SAN DIEGO – Forensic toxicologist Donna Papsun spends her days with drugs, but she doesn’t see patients or try to make anyone better. Still, her work is crucial to every medical professional who needs to know which new illicit drugs their patients have been taking.
In Willow Grove, Pa., a suburb of Philadelphia, Ms. Papsun and her colleagues at NMS Labs develop screening tests for designer drugs that have just appeared on the black market or crossed the Drug Enforcement Administration’s (DEA) radar.
Donna Papsun
It’s not an easy task for a variety of reasons, not the least of which is the challenge of finding a sample of the drug in question, which can be difficult to accomplish – even if it is made legally.
As Ms. Papsun told an audience at the annual meeting of the American Psychiatric Association, she faced a unique obstacle last summer, when an elephant tranquilizer called carfentanil, a derivative of fentanyl, began to make headlines. The obstacle? The U.S.-Canada border.
She wanted to develop a test for the opioid but couldn’t start until she got a reference sample of the controlled substance from carfentanil’s only manufacturer, a firm in Canada. It took months. “Crossing an international border caused all sorts of problems,” she said.
New designer drugs are constantly hitting the market. They’re often especially appealing – and especially risky – because routine drug tests can’t detect them, at least not yet.
In an interview, Ms. Papsun talked about the challenges of trying to keep up with the drug makers – and users.
“Designer drug testing developed back in 2008 will not catch anything that is seen in today’s designer drug market,” she said. “Designer drug testing requires constant attention, assessment, resources, and updating.”
Question: How long does it typically take to create a test for a new strain of illicit drug?
Answer: This can take anywhere from 3 to 9 months, and potentially longer, and it depends on many factors. Once a new drug has hit the market, we check to see if there is certified reference material available. If there is, then we can start to develop a test. Development includes identifying a successful chemical extraction technique – isolating the drug in question from biological matrix such as blood or urine – as well as a platform that reliably detects the drug without falsely reporting positives.
After development, the test has to go through a process called validation, which is a series of experiments to prove that the developed method works rigorously, day after day, and provides the same results. This is very important in forensic toxicology, because our results may be involved in criminal and civil litigation and must stand up to the rigors of court.
Q: What are some examples of the types of drugs that you’ve had to develop tests for?
A: Just in the past year, we have developed tests for new designer opioids (including carfentanil, furanylfentanyl, acrylfentanyl, and U-47700), designer benzodiazepines (including etizolam, diclazepam, flubromazolam, and flubromazepam) and new designer stimulants (including n-ethyl pentylone and dibutylone).
We have a synthetic cannabinoid test that was developed for the first time back in 2010. That test has been redeveloped several times since then, because we constantly have to update the test to keep up with the rapid changes in market availability of substances.
Q: What are some of the challenges that you face in terms of getting samples of human fluids that you can test for the drugs?
A: Most of the samples we see are from either death investigation cases or driving-under-the-influence cases. Samples from intoxications at hospitals are important, because those data help [us] understand the concentrations of drugs at which people can survive. But often, if the patients survive, their biological specimens are not forwarded for specialized toxicology testing. Most hospital systems do not have the analytical capabilities to detect designer drugs, and most lack the resources to seek out the causal agent for an intoxication or apparent overdose.
Q: At the APA meeting, you talked about the risk that you’ll hear about a strain from the DEA, develop a test and find out it’s obsolete because the drug isn’t used anymore. Does that happen very often?
A: Yes. The problem with designer drugs is that there are so many, so you can spend a lot of time, money, and other resources dedicated to developing and validating a test for a drug that may or may not even be popular.
As a business, you have to make decisions regarding prioritization: Do we build a test for a drug that has only been reported once, or do we focus our efforts on a substance that has been reported dozens of times?
We certainly have spent time and resources developing a test that became obsolete, or never reported a positive case. For example, we developed a test for desomorphine, and we have never chemically confirmed desomorphine in a biological specimen. It definitely is hit or miss, but we spend a lot of time and research a lot of different avenues to make educated decisions regarding the substances we develop tests for.
SAN DIEGO – Forensic toxicologist Donna Papsun spends her days with drugs, but she doesn’t see patients or try to make anyone better. Still, her work is crucial to every medical professional who needs to know which new illicit drugs their patients have been taking.
In Willow Grove, Pa., a suburb of Philadelphia, Ms. Papsun and her colleagues at NMS Labs develop screening tests for designer drugs that have just appeared on the black market or crossed the Drug Enforcement Administration’s (DEA) radar.
Donna Papsun
It’s not an easy task for a variety of reasons, not the least of which is the challenge of finding a sample of the drug in question, which can be difficult to accomplish – even if it is made legally.
As Ms. Papsun told an audience at the annual meeting of the American Psychiatric Association, she faced a unique obstacle last summer, when an elephant tranquilizer called carfentanil, a derivative of fentanyl, began to make headlines. The obstacle? The U.S.-Canada border.
She wanted to develop a test for the opioid but couldn’t start until she got a reference sample of the controlled substance from carfentanil’s only manufacturer, a firm in Canada. It took months. “Crossing an international border caused all sorts of problems,” she said.
New designer drugs are constantly hitting the market. They’re often especially appealing – and especially risky – because routine drug tests can’t detect them, at least not yet.
In an interview, Ms. Papsun talked about the challenges of trying to keep up with the drug makers – and users.
“Designer drug testing developed back in 2008 will not catch anything that is seen in today’s designer drug market,” she said. “Designer drug testing requires constant attention, assessment, resources, and updating.”
Question: How long does it typically take to create a test for a new strain of illicit drug?
Answer: This can take anywhere from 3 to 9 months, and potentially longer, and it depends on many factors. Once a new drug has hit the market, we check to see if there is certified reference material available. If there is, then we can start to develop a test. Development includes identifying a successful chemical extraction technique – isolating the drug in question from biological matrix such as blood or urine – as well as a platform that reliably detects the drug without falsely reporting positives.
After development, the test has to go through a process called validation, which is a series of experiments to prove that the developed method works rigorously, day after day, and provides the same results. This is very important in forensic toxicology, because our results may be involved in criminal and civil litigation and must stand up to the rigors of court.
Q: What are some examples of the types of drugs that you’ve had to develop tests for?
A: Just in the past year, we have developed tests for new designer opioids (including carfentanil, furanylfentanyl, acrylfentanyl, and U-47700), designer benzodiazepines (including etizolam, diclazepam, flubromazolam, and flubromazepam) and new designer stimulants (including n-ethyl pentylone and dibutylone).
We have a synthetic cannabinoid test that was developed for the first time back in 2010. That test has been redeveloped several times since then, because we constantly have to update the test to keep up with the rapid changes in market availability of substances.
Q: What are some of the challenges that you face in terms of getting samples of human fluids that you can test for the drugs?
A: Most of the samples we see are from either death investigation cases or driving-under-the-influence cases. Samples from intoxications at hospitals are important, because those data help [us] understand the concentrations of drugs at which people can survive. But often, if the patients survive, their biological specimens are not forwarded for specialized toxicology testing. Most hospital systems do not have the analytical capabilities to detect designer drugs, and most lack the resources to seek out the causal agent for an intoxication or apparent overdose.
Q: At the APA meeting, you talked about the risk that you’ll hear about a strain from the DEA, develop a test and find out it’s obsolete because the drug isn’t used anymore. Does that happen very often?
A: Yes. The problem with designer drugs is that there are so many, so you can spend a lot of time, money, and other resources dedicated to developing and validating a test for a drug that may or may not even be popular.
As a business, you have to make decisions regarding prioritization: Do we build a test for a drug that has only been reported once, or do we focus our efforts on a substance that has been reported dozens of times?
We certainly have spent time and resources developing a test that became obsolete, or never reported a positive case. For example, we developed a test for desomorphine, and we have never chemically confirmed desomorphine in a biological specimen. It definitely is hit or miss, but we spend a lot of time and research a lot of different avenues to make educated decisions regarding the substances we develop tests for.
SAN DIEGO – Forensic toxicologist Donna Papsun spends her days with drugs, but she doesn’t see patients or try to make anyone better. Still, her work is crucial to every medical professional who needs to know which new illicit drugs their patients have been taking.
In Willow Grove, Pa., a suburb of Philadelphia, Ms. Papsun and her colleagues at NMS Labs develop screening tests for designer drugs that have just appeared on the black market or crossed the Drug Enforcement Administration’s (DEA) radar.
Donna Papsun
It’s not an easy task for a variety of reasons, not the least of which is the challenge of finding a sample of the drug in question, which can be difficult to accomplish – even if it is made legally.
