had spread significantly, leading the World Health Organization (WHO) to designate COVID-19 a public health emergency of international concern. On March 11, 2020, the WHO declared COVID-19 a global pandemic.² As of August 18, 2020, the virus has infected > 21 million people, with > 750,000 deaths worldwide.3 The spread of COVID-19 has had a dramatic impact on social, economic, and health care issues throughout the world, which has been discussed elsewhere.⁴

Prior to the this century, members of the coronavirus family had minimal impact on human health.5 However, in the past 20 years, outbreaks have highlighted an emerging importance of coronaviruses in morbidity and mortality on a global scale. Although less prevalent than COVID-19, severe acute respiratory syndrome (SARS) in 2002 to 2003 and Middle East respiratory syndrome (MERS) in 2012 likely had higher mortality rates than the current pandemic.⁵ Based on this recent history, it is reasonable to assume that we will continue to see novel diseases with similar significant health and societal implications. The challenges presented to health care providers (HCPs) by such novel viral pathogens are numerous, including methods for rapid diagnosis, prevention, and treatment. In the current study, we focus on diagnosis issues, which were evident with COVID-19 with the time required to develop rapid and effective diagnostic modalities.

We have previously reported the utility of using artificial intelligence (AI) in the histopathologic diagnosis of cancer.^6-8 AI was first described in 1956 and involves the field of computer science in which machines are trained to learn from experience.⁹ Machine learning (ML) is a subset of AI and is achieved by using mathematic models to compute sample datasets.¹⁰ Current ML employs deep learning with neural network algorithms, which can recognize patterns and achieve complex computational tasks often far quicker and with increased precision than can humans.^11-13 In addition to applications in pathology, ML algorithms have both prognostic and diagnostic applications in multiple medical specialties, such as radiology, dermatology, ophthalmology, and cardiology.6 It is predicted that AI will impact almost every aspect of health care in the future.¹⁴

In this article, we examine the potential for AI to diagnose patients with COVID-19 pneumonia using chest radiographs (CXR) alone. This is done using Microsoft CustomVision (www.customvision.ai), a readily available, automated ML platform. Employing AI to both screen and diagnose emerging health emergencies such as COVID-19 has the potential to dramatically change how we approach medical care in the future. In addition, we describe the creation of a publicly available website (interknowlogy-covid-19 .azurewebsites.net) that could augment COVID-19 pneumonia CXR diagnosis.

Methods

For the training dataset, 103 CXR images of COVID-19 were downloaded from GitHub covid-chest-xray dataset^.15 Five hundred images of non-COVID-19 pneumonia and 500 images of the normal lung were downloaded from the Kaggle RSNA Pneumonia Detection Challenge dataset.¹⁶ To balance the dataset, we expanded the COVID-19 dataset to 500 images by slight rotation (probability = 1, max rotation = 5) and zooming (probability = 0.5, percentage area = 0.9) of the original images using the Augmentor Python package.¹⁷

Validation Dataset

For the validation dataset 30 random CXR images were obtained from the US Department of Veterans Affairs (VA) PACS (picture archiving and communication system). This dataset included 10 CXR images from hospitalized patients with COVID-19, 10 CXR pneumonia images from patients without COVID-19, and 10 normal CXRs. COVID-19 diagnoses were confirmed with a positive test result from the Xpert Xpress SARS-CoV-2 polymerase chain reaction (PCR) platform.¹⁸

Microsoft Custom

Vision Microsoft CustomVision is an automated image classification and object detection system that is a part of Microsoft Azure Cognitive Services (azure.microsoft.com). It has a pay-as-you-go model with fees depending on the computing needs and usage. It offers a free trial to users for 2 initial projects. The service is online with an easy-to-follow graphical user interface. No coding skills are necessary.

We created a new classification project in CustomVision and chose a compact general domain for small size and easy export to TensorFlow. js model format. TensorFlow.js is a JavaScript library that enables dynamic download and execution of ML models. After the project was created, we proceeded to upload our image dataset. Each class was uploaded separately and tagged with the appropriate label (covid pneumonia, non-covid pneumonia, or normal lung). The system rejected 16 COVID-19 images as duplicates. The final CustomVision training dataset consisted of 484 images of COVID-19 pneumonia, 500 images of non-COVID-19 pneumonia, and 500 images of normal lungs. Once uploaded, CustomVision self-trains using the dataset upon initiating the program (Figure 1).