As Ms. Papsun told an audience at the annual meeting of the American Psychiatric Association, she faced a unique obstacle last summer, when an elephant tranquilizer called carfentanil, a derivative of fentanyl, began to make headlines. The obstacle? The U.S.-Canada border.
She wanted to develop a test for the opioid but couldn’t start until she got a reference sample of the controlled substance from carfentanil’s only manufacturer, a firm in Canada. It took months. “Crossing an international border caused all sorts of problems,” she said.
New designer drugs are constantly hitting the market. They’re often especially appealing – and especially risky – because routine drug tests can’t detect them, at least not yet.
In an interview, Ms. Papsun talked about the challenges of trying to keep up with the drug makers – and users.
“Designer drug testing developed back in 2008 will not catch anything that is seen in today’s designer drug market,” she said. “Designer drug testing requires constant attention, assessment, resources, and updating.”
Question: How long does it typically take to create a test for a new strain of illicit drug?
Answer: This can take anywhere from 3 to 9 months, and potentially longer, and it depends on many factors. Once a new drug has hit the market, we check to see if there is certified reference material available. If there is, then we can start to develop a test. Development includes identifying a successful chemical extraction technique – isolating the drug in question from biological matrix such as blood or urine – as well as a platform that reliably detects the drug without falsely reporting positives.
After development, the test has to go through a process called validation, which is a series of experiments to prove that the developed method works rigorously, day after day, and provides the same results. This is very important in forensic toxicology, because our results may be involved in criminal and civil litigation and must stand up to the rigors of court.
Q: What are some examples of the types of drugs that you’ve had to develop tests for?
A: Just in the past year, we have developed tests for new designer opioids (including carfentanil, furanylfentanyl, acrylfentanyl, and U-47700), designer benzodiazepines (including etizolam, diclazepam, flubromazolam, and flubromazepam) and new designer stimulants (including n-ethyl pentylone and dibutylone).
We have a synthetic cannabinoid test that was developed for the first time back in 2010. That test has been redeveloped several times since then, because we constantly have to update the test to keep up with the rapid changes in market availability of substances.
Q: What are some of the challenges that you face in terms of getting samples of human fluids that you can test for the drugs?
A: Most of the samples we see are from either death investigation cases or driving-under-the-influence cases. Samples from intoxications at hospitals are important, because those data help [us] understand the concentrations of drugs at which people can survive. But often, if the patients survive, their biological specimens are not forwarded for specialized toxicology testing. Most hospital systems do not have the analytical capabilities to detect designer drugs, and most lack the resources to seek out the causal agent for an intoxication or apparent overdose.
Q: At the APA meeting, you talked about the risk that you’ll hear about a strain from the DEA, develop a test and find out it’s obsolete because the drug isn’t used anymore. Does that happen very often?
A: Yes. The problem with designer drugs is that there are so many, so you can spend a lot of time, money, and other resources dedicated to developing and validating a test for a drug that may or may not even be popular.
As a business, you have to make decisions regarding prioritization: Do we build a test for a drug that has only been reported once, or do we focus our efforts on a substance that has been reported dozens of times?
We certainly have spent time and resources developing a test that became obsolete, or never reported a positive case. For example, we developed a test for desomorphine, and we have never chemically confirmed desomorphine in a biological specimen. It definitely is hit or miss, but we spend a lot of time and research a lot of different avenues to make educated decisions regarding the substances we develop tests for.
The US Food and Drug Administration (FDA) has granted approval for L-glutamine oral powder (Endari), the first treatment approved to treat sickle cell disease (SCD) in the US in nearly 20 years.
L-glutamine oral powder, a product developed by Emmaus Medical Inc., is intended to reduce severe complications of SCD in patients age 5 and older.
The FDA’s approval of L-glutamine was supported by efficacy data from a phase 3 trial.
The trial enrolled 230 adults and children with SCD, and they were randomized to receive L-glutamine or placebo.
Patients who received L-glutamine had fewer sickle cell crises, hospitalizations, cumulative hospital days, and cases of acute chest syndrome than patients who received placebo.
The FDA approval of L-glutamine was also supported by safety data from 298 patients treated with L-glutamine and 111 patients treated with placebo in the phase 2 and phase 3 studies.
Based on these data, L-glutamine was considered well-tolerated in pediatric and adult patients. The most common adverse events (occurring in more than 10% of patients receiving L-glutamine) were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain (non-cardiac).
The US Food and Drug Administration (FDA) has granted approval for L-glutamine oral powder (Endari), the first treatment approved to treat sickle cell disease (SCD) in the US in nearly 20 years.
L-glutamine oral powder, a product developed by Emmaus Medical Inc., is intended to reduce severe complications of SCD in patients age 5 and older.
The FDA’s approval of L-glutamine was supported by efficacy data from a phase 3 trial.
The trial enrolled 230 adults and children with SCD, and they were randomized to receive L-glutamine or placebo.
Patients who received L-glutamine had fewer sickle cell crises, hospitalizations, cumulative hospital days, and cases of acute chest syndrome than patients who received placebo.
The FDA approval of L-glutamine was also supported by safety data from 298 patients treated with L-glutamine and 111 patients treated with placebo in the phase 2 and phase 3 studies.
Based on these data, L-glutamine was considered well-tolerated in pediatric and adult patients. The most common adverse events (occurring in more than 10% of patients receiving L-glutamine) were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain (non-cardiac).
Image by Betty Pace
A sickled red blood cell beside a normal one
The US Food and Drug Administration (FDA) has granted approval for L-glutamine oral powder (Endari), the first treatment approved to treat sickle cell disease (SCD) in the US in nearly 20 years.
L-glutamine oral powder, a product developed by Emmaus Medical Inc., is intended to reduce severe complications of SCD in patients age 5 and older.
The FDA’s approval of L-glutamine was supported by efficacy data from a phase 3 trial.
The trial enrolled 230 adults and children with SCD, and they were randomized to receive L-glutamine or placebo.
Patients who received L-glutamine had fewer sickle cell crises, hospitalizations, cumulative hospital days, and cases of acute chest syndrome than patients who received placebo.
The FDA approval of L-glutamine was also supported by safety data from 298 patients treated with L-glutamine and 111 patients treated with placebo in the phase 2 and phase 3 studies.
Based on these data, L-glutamine was considered well-tolerated in pediatric and adult patients. The most common adverse events (occurring in more than 10% of patients receiving L-glutamine) were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain (non-cardiac).
Objective. To examine the screening practices of family practitioners (FPs) and pediatricians for type 2 diabetes (T2D) in adolescents.
Design. Cross-sectional study.
Setting and participants. The researchers randomly sampled 700 pediatricians and 700 FPs who participated in direct patient care using the American Medical Association Physician Masterfile using a mail survey. Exclusion criteria included providers who were residents, hospital staff, retirees, or employed by federally owned medical facilities, certified with a subspecialty, or over age 70.
Main outcome measures. Providers were given a hypothetical case of an obese, female, teenaged patient with concurrent associated risk factors for T2D (family history of T2D, minority race, signs of insulin resistance) and asked what initial screening tests they would order. Respondents were then informed of the updated American Diabetes Association (ADA) guidelines that added hemoglobin A1c as a screening test to diagnose diabetes. The survey then asked if knowing this change in recommendation has changed or will change their screening practices in adolescents.
Main results. 1400 surveys were mailed. After 2 were excluded due to mailing issues, 52% of providers provided responses. Of these, 129 providers reported that they did not care for adolescents (age 10–17), resulting in 604 providers in the final sample, 398 pediatricians and 335 FPs.
The vast majority (92%) said they would screen the hypothetical case for diabetes, with most initially ordering a fasting test (fasting plasma glucose or 2-hour glucose tolerance test) (63%) or A1c test (58%). Of the 58% who planned to order HbA1c, only 35% ordered it in combination with a fasting test. HbA1c was significantly more likely to be ordered by pediatricians than by FPs (P = 0.001). After being presented with the new guidelines, 84% said then would now order HbA1c, a 27% increase.
Conclusion. In response to information about the new guidelines, providers were more likely to order A1c as part of initial testing. Due to the lower test performance in children and increased cost of the test, the use of HbA1c without fasting tests may result in missed diagnosis of T2D in adolescents as well as increased health care costs.
Commentary
Rates of childhood obesity continue to rise throughout the United States. Obese children are at risk for numerous comorbidities such as hypertension, hyperlipidemia, and T2D [1,2]. It is important for providers to use effective screening tools for risk assessment of prediabetes/T2DM in children.