Website Creation

CustomVision was used to train the model. It can be used to execute the model continuously, or the model can be compacted and decoupled from CustomVision. In this case, the model was compacted and decoupled for use in an online application. An Angular online application was created with TensorFlow.js. Within a user’s web browser, the model is executed when an image of a CXR is submitted. Confidence values for each classification are returned. In this design, after the initial webpage and model is downloaded, the webpage no longer needs to access any server components and performs all operations in the browser. Although the solution works well on mobile phone browsers and in low bandwidth situations, the quality of predictions may depend on the browser and device used. At no time does an image get submitted to the cloud.

Result

Overall, our trained model showed 92.9% precision and recall. Precision and recall results for each label were 98.9% and 94.8%, respectively for COVID-19 pneumonia; 91.8% and 89%, respectively, for non- COVID-19 pneumonia; and 88.8% and 95%, respectively, for normal lung (Figure 2). Next, we proceeded to validate the training model on the VA data by making individual predictions on 30 images from the VA dataset. Our model performed well with 100% sensitivity (recall), 95% specificity, 97% accuracy, 91% positive predictive value (precision), and 100% negative predictive value (Table).

Discussion

We successfully demonstrated the potential of using AI algorithms in assessing CXRs for COVID-19. We first trained the CustomVision automated image classification and object detection system to differentiate cases of COVID-19 from pneumonia from other etiologies as well as normal lung CXRs. We then tested our model against known patients from the James A. Haley Veterans’ Hospital in Tampa, Florida. The program achieved 100% sensitivity (recall), 95% specificity, 97% accuracy, 91% positive predictive value (precision), and 100% negative predictive value in differentiating the 3 scenarios. Using the trained ML model, we proceeded to create a website that could augment COVID-19 CXR diagnosis.¹⁹ The website works on mobile as well as desktop platforms. A health care provider can take a CXR photo with a mobile phone or upload the image file. The ML algorithm would provide the probability of COVID-19 pneumonia, non-COVID-19 pneumonia, or normal lung diagnosis (Figure 3).

Emerging diseases such as COVID-19 present numerous challenges to HCPs, governments, and businesses, as well as to individual members of society. As evidenced with COVID-19, the time from first recognition of an emerging pathogen to the development of methods for reliable diagnosis and treatment can be months, even with a concerted international effort. The gold standard for diagnosis of COVID-19 is by reverse transcriptase PCR (RT-PCR) technologies; however, early RT-PCR testing produced less than optimal results.^20-22 Even after the development of reliable tests for detection, making test kits readily available to health care providers on an adequate scale presents an additional challenge as evident with COVID-19.

Use of X-ray vs Computed Tomography

The lack of availability of diagnostic RTPCR with COVID-19 initially placed increased reliability on presumptive diagnoses via imaging in some situations.²³ Most of the literature evaluating radiographs of patients with COVID-19 focuses on chest computed tomography (CT) findings, with initial results suggesting CT was more accurate than early RT-PCR methodologies.21,22,24 The Radiological Society of North America Expert consensus statement on chest CT for COVID-19 states that CT findings can even precede positivity on RT-PCR in some cases.²² However, currently it does not recommend the use of CT scanning as a screening tool. Furthermore, the actual sensitivity and specificity of CT interpretation by radiologists for COVID-19 are unknown.²²

Characteristic CT findings include ground-glass opacities (GGOs) and consolidation most commonly in the lung periphery, though a diffuse distribution was found in a minority of patients.^21,23,25-27 Lomoro and colleagues recently summarized the CT findings from several reports that described abnormalities as most often bilateral and peripheral, subpleural, and affecting the lower lobes.26 Not surprisingly, CT appears more sensitive at detecting changes with COVID-19 than does CXR, with reports that a minority of patients exhibited CT changes before changes were visible on CXR.^23,26

We focused our study on the potential of AI in the examination of CXRs in patients with COVID-19, as there are several limitations to the routine use of CT scans with conditions such as COVID-19. Aside from the more considerable time required to obtain CTs, there are issues with contamination of CT suites, sometimes requiring a dedicated COVID-19 CT scanner.^23,28 The time constraints of decontamination or limited utilization of CT suites can delay or disrupt services for patients with and without COVID-19. Because of these factors, CXR may be a better resource to minimize the risk of infection to other patients. Also, accurate assessment of abnormalities on CXR for COVID-19 may identify patients in whom the CXR was performed for other purposes.²³ CXR is more readily available than CT, especially in more remote or underdeveloped areas.²⁸ Finally, as with CT, CXR abnormalities are reported to have appeared before RT-PCR tests became positive for a minority of patients.²³

CXR findings described in patients with COVID-19 are similar to those of CT and include GGOs, consolidation, and hazy increased opacities.^{23,25,26,28,29} Like CT, the majority of patients who received CXR demonstrated greater involvement in the lower zones and peripherally.^{23,25,26,28,29} Most patients showed bilateral involvement. However, while these findings are common in patients with COVID-19, they are not specific and can be seen in other conditions, such as other viral pneumonia, bacterial pneumonia, injury from drug toxicity, inhalation injury, connective tissue disease, and idiopathic conditions.

Application of AI for COVID-19

Applications of AI in interpreting radiographs of various types are numerous, and extensive literature has been written on the topic.³⁰ Using deep learning algorithms, AI has multiple possible roles to augment traditional radiograph interpretation. These include the potential for screening, triaging, and increasing the speed to render diagnoses. It also can provide a rapid “second opinion” to the radiologist to support the final interpretation. In areas with critical shortages of radiologists, AI potentially can be used to render the definitive diagnosis. In COVID- 19, imaging studies have been shown to correlate with disease severity and mortality, and AI could assist in monitoring the course of the disease as it progresses and potentially identify patients at greatest risk.²⁷ Furthermore, early results from PCR have been considered suboptimal, and it is known that patients with COVID-19 can test negative initially even by reliable testing methodologies. As AI technology progresses, interpretation can detect and guide triage and treatment of patients with high suspicions of COVID-19 but negative initial PCR results, or in situations where test availability is limited or results are delayed. There are numerous potential benefits should a rapid diagnostic test as simple as a CXR be able to reliably impact containment and prevention of the spread of contagions such as COVID- 19 early in its course.

Few studies have assessed using AI in the radiologic diagnosis of COVID-19, most of which use CT scanning. Bai and colleagues demonstrated increased accuracy, sensitivity, and specificity in distinguishing chest CTs of COVID-19 patients from other types of pneumonia.^21,31 A separate study demonstrated the utility of using AI to differentiate COVID-19 from community-acquired pneumonia with CT.32 However, the effective utility of AI for CXR interpretation also has been demonstrated.^14,33 Implementation of convolutional neural network layers has allowed for reliable differentiation of viral and bacterial pneumonia with CXR imaging.³⁴ Evidence suggests that there is great potential in the application of AI in the interpretation of radiographs of all types.

Finally, we have developed a publicly available website based on our studies.¹⁸ This website is for research use only as it is based on data from our preliminary investigation. To appear within the website, images must have protected health information removed before uploading. The information on the website, including text, graphics, images, or other material, is for research and may not be appropriate for all circumstances. The website does not provide medical, professional, or licensed advice and is not a substitute for consultation with a HCP. Medical advice should be sought from a qualified HCP for any questions, and the website should not be used for medical diagnosis or treatment.

Limitations

In our preliminary study, we have demonstrated the potential impact AI can have in multiple aspects of patient care for emerging pathogens such as COVID-19 using a test as readily available as a CXR. However, several limitations to this investigation should be mentioned. The study is retrospective in nature with limited sample size and with X-rays from patients with various stages of COVID-19 pneumonia. Also, cases of non-COVID-19 pneumonia are not stratified into different types or etiologies. We intend to demonstrate the potential of AI in differentiating COVID-19 pneumonia from non-COVID-19 pneumonia of any etiology, though future studies should address comparison of COVID-19 cases to more specific types of pneumonias, such as of bacterial or viral origin. Furthermore, the present study does not address any potential effects of additional radiographic findings from coexistent conditions, such as pulmonary edema as seen in congestive heart failure, pleural effusions (which can be seen with COVID-19 pneumonia, though rarely), interstitial lung disease, etc. Future studies are required to address these issues. Ultimately, prospective studies to assess AI-assisted radiographic interpretation in conditions such as COVID-19 are required to demonstrate the impact on diagnosis, treatment, outcome, and patient safety as these technologies are implemented.

Conclusions

We have used a readily available, commercial platform to demonstrate the potential of AI to assist in the successful diagnosis of COVID-19 pneumonia on CXR images. While this technology has numerous applications in radiology, we have focused on the potential impact on future world health crises such as COVID-19. The findings have implications for screening and triage, initial diagnosis, monitoring disease progression, and identifying patients at increased risk of morbidity and mortality. Based on the data, a website was created to demonstrate how such technologies could be shared and distributed to others to combat entities such as COVID-19 moving forward. Our study offers a small window into the potential for how AI will likely dramatically change the practice of medicine in the future.