The standard tests for diagnosing diabetes are the fasting plasma glucose test and the 2-hour plasma glucose test. While accurate, these tests are not convenient. In 2010, the ADA added an easier method of testing for T2D: an HbA1c, with results greater than or equal to 6.5% indicating diabetes [3]. However, this recommendation is controversial, given studies suggesting that HbA1c is not as reliable in children as it is in adults [4–6]. The ADA itself acknowledges that there are limited data in the pediatric population.
In this study, most providers were unaware of the 4-year-old revised guidelines offering the A1c option but are planning to apply the guidelines going forward. According to the study, this would result in a 27% increase in providers utilizing HbA1c.
Should increased uptake of A1c as an initial screening test be a concern? Using it in combination with other tests may be useful for assessing which adolescents will need further testing [3–6].Additionally, by starting with a test that can be performed in the office with no regard to fasting time, it is possible that more cases of T2D will be found by primary care providers treating adolescents.
A weakness of the study is the potential for response bias related to mailed surveys. An additional weakness is that the researchers utilized only 1 hypothetical situation. Providing additional hypothetical situations may have allowed for further understanding of screening practices. The investigators also did not include nurse practitioners or physician assistants in their sample, a growing percentage of whom may care for adolescent populations at risk for T2D or be primary referral sources.
Applications for Clinical Practice
Providers can use HbA1c to screen for diabetes in nonfasting adolescents at risk for diabetes. While the test may not be as accurate in pediatric patients, utilizing HbA1C as directed by the ADA may aid in diagnosing patients that may otherwise miss follow-up appointments to complete a fasting test.
—Jennifer L. Nahum, MSN, CPNP-AC, PPCNP-BC, and Allison Squires, PhD, RN
References
1. Freedman DS, Dietz WH, Srinivasan SR, Berenson GS. The relation of overweight to cardiovascular risk factors among children and adolescents: the Bogalusa Heart Study. Pediatrics 1999;103(6 Pt 1):1175–82.
2. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr 1996;128(5 Pt 1):608–15.
3. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics 2000 Mar;105(3 Pt 1):671–80.
4. Lee JM, Gebremariam A, Wu EL, et al. Evaluation of nonfasting tests to screen for childhood and adolescent dysglycemia. Diabetes Care 2011;34:2597–602.
5. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 2011;34:1306–11.
6. Lee JM, Wu EL, Tarini B, et al Diagnosis of diabetes using hemoglobin A1c: should recommendations in adults be extrapolated to adolescents? J Pediatr 2011;158:947–952.
Issue
Journal of Clinical Outcomes Management - July 2014, Vol. 21, No. 7
Objective. To examine the screening practices of family practitioners (FPs) and pediatricians for type 2 diabetes (T2D) in adolescents.
Design. Cross-sectional study.
Setting and participants. The researchers randomly sampled 700 pediatricians and 700 FPs who participated in direct patient care using the American Medical Association Physician Masterfile using a mail survey. Exclusion criteria included providers who were residents, hospital staff, retirees, or employed by federally owned medical facilities, certified with a subspecialty, or over age 70.
Main outcome measures. Providers were given a hypothetical case of an obese, female, teenaged patient with concurrent associated risk factors for T2D (family history of T2D, minority race, signs of insulin resistance) and asked what initial screening tests they would order. Respondents were then informed of the updated American Diabetes Association (ADA) guidelines that added hemoglobin A1c as a screening test to diagnose diabetes. The survey then asked if knowing this change in recommendation has changed or will change their screening practices in adolescents.
Main results. 1400 surveys were mailed. After 2 were excluded due to mailing issues, 52% of providers provided responses. Of these, 129 providers reported that they did not care for adolescents (age 10–17), resulting in 604 providers in the final sample, 398 pediatricians and 335 FPs.
The vast majority (92%) said they would screen the hypothetical case for diabetes, with most initially ordering a fasting test (fasting plasma glucose or 2-hour glucose tolerance test) (63%) or A1c test (58%). Of the 58% who planned to order HbA1c, only 35% ordered it in combination with a fasting test. HbA1c was significantly more likely to be ordered by pediatricians than by FPs (P = 0.001). After being presented with the new guidelines, 84% said then would now order HbA1c, a 27% increase.
Conclusion. In response to information about the new guidelines, providers were more likely to order A1c as part of initial testing. Due to the lower test performance in children and increased cost of the test, the use of HbA1c without fasting tests may result in missed diagnosis of T2D in adolescents as well as increased health care costs.
Commentary
Rates of childhood obesity continue to rise throughout the United States. Obese children are at risk for numerous comorbidities such as hypertension, hyperlipidemia, and T2D [1,2]. It is important for providers to use effective screening tools for risk assessment of prediabetes/T2DM in children.
The standard tests for diagnosing diabetes are the fasting plasma glucose test and the 2-hour plasma glucose test. While accurate, these tests are not convenient. In 2010, the ADA added an easier method of testing for T2D: an HbA1c, with results greater than or equal to 6.5% indicating diabetes [3]. However, this recommendation is controversial, given studies suggesting that HbA1c is not as reliable in children as it is in adults [4–6]. The ADA itself acknowledges that there are limited data in the pediatric population.
In this study, most providers were unaware of the 4-year-old revised guidelines offering the A1c option but are planning to apply the guidelines going forward. According to the study, this would result in a 27% increase in providers utilizing HbA1c.
Should increased uptake of A1c as an initial screening test be a concern? Using it in combination with other tests may be useful for assessing which adolescents will need further testing [3–6].Additionally, by starting with a test that can be performed in the office with no regard to fasting time, it is possible that more cases of T2D will be found by primary care providers treating adolescents.
A weakness of the study is the potential for response bias related to mailed surveys. An additional weakness is that the researchers utilized only 1 hypothetical situation. Providing additional hypothetical situations may have allowed for further understanding of screening practices. The investigators also did not include nurse practitioners or physician assistants in their sample, a growing percentage of whom may care for adolescent populations at risk for T2D or be primary referral sources.
Applications for Clinical Practice
Providers can use HbA1c to screen for diabetes in nonfasting adolescents at risk for diabetes. While the test may not be as accurate in pediatric patients, utilizing HbA1C as directed by the ADA may aid in diagnosing patients that may otherwise miss follow-up appointments to complete a fasting test.
—Jennifer L. Nahum, MSN, CPNP-AC, PPCNP-BC, and Allison Squires, PhD, RN
Study Overview
Objective. To examine the screening practices of family practitioners (FPs) and pediatricians for type 2 diabetes (T2D) in adolescents.
Design. Cross-sectional study.
Setting and participants. The researchers randomly sampled 700 pediatricians and 700 FPs who participated in direct patient care using the American Medical Association Physician Masterfile using a mail survey. Exclusion criteria included providers who were residents, hospital staff, retirees, or employed by federally owned medical facilities, certified with a subspecialty, or over age 70.
Main outcome measures. Providers were given a hypothetical case of an obese, female, teenaged patient with concurrent associated risk factors for T2D (family history of T2D, minority race, signs of insulin resistance) and asked what initial screening tests they would order. Respondents were then informed of the updated American Diabetes Association (ADA) guidelines that added hemoglobin A1c as a screening test to diagnose diabetes. The survey then asked if knowing this change in recommendation has changed or will change their screening practices in adolescents.
Main results. 1400 surveys were mailed. After 2 were excluded due to mailing issues, 52% of providers provided responses. Of these, 129 providers reported that they did not care for adolescents (age 10–17), resulting in 604 providers in the final sample, 398 pediatricians and 335 FPs.
The vast majority (92%) said they would screen the hypothetical case for diabetes, with most initially ordering a fasting test (fasting plasma glucose or 2-hour glucose tolerance test) (63%) or A1c test (58%). Of the 58% who planned to order HbA1c, only 35% ordered it in combination with a fasting test. HbA1c was significantly more likely to be ordered by pediatricians than by FPs (P = 0.001). After being presented with the new guidelines, 84% said then would now order HbA1c, a 27% increase.
Conclusion. In response to information about the new guidelines, providers were more likely to order A1c as part of initial testing. Due to the lower test performance in children and increased cost of the test, the use of HbA1c without fasting tests may result in missed diagnosis of T2D in adolescents as well as increased health care costs.
Commentary
Rates of childhood obesity continue to rise throughout the United States. Obese children are at risk for numerous comorbidities such as hypertension, hyperlipidemia, and T2D [1,2]. It is important for providers to use effective screening tools for risk assessment of prediabetes/T2DM in children.
The standard tests for diagnosing diabetes are the fasting plasma glucose test and the 2-hour plasma glucose test. While accurate, these tests are not convenient. In 2010, the ADA added an easier method of testing for T2D: an HbA1c, with results greater than or equal to 6.5% indicating diabetes [3]. However, this recommendation is controversial, given studies suggesting that HbA1c is not as reliable in children as it is in adults [4–6]. The ADA itself acknowledges that there are limited data in the pediatric population.
In this study, most providers were unaware of the 4-year-old revised guidelines offering the A1c option but are planning to apply the guidelines going forward. According to the study, this would result in a 27% increase in providers utilizing HbA1c.
Should increased uptake of A1c as an initial screening test be a concern? Using it in combination with other tests may be useful for assessing which adolescents will need further testing [3–6].Additionally, by starting with a test that can be performed in the office with no regard to fasting time, it is possible that more cases of T2D will be found by primary care providers treating adolescents.
A weakness of the study is the potential for response bias related to mailed surveys. An additional weakness is that the researchers utilized only 1 hypothetical situation. Providing additional hypothetical situations may have allowed for further understanding of screening practices. The investigators also did not include nurse practitioners or physician assistants in their sample, a growing percentage of whom may care for adolescent populations at risk for T2D or be primary referral sources.
Applications for Clinical Practice
Providers can use HbA1c to screen for diabetes in nonfasting adolescents at risk for diabetes. While the test may not be as accurate in pediatric patients, utilizing HbA1C as directed by the ADA may aid in diagnosing patients that may otherwise miss follow-up appointments to complete a fasting test.
—Jennifer L. Nahum, MSN, CPNP-AC, PPCNP-BC, and Allison Squires, PhD, RN
References
1. Freedman DS, Dietz WH, Srinivasan SR, Berenson GS. The relation of overweight to cardiovascular risk factors among children and adolescents: the Bogalusa Heart Study. Pediatrics 1999;103(6 Pt 1):1175–82.
2. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr 1996;128(5 Pt 1):608–15.
3. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics 2000 Mar;105(3 Pt 1):671–80.
4. Lee JM, Gebremariam A, Wu EL, et al. Evaluation of nonfasting tests to screen for childhood and adolescent dysglycemia. Diabetes Care 2011;34:2597–602.
5. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 2011;34:1306–11.
6. Lee JM, Wu EL, Tarini B, et al Diagnosis of diabetes using hemoglobin A1c: should recommendations in adults be extrapolated to adolescents? J Pediatr 2011;158:947–952.
References
1. Freedman DS, Dietz WH, Srinivasan SR, Berenson GS. The relation of overweight to cardiovascular risk factors among children and adolescents: the Bogalusa Heart Study. Pediatrics 1999;103(6 Pt 1):1175–82.
2. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr 1996;128(5 Pt 1):608–15.
3. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics 2000 Mar;105(3 Pt 1):671–80.
4. Lee JM, Gebremariam A, Wu EL, et al. Evaluation of nonfasting tests to screen for childhood and adolescent dysglycemia. Diabetes Care 2011;34:2597–602.
5. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 2011;34:1306–11.
6. Lee JM, Wu EL, Tarini B, et al Diagnosis of diabetes using hemoglobin A1c: should recommendations in adults be extrapolated to adolescents? J Pediatr 2011;158:947–952.
Issue
Journal of Clinical Outcomes Management - July 2014, Vol. 21, No. 7
Issue
Journal of Clinical Outcomes Management - July 2014, Vol. 21, No. 7
PARIS – Percutaneous left atrial appendage closure with an Amplatzer device in patients with nonvalvular atrial fibrillation was associated with significantly lower rates of all-cause and cardiovascular mortality, compared with oral anticoagulation, in a large propensity score–matched observational registry study.
Left atrial appendage closure (LAAC) also bested oral anticoagulation (OAC) with warfarin or a novel oral anticoagulant (NOAC) in terms of net clinical benefit on the basis of the device therapy’s greater protection against stroke and systemic embolism coupled with a trend, albeit not statistically significant, for fewer bleeding events, Steffen Gloekler, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
The Watchman LAAC device, commercially available both in Europe and the United States, has previously been shown to be superior to OAC in terms of efficacy and noninferior regarding safety. But there have been no randomized trials of an Amplatzer device versus OAC. This lack of data was the impetus for Dr. Gloekler and his coinvestigators to create a meticulously propensity-matched observational registry.
Five hundred consecutive patients with AF who received an Amplatzer Cardiac Plug or its second-generation version, the Amplatzer Amulet, during 2009-2014 were tightly matched to an equal number of AF patients on OAC based on age, sex, body mass index, left ventricular ejection fraction, renal function, coronary artery disease status, hemoglobin level, CHA2DS2-VASc score, and HAS-BLED score. During a mean 2.7 years, or 2,645 patient-years, of follow-up, the composite primary efficacy endpoint, composed of stroke, systemic embolism, and cardiovascular or unexplained death occurred in 5.6% of the LAAC group, compared with 7.8% of controls in the OAC arm, for a statistically significant 30% relative risk reduction. Disabling stroke occurred in 0.7% of Amplatzer patients versus 1.5% of controls. The ischemic stroke rate was 1.5% in the device therapy group and 2% in the OAC arm.
All-cause mortality occurred in 8.3% of Amplatzer patients and 11.6% of the OAC group, for a 28% relative risk reduction. The cardiovascular death rate was 4% in the Amplatzer group, compared with 6.5% of controls, for a 36% risk reduction.
The composite safety endpoint, comprising all major procedural adverse events and major or life-threatening bleeding during follow-up, occurred in 3.6% of the Amplatzer group and 4.6% of the OAC group, for a 20% relative risk reduction that is not significant at this point because of the low number of events. Major, life-threatening, or fatal bleeding occurred in 2% of Amplatzer recipients versus 5.5% of controls, added Dr. Gloekler of University Hospital in Bern, Switzerland.
The net clinical benefit, a composite of death, bleeding, or stroke, occurred in 8.1% of the Amplatzer group, compared with 10.9% of controls, for a significant 24% reduction in relative risk in favor of device therapy.
Of note, at 2.7 years of follow-up only 55% of the OAC group were still taking an anticoagulant: 38% of the original 500 patients were on warfarin, and 17% were taking a NOAC. At that point, 8% of the Amplatzer group were on any anticoagulation therapy.
Discussion of the study focused on that low rate of medication adherence in the OAC arm. Dr. Gloekler’s response was that, after looking at the literature, he was no longer surprised by the finding that only 55% of the control group were on OAC at follow-up.
“If you look in the literature, that’s exactly the real-world adherence for OACs. Even in all four certification trials for the NOACs, the rate of discontinuation was 30% after 2 years – and these were controlled studies. Ours was observational, and it depicts a good deal of the problem with any OAC in my eyes,” Dr. Gloekler said.
Patients on warfarin in the real-world Amplatzer registry study spent on average a mere 30% of time in the therapeutic international normalized ratio range of 2-3.
“That means 70% of the time patients are higher and have an increased bleeding risk or they are lower and don’t have adequate stroke protection,” he noted.
This prompted one observer to comment, “We either have to do a better job in our clinics with OAC or we have to occlude more appendages.”
A large pivotal U.S. trial aimed at winning FDA approval for the Amplatzer Amulet for LAAC is underway. Patients with AF are being randomized to the approved Watchman or investigational Amulet at roughly 100 U.S. and 50 foreign sites.
Dr. Gloekler reported receiving research funds for the registry from the Swiss Heart Foundation and Abbott.
PARIS – Percutaneous left atrial appendage closure with an Amplatzer device in patients with nonvalvular atrial fibrillation was associated with significantly lower rates of all-cause and cardiovascular mortality, compared with oral anticoagulation, in a large propensity score–matched observational registry study.
Left atrial appendage closure (LAAC) also bested oral anticoagulation (OAC) with warfarin or a novel oral anticoagulant (NOAC) in terms of net clinical benefit on the basis of the device therapy’s greater protection against stroke and systemic embolism coupled with a trend, albeit not statistically significant, for fewer bleeding events, Steffen Gloekler, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
The Watchman LAAC device, commercially available both in Europe and the United States, has previously been shown to be superior to OAC in terms of efficacy and noninferior regarding safety. But there have been no randomized trials of an Amplatzer device versus OAC. This lack of data was the impetus for Dr. Gloekler and his coinvestigators to create a meticulously propensity-matched observational registry.
Five hundred consecutive patients with AF who received an Amplatzer Cardiac Plug or its second-generation version, the Amplatzer Amulet, during 2009-2014 were tightly matched to an equal number of AF patients on OAC based on age, sex, body mass index, left ventricular ejection fraction, renal function, coronary artery disease status, hemoglobin level, CHA2DS2-VASc score, and HAS-BLED score. During a mean 2.7 years, or 2,645 patient-years, of follow-up, the composite primary efficacy endpoint, composed of stroke, systemic embolism, and cardiovascular or unexplained death occurred in 5.6% of the LAAC group, compared with 7.8% of controls in the OAC arm, for a statistically significant 30% relative risk reduction. Disabling stroke occurred in 0.7% of Amplatzer patients versus 1.5% of controls. The ischemic stroke rate was 1.5% in the device therapy group and 2% in the OAC arm.
All-cause mortality occurred in 8.3% of Amplatzer patients and 11.6% of the OAC group, for a 28% relative risk reduction. The cardiovascular death rate was 4% in the Amplatzer group, compared with 6.5% of controls, for a 36% risk reduction.
The composite safety endpoint, comprising all major procedural adverse events and major or life-threatening bleeding during follow-up, occurred in 3.6% of the Amplatzer group and 4.6% of the OAC group, for a 20% relative risk reduction that is not significant at this point because of the low number of events. Major, life-threatening, or fatal bleeding occurred in 2% of Amplatzer recipients versus 5.5% of controls, added Dr. Gloekler of University Hospital in Bern, Switzerland.
The net clinical benefit, a composite of death, bleeding, or stroke, occurred in 8.1% of the Amplatzer group, compared with 10.9% of controls, for a significant 24% reduction in relative risk in favor of device therapy.
Of note, at 2.7 years of follow-up only 55% of the OAC group were still taking an anticoagulant: 38% of the original 500 patients were on warfarin, and 17% were taking a NOAC. At that point, 8% of the Amplatzer group were on any anticoagulation therapy.
Discussion of the study focused on that low rate of medication adherence in the OAC arm. Dr. Gloekler’s response was that, after looking at the literature, he was no longer surprised by the finding that only 55% of the control group were on OAC at follow-up.
“If you look in the literature, that’s exactly the real-world adherence for OACs. Even in all four certification trials for the NOACs, the rate of discontinuation was 30% after 2 years – and these were controlled studies. Ours was observational, and it depicts a good deal of the problem with any OAC in my eyes,” Dr. Gloekler said.
Patients on warfarin in the real-world Amplatzer registry study spent on average a mere 30% of time in the therapeutic international normalized ratio range of 2-3.
“That means 70% of the time patients are higher and have an increased bleeding risk or they are lower and don’t have adequate stroke protection,” he noted.
This prompted one observer to comment, “We either have to do a better job in our clinics with OAC or we have to occlude more appendages.”
A large pivotal U.S. trial aimed at winning FDA approval for the Amplatzer Amulet for LAAC is underway. Patients with AF are being randomized to the approved Watchman or investigational Amulet at roughly 100 U.S. and 50 foreign sites.
Dr. Gloekler reported receiving research funds for the registry from the Swiss Heart Foundation and Abbott.
PARIS – Percutaneous left atrial appendage closure with an Amplatzer device in patients with nonvalvular atrial fibrillation was associated with significantly lower rates of all-cause and cardiovascular mortality, compared with oral anticoagulation, in a large propensity score–matched observational registry study.
Left atrial appendage closure (LAAC) also bested oral anticoagulation (OAC) with warfarin or a novel oral anticoagulant (NOAC) in terms of net clinical benefit on the basis of the device therapy’s greater protection against stroke and systemic embolism coupled with a trend, albeit not statistically significant, for fewer bleeding events, Steffen Gloekler, MD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
The Watchman LAAC device, commercially available both in Europe and the United States, has previously been shown to be superior to OAC in terms of efficacy and noninferior regarding safety. But there have been no randomized trials of an Amplatzer device versus OAC. This lack of data was the impetus for Dr. Gloekler and his coinvestigators to create a meticulously propensity-matched observational registry.
Five hundred consecutive patients with AF who received an Amplatzer Cardiac Plug or its second-generation version, the Amplatzer Amulet, during 2009-2014 were tightly matched to an equal number of AF patients on OAC based on age, sex, body mass index, left ventricular ejection fraction, renal function, coronary artery disease status, hemoglobin level, CHA2DS2-VASc score, and HAS-BLED score. During a mean 2.7 years, or 2,645 patient-years, of follow-up, the composite primary efficacy endpoint, composed of stroke, systemic embolism, and cardiovascular or unexplained death occurred in 5.6% of the LAAC group, compared with 7.8% of controls in the OAC arm, for a statistically significant 30% relative risk reduction. Disabling stroke occurred in 0.7% of Amplatzer patients versus 1.5% of controls. The ischemic stroke rate was 1.5% in the device therapy group and 2% in the OAC arm.
All-cause mortality occurred in 8.3% of Amplatzer patients and 11.6% of the OAC group, for a 28% relative risk reduction. The cardiovascular death rate was 4% in the Amplatzer group, compared with 6.5% of controls, for a 36% risk reduction.
The composite safety endpoint, comprising all major procedural adverse events and major or life-threatening bleeding during follow-up, occurred in 3.6% of the Amplatzer group and 4.6% of the OAC group, for a 20% relative risk reduction that is not significant at this point because of the low number of events. Major, life-threatening, or fatal bleeding occurred in 2% of Amplatzer recipients versus 5.5% of controls, added Dr. Gloekler of University Hospital in Bern, Switzerland.
The net clinical benefit, a composite of death, bleeding, or stroke, occurred in 8.1% of the Amplatzer group, compared with 10.9% of controls, for a significant 24% reduction in relative risk in favor of device therapy.
Of note, at 2.7 years of follow-up only 55% of the OAC group were still taking an anticoagulant: 38% of the original 500 patients were on warfarin, and 17% were taking a NOAC. At that point, 8% of the Amplatzer group were on any anticoagulation therapy.
Discussion of the study focused on that low rate of medication adherence in the OAC arm. Dr. Gloekler’s response was that, after looking at the literature, he was no longer surprised by the finding that only 55% of the control group were on OAC at follow-up.
“If you look in the literature, that’s exactly the real-world adherence for OACs. Even in all four certification trials for the NOACs, the rate of discontinuation was 30% after 2 years – and these were controlled studies. Ours was observational, and it depicts a good deal of the problem with any OAC in my eyes,” Dr. Gloekler said.
Patients on warfarin in the real-world Amplatzer registry study spent on average a mere 30% of time in the therapeutic international normalized ratio range of 2-3.
“That means 70% of the time patients are higher and have an increased bleeding risk or they are lower and don’t have adequate stroke protection,” he noted.
This prompted one observer to comment, “We either have to do a better job in our clinics with OAC or we have to occlude more appendages.”
A large pivotal U.S. trial aimed at winning FDA approval for the Amplatzer Amulet for LAAC is underway. Patients with AF are being randomized to the approved Watchman or investigational Amulet at roughly 100 U.S. and 50 foreign sites.
Dr. Gloekler reported receiving research funds for the registry from the Swiss Heart Foundation and Abbott.
Key clinical point: Patients with atrial fibrillation who received an Amplatzer left atrial appendage closure device did significantly better over time than a matched group on oral anticoagulation.
Major finding: The primary composite efficacy endpoint of stroke, systemic embolism, or cardiovascular or unexplained death during a mean 2.7 years of follow-up occurred in 5.6% of Amplatzer device recipients, a 30% reduction, compared with the 7.8% rate in the oral anticoagulation group.
Data source: This observational registry included 500 patients with atrial fibrillation who received an Amplatzer left atrial appendage closure device and an equal number of carefully matched AF patients on oral anticoagulation.
Disclosures: The study presenter reported receiving research funds for the registry from the Swiss Heart Foundation and Abbott.
Outpatient care represents the largest share of mental health treatment expenditures, and it continues to get larger, while components such as retail drug prescriptions and inpatient care have declined, according to the National Center of Health Statistics.
In 2014, outpatient care took a $65.5-billion slice (about 35%) out of the $186-billion mental health care spending pie, compared with the $51.1 billion (27%) spent on retail drug prescriptions, which was the next-largest portion. Inpatient care was third with $30.3 billion in spending (16% of the total), followed by residential care at $23.2 billion (12%), and insurance administration at $15.9 billion (9%), the NCHS reported in “Health, United States, 2016.”
The distribution of spending has changed considerably since 1986, when mental health expenditures totaled $32.4 billion and inpatient care was the largest share at 41%, outpatient care was 24%, residential care was 22%, retail prescription drugs were 8%, and insurance administration was 5%, according to data from the Substance Abuse and Mental Health Services Administration’s Behavioral Health Spending and Use Accounts.
Outpatient care represents the largest share of mental health treatment expenditures, and it continues to get larger, while components such as retail drug prescriptions and inpatient care have declined, according to the National Center of Health Statistics.
In 2014, outpatient care took a $65.5-billion slice (about 35%) out of the $186-billion mental health care spending pie, compared with the $51.1 billion (27%) spent on retail drug prescriptions, which was the next-largest portion. Inpatient care was third with $30.3 billion in spending (16% of the total), followed by residential care at $23.2 billion (12%), and insurance administration at $15.9 billion (9%), the NCHS reported in “Health, United States, 2016.”
The distribution of spending has changed considerably since 1986, when mental health expenditures totaled $32.4 billion and inpatient care was the largest share at 41%, outpatient care was 24%, residential care was 22%, retail prescription drugs were 8%, and insurance administration was 5%, according to data from the Substance Abuse and Mental Health Services Administration’s Behavioral Health Spending and Use Accounts.
Outpatient care represents the largest share of mental health treatment expenditures, and it continues to get larger, while components such as retail drug prescriptions and inpatient care have declined, according to the National Center of Health Statistics.
In 2014, outpatient care took a $65.5-billion slice (about 35%) out of the $186-billion mental health care spending pie, compared with the $51.1 billion (27%) spent on retail drug prescriptions, which was the next-largest portion. Inpatient care was third with $30.3 billion in spending (16% of the total), followed by residential care at $23.2 billion (12%), and insurance administration at $15.9 billion (9%), the NCHS reported in “Health, United States, 2016.”
The distribution of spending has changed considerably since 1986, when mental health expenditures totaled $32.4 billion and inpatient care was the largest share at 41%, outpatient care was 24%, residential care was 22%, retail prescription drugs were 8%, and insurance administration was 5%, according to data from the Substance Abuse and Mental Health Services Administration’s Behavioral Health Spending and Use Accounts.
The Food and Drug Administration approved L-glutamine oral powder for reducing severe complications of sickle cell disease in patients aged 5 years and older.
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
This is only the second drug approved by FDA for sickle cell disease, and the first approval in nearly 20 years, Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence, said in the agency’s announcement.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
The Food and Drug Administration approved L-glutamine oral powder for reducing severe complications of sickle cell disease in patients aged 5 years and older.
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
This is only the second drug approved by FDA for sickle cell disease, and the first approval in nearly 20 years, Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence, said in the agency’s announcement.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
The Food and Drug Administration approved L-glutamine oral powder for reducing severe complications of sickle cell disease in patients aged 5 years and older.
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
This is only the second drug approved by FDA for sickle cell disease, and the first approval in nearly 20 years, Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence, said in the agency’s announcement.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.
Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
Neil Osterweil/Frontline Medical News
Dr. Franck Morschhauser
Tazemetostat is an oral inhibitor of both the wild-type and mutated forms of the gene encoding for EZH2, a histone methyltransferase. The drug shows significantly more activity against the mutated form of the gene than the wild type, but some patients in the trial with the wild-type gene have had complete responses, Dr. Morschhauser said at the International Conference on Malignant Lymphoma.
“What we observed is a four-fold increase in [ORR in] follicular lymphoma-mutated patients compared to wild-type patients, a two-fold increase in DLBCL patients mutated compared to wild-type patients,” he said.
“But if we had focused [only] on the actionable mutation, we would have missed those other complete responders in the wild-type setting,” he added.
EZH2, an epigenetic regulator of gene expression, had been shown in preclinical studies to play an important role in multiple forms of cancers, and activating mutations of EZH2 have been shown to be oncogenic drivers in approximately 20% of FL and germinal center B-cell–like DLBCL, Dr. Morschhauser explained.
EZH2 has also been shown to be over-expressed in leukemia-initiating cells in patients with chronic myeloid leukemia, and EZH2 inhibitors are being explored as a possible therapy for patients with chronic myeloid leukemia that has become resistant to tyrosine kinase inhibitors.
Large multicenter study
Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.
In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.
The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.
Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.
Among the patients with FL, 75% had significant reduction in tumor burden.
The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.
The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.
The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.
In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.
Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.
“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.
The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.
The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.
LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.
Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
Neil Osterweil/Frontline Medical News
Dr. Franck Morschhauser
Tazemetostat is an oral inhibitor of both the wild-type and mutated forms of the gene encoding for EZH2, a histone methyltransferase. The drug shows significantly more activity against the mutated form of the gene than the wild type, but some patients in the trial with the wild-type gene have had complete responses, Dr. Morschhauser said at the International Conference on Malignant Lymphoma.
“What we observed is a four-fold increase in [ORR in] follicular lymphoma-mutated patients compared to wild-type patients, a two-fold increase in DLBCL patients mutated compared to wild-type patients,” he said.
“But if we had focused [only] on the actionable mutation, we would have missed those other complete responders in the wild-type setting,” he added.
EZH2, an epigenetic regulator of gene expression, had been shown in preclinical studies to play an important role in multiple forms of cancers, and activating mutations of EZH2 have been shown to be oncogenic drivers in approximately 20% of FL and germinal center B-cell–like DLBCL, Dr. Morschhauser explained.
EZH2 has also been shown to be over-expressed in leukemia-initiating cells in patients with chronic myeloid leukemia, and EZH2 inhibitors are being explored as a possible therapy for patients with chronic myeloid leukemia that has become resistant to tyrosine kinase inhibitors.
Large multicenter study
Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.
In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.
The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.
Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.
Among the patients with FL, 75% had significant reduction in tumor burden.
The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.
The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.
The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.
In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.
Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.
“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.
The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.
The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.
LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.
Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
Neil Osterweil/Frontline Medical News
Dr. Franck Morschhauser
Tazemetostat is an oral inhibitor of both the wild-type and mutated forms of the gene encoding for EZH2, a histone methyltransferase. The drug shows significantly more activity against the mutated form of the gene than the wild type, but some patients in the trial with the wild-type gene have had complete responses, Dr. Morschhauser said at the International Conference on Malignant Lymphoma.
“What we observed is a four-fold increase in [ORR in] follicular lymphoma-mutated patients compared to wild-type patients, a two-fold increase in DLBCL patients mutated compared to wild-type patients,” he said.
“But if we had focused [only] on the actionable mutation, we would have missed those other complete responders in the wild-type setting,” he added.
EZH2, an epigenetic regulator of gene expression, had been shown in preclinical studies to play an important role in multiple forms of cancers, and activating mutations of EZH2 have been shown to be oncogenic drivers in approximately 20% of FL and germinal center B-cell–like DLBCL, Dr. Morschhauser explained.
EZH2 has also been shown to be over-expressed in leukemia-initiating cells in patients with chronic myeloid leukemia, and EZH2 inhibitors are being explored as a possible therapy for patients with chronic myeloid leukemia that has become resistant to tyrosine kinase inhibitors.
Large multicenter study
Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.
In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.
The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.
Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.
Among the patients with FL, 75% had significant reduction in tumor burden.
The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.
The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.
The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.
In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.
Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.
“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.
The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.
The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.
Key clinical point: The experimental drug tazemetostat induced responses in patients with heavily pretreated follicular lymphoma (FL) with mutations in EZH2.
Major finding: The overall response rate among patients with FL with mutated EZH2 was 92%.
Data source: Multicenter, open-label phase II study in patients with relapsed/refractory FL and diffuse large B cell lymphoma.
Disclosures: The study is sponsored by Epizyme. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.
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Opioid prescribing in the United States declined overall between 2010 and 2015, but remained stable or increased in some counties, according to a report from the Centers for Disease Control and Prevention. The findings were published online in the CDC’s Morbidity and Mortality Weekly Report.
“The bottom line remains: We have too many people getting too many prescriptions at too high a dose,” Anne Schuchat, MD, acting director of the CDC, said in a July 6 teleconference.
Providers in the highest-prescribing counties prescribed six times more opioids per person than in the lowest-prescribing counties in 2015, she noted.
CDC researchers calculated prescribing rates from 2006 to 2015 by dividing the number of opioid prescriptions by the population estimates from the U.S. census for each year and created quartiles using morphine milligram equivalent per capita to analyze opioid distribution. Annual opioid prescribing rates increased from 72 to 81 prescriptions per 100 persons from 2006 to 2010 and remained relatively constant from 2010 to 2012 before showing a 13% decrease to 71 prescriptions per 100 persons from 2012 to 2015 (MMWR. 2017 Jul 7;66[26]:697-704. doi: 10.15585/mmwr.mm6626a4).
But despite these overall declines, “We are now experiencing the highest overdose death rates ever recorded in the United States,” Dr. Schuchat said. Quartiles were created using MME per capita to characterize the distribution of opioids prescribed.
In the report, areas associated with higher opioid prescribing rates on a county level included small cities or towns, areas that had a higher proportion of white residents, areas with more doctors and dentists, and areas with more cases of arthritis, diabetes, or other disabilities, she said.
The findings suggest a need for more consistency among health care providers about prescription opioids, Dr. Schuchat said. “Clinical practice is all over the place, which is a sign that you need better standards; we hope the 2016 guidelines are a turning point for better prescribing,” she said.
The CDC’s guidelines on opioid prescribing were released in 2016. The guidelines recommend alternatives when possible. Clinicians should instead consider nonopioid therapy, other types of pain medication, and nondrug pain relief options, such as physical therapy and cognitive-behavioral therapy. Other concerns include the length and strength of opioid prescriptions. Even taking opioids for a few months increases the risk for addiction, Dr. Schuchat said.
“Physicians must continue to lead efforts to reverse the epidemic by using prescription drug–monitoring programs, eliminating stigma, prescribing the overdose reversal drug naloxone, and enhancing their education about safe opioid prescribing and effective pain management,” Patrice A. Harris, MD, chair of the American Medical Association Opioid Task Force, said in a statement in response to the report. “Our country must do more to provide evidence-based, comprehensive treatment for pain and for substance use disorders,” she said.
“We really encourage clinicians to look to the guidelines and the tools that are available,” Dr. Schuchat said. “We do know that internists and other primary care physicians prescribe most of the opioids, so it is important for them to be aware.” The CDC has developed a checklist and a mobile app that have been downloaded by thousands of clinicians so far, she noted. Changes in annual prescribing hold promise that practices can improve, she said.
The researchers reported no conflicts of interest.
Opioid prescribing in the United States declined overall between 2010 and 2015, but remained stable or increased in some counties, according to a report from the Centers for Disease Control and Prevention. The findings were published online in the CDC’s Morbidity and Mortality Weekly Report.
“The bottom line remains: We have too many people getting too many prescriptions at too high a dose,” Anne Schuchat, MD, acting director of the CDC, said in a July 6 teleconference.
Providers in the highest-prescribing counties prescribed six times more opioids per person than in the lowest-prescribing counties in 2015, she noted.
CDC researchers calculated prescribing rates from 2006 to 2015 by dividing the number of opioid prescriptions by the population estimates from the U.S. census for each year and created quartiles using morphine milligram equivalent per capita to analyze opioid distribution. Annual opioid prescribing rates increased from 72 to 81 prescriptions per 100 persons from 2006 to 2010 and remained relatively constant from 2010 to 2012 before showing a 13% decrease to 71 prescriptions per 100 persons from 2012 to 2015 (MMWR. 2017 Jul 7;66[26]:697-704. doi: 10.15585/mmwr.mm6626a4).
But despite these overall declines, “We are now experiencing the highest overdose death rates ever recorded in the United States,” Dr. Schuchat said. Quartiles were created using MME per capita to characterize the distribution of opioids prescribed.
In the report, areas associated with higher opioid prescribing rates on a county level included small cities or towns, areas that had a higher proportion of white residents, areas with more doctors and dentists, and areas with more cases of arthritis, diabetes, or other disabilities, she said.
The findings suggest a need for more consistency among health care providers about prescription opioids, Dr. Schuchat said. “Clinical practice is all over the place, which is a sign that you need better standards; we hope the 2016 guidelines are a turning point for better prescribing,” she said.
The CDC’s guidelines on opioid prescribing were released in 2016. The guidelines recommend alternatives when possible. Clinicians should instead consider nonopioid therapy, other types of pain medication, and nondrug pain relief options, such as physical therapy and cognitive-behavioral therapy. Other concerns include the length and strength of opioid prescriptions. Even taking opioids for a few months increases the risk for addiction, Dr. Schuchat said.
“Physicians must continue to lead efforts to reverse the epidemic by using prescription drug–monitoring programs, eliminating stigma, prescribing the overdose reversal drug naloxone, and enhancing their education about safe opioid prescribing and effective pain management,” Patrice A. Harris, MD, chair of the American Medical Association Opioid Task Force, said in a statement in response to the report. “Our country must do more to provide evidence-based, comprehensive treatment for pain and for substance use disorders,” she said.
“We really encourage clinicians to look to the guidelines and the tools that are available,” Dr. Schuchat said. “We do know that internists and other primary care physicians prescribe most of the opioids, so it is important for them to be aware.” The CDC has developed a checklist and a mobile app that have been downloaded by thousands of clinicians so far, she noted. Changes in annual prescribing hold promise that practices can improve, she said.
The researchers reported no conflicts of interest.
Opioid prescribing in the United States declined overall between 2010 and 2015, but remained stable or increased in some counties, according to a report from the Centers for Disease Control and Prevention. The findings were published online in the CDC’s Morbidity and Mortality Weekly Report.
“The bottom line remains: We have too many people getting too many prescriptions at too high a dose,” Anne Schuchat, MD, acting director of the CDC, said in a July 6 teleconference.
Providers in the highest-prescribing counties prescribed six times more opioids per person than in the lowest-prescribing counties in 2015, she noted.
CDC researchers calculated prescribing rates from 2006 to 2015 by dividing the number of opioid prescriptions by the population estimates from the U.S. census for each year and created quartiles using morphine milligram equivalent per capita to analyze opioid distribution. Annual opioid prescribing rates increased from 72 to 81 prescriptions per 100 persons from 2006 to 2010 and remained relatively constant from 2010 to 2012 before showing a 13% decrease to 71 prescriptions per 100 persons from 2012 to 2015 (MMWR. 2017 Jul 7;66[26]:697-704. doi: 10.15585/mmwr.mm6626a4).
But despite these overall declines, “We are now experiencing the highest overdose death rates ever recorded in the United States,” Dr. Schuchat said. Quartiles were created using MME per capita to characterize the distribution of opioids prescribed.
In the report, areas associated with higher opioid prescribing rates on a county level included small cities or towns, areas that had a higher proportion of white residents, areas with more doctors and dentists, and areas with more cases of arthritis, diabetes, or other disabilities, she said.
The findings suggest a need for more consistency among health care providers about prescription opioids, Dr. Schuchat said. “Clinical practice is all over the place, which is a sign that you need better standards; we hope the 2016 guidelines are a turning point for better prescribing,” she said.
The CDC’s guidelines on opioid prescribing were released in 2016. The guidelines recommend alternatives when possible. Clinicians should instead consider nonopioid therapy, other types of pain medication, and nondrug pain relief options, such as physical therapy and cognitive-behavioral therapy. Other concerns include the length and strength of opioid prescriptions. Even taking opioids for a few months increases the risk for addiction, Dr. Schuchat said.
“Physicians must continue to lead efforts to reverse the epidemic by using prescription drug–monitoring programs, eliminating stigma, prescribing the overdose reversal drug naloxone, and enhancing their education about safe opioid prescribing and effective pain management,” Patrice A. Harris, MD, chair of the American Medical Association Opioid Task Force, said in a statement in response to the report. “Our country must do more to provide evidence-based, comprehensive treatment for pain and for substance use disorders,” she said.
“We really encourage clinicians to look to the guidelines and the tools that are available,” Dr. Schuchat said. “We do know that internists and other primary care physicians prescribe most of the opioids, so it is important for them to be aware.” The CDC has developed a checklist and a mobile app that have been downloaded by thousands of clinicians so far, she noted. Changes in annual prescribing hold promise that practices can improve, she said.
The researchers reported no conflicts of interest.
The Food and Drug Administration has approved abatacept, a selective T-cell costimulation modulator, for treating adults with active psoriatic arthritis (PsA), the manufacturer, Bristol-Myers Squibb, has announced.
Approval of abatacept (Orencia) was based on two randomized, double-blind, placebo-controlled studies (PsA-I and PsA-II) in 594 adults with PsA for more than 7 years, according to the July 6 announcement. Patients had active PsA (at least three swollen joints and at least three tender joints), despite previous disease-modifying antirheumatic drug (DMARD) therapy and had one qualifying psoriatic skin lesion measuring at least 2 cm in diameter. The studies included patients treated with TNF inhibitors (TNFi) previously.
In the PsA-I trial, 170 patients received abatacept administered intravenously (IV) at days 1, 15, 29, and then every 28 days for 24 weeks, followed by open-label abatacept every 28 days. Patients were then randomized to placebo or treatment with abatacept 3 mg/kg, 10 mg/kg, or two doses of 30 mg/kg followed by weight range–based dosing of 10 mg/kg without escape for 24 weeks.
In the PsA-II trial, 424 patients received weekly doses of placebo or abatacept 25 mg administered subcutaneously (SC) without a loading dose for 24 weeks, followed by open-label abatacept at a dose of 125 mg SC weekly.
Compared with those on placebo, more patients treated with abatacept 10 mg/kg IV or 125 mg SC achieved an ACR 20 (American College of Rheumatology 20) response at 24 weeks: 47.5% vs. 19.0% and 39.4% vs. 22.3%, respectively (P less than .05).
Other results included a greater proportion of abatacept SC patients with at least a 0.35 decrease from baseline on the Health Assessment Questionnaire-Disability Index: 31% vs. 24% on placebo at 24 weeks. Responses were seen regardless of prior anti-TNFi treatment and regardless of concomitant non-biologic DMARD treatment. In addition, patients on abatacept IV and SC had improvements in enthesitis and dactylitis at 24 weeks.
The safety profile of abatacept in the two studies was “consistent with the safety profile” in rheumatoid arthritis, according to the company release.
Abatacept, initially approved in 2005, was previously approved for RA in adults and for juvenile idiopathic arthritis
Find the updated prescribing information for abatacept here.
The Food and Drug Administration has approved abatacept, a selective T-cell costimulation modulator, for treating adults with active psoriatic arthritis (PsA), the manufacturer, Bristol-Myers Squibb, has announced.
Approval of abatacept (Orencia) was based on two randomized, double-blind, placebo-controlled studies (PsA-I and PsA-II) in 594 adults with PsA for more than 7 years, according to the July 6 announcement. Patients had active PsA (at least three swollen joints and at least three tender joints), despite previous disease-modifying antirheumatic drug (DMARD) therapy and had one qualifying psoriatic skin lesion measuring at least 2 cm in diameter. The studies included patients treated with TNF inhibitors (TNFi) previously.
In the PsA-I trial, 170 patients received abatacept administered intravenously (IV) at days 1, 15, 29, and then every 28 days for 24 weeks, followed by open-label abatacept every 28 days. Patients were then randomized to placebo or treatment with abatacept 3 mg/kg, 10 mg/kg, or two doses of 30 mg/kg followed by weight range–based dosing of 10 mg/kg without escape for 24 weeks.
In the PsA-II trial, 424 patients received weekly doses of placebo or abatacept 25 mg administered subcutaneously (SC) without a loading dose for 24 weeks, followed by open-label abatacept at a dose of 125 mg SC weekly.
Compared with those on placebo, more patients treated with abatacept 10 mg/kg IV or 125 mg SC achieved an ACR 20 (American College of Rheumatology 20) response at 24 weeks: 47.5% vs. 19.0% and 39.4% vs. 22.3%, respectively (P less than .05).
Other results included a greater proportion of abatacept SC patients with at least a 0.35 decrease from baseline on the Health Assessment Questionnaire-Disability Index: 31% vs. 24% on placebo at 24 weeks. Responses were seen regardless of prior anti-TNFi treatment and regardless of concomitant non-biologic DMARD treatment. In addition, patients on abatacept IV and SC had improvements in enthesitis and dactylitis at 24 weeks.
The safety profile of abatacept in the two studies was “consistent with the safety profile” in rheumatoid arthritis, according to the company release.
Abatacept, initially approved in 2005, was previously approved for RA in adults and for juvenile idiopathic arthritis
Find the updated prescribing information for abatacept here.
The Food and Drug Administration has approved abatacept, a selective T-cell costimulation modulator, for treating adults with active psoriatic arthritis (PsA), the manufacturer, Bristol-Myers Squibb, has announced.
Approval of abatacept (Orencia) was based on two randomized, double-blind, placebo-controlled studies (PsA-I and PsA-II) in 594 adults with PsA for more than 7 years, according to the July 6 announcement. Patients had active PsA (at least three swollen joints and at least three tender joints), despite previous disease-modifying antirheumatic drug (DMARD) therapy and had one qualifying psoriatic skin lesion measuring at least 2 cm in diameter. The studies included patients treated with TNF inhibitors (TNFi) previously.
In the PsA-I trial, 170 patients received abatacept administered intravenously (IV) at days 1, 15, 29, and then every 28 days for 24 weeks, followed by open-label abatacept every 28 days. Patients were then randomized to placebo or treatment with abatacept 3 mg/kg, 10 mg/kg, or two doses of 30 mg/kg followed by weight range–based dosing of 10 mg/kg without escape for 24 weeks.
In the PsA-II trial, 424 patients received weekly doses of placebo or abatacept 25 mg administered subcutaneously (SC) without a loading dose for 24 weeks, followed by open-label abatacept at a dose of 125 mg SC weekly.
Compared with those on placebo, more patients treated with abatacept 10 mg/kg IV or 125 mg SC achieved an ACR 20 (American College of Rheumatology 20) response at 24 weeks: 47.5% vs. 19.0% and 39.4% vs. 22.3%, respectively (P less than .05).
Other results included a greater proportion of abatacept SC patients with at least a 0.35 decrease from baseline on the Health Assessment Questionnaire-Disability Index: 31% vs. 24% on placebo at 24 weeks. Responses were seen regardless of prior anti-TNFi treatment and regardless of concomitant non-biologic DMARD treatment. In addition, patients on abatacept IV and SC had improvements in enthesitis and dactylitis at 24 weeks.
The safety profile of abatacept in the two studies was “consistent with the safety profile” in rheumatoid arthritis, according to the company release.
Abatacept, initially approved in 2005, was previously approved for RA in adults and for juvenile idiopathic arthritis
Find the updated prescribing information for abatacept here.
Interstitial lung disease (ILD) encompasses a diverse group of disorders that cause inflammation and fibrosis of the lung parenchyma. The clinical manifestations, disease course, management and prognosis of ILD vary depending on the underlying subtype, making accurate classification and diagnosis an important initial step. While a comprehensive list of ILD contains dozens of disorders, the majority of patients will fall into 1 of 3 categories: exposure-related ILD, connective tissue disease-related ILD (CT-ILD), and the idiopathic interstitial pneumonias (Table).
An essential first step in the evaluation of every hospitalized patient with ILD is establishing a diagnosis. A common mistake among clinicians who diagnose patients with ILD is not realizing that ILD is a collection of diseases with different etiologies, natural histories, and treatments. A careful evaluation should be performed in every hospitalized patient with ILD to ensure an accurate diagnosis, ideally in the context of a multidisciplinary conference with pulmonary, radiology, pathology, and other specialties, as appropriate. A multidisciplinary panel of the American Thoracic Society/European Respiratory Society recently published a revised classification of ILD based on a combination of clinical, radiologic, and histopathologic findings, which may aid in refining the diagnosis.1
There are 3 main scenarios in which the hospital physician will encounter patients with ILD.
Acute presentation of new-onset disease. While many ILDs present insidiously, some cases present acutely and require hospitalization. The most common of these are acute hypersensitivity pneumonitis (HP), CT-ILD (in particular, myositis-related and systemic lupus erythematosus-related), drug-induced ILD (eg, amiodarone, nitrofurantoin), cryptogenic organizing pneumonia (COP), acute eosinophilic pneumonia (AEP), and acute interstitial pneumonia (AIP).
Acute presentation of established (chronic) disease. Patients with chronic forms of ILD can present to the hospital with an acute exacerbation of disease. This can be caused by extra-parenchymal complications, including pulmonary embolism, pneumothorax, and pleural effusion; parenchymal complications such as infectious pneumonia, aspiration pneumonitis, and congestive heart failure; or without an identifiable cause. This latter presentation is most commonly seen in idiopathic pulmonary fibrosis (IPF).2,3
Elective hospitalization for diagnostic surgical lung biopsy. Patients with ILD may be hospitalized electively for a laparoscopic surgical lung biopsy as part of their diagnostic evaluations.
Physicians caring for a hospitalized ILD patient must be familiar with the clinical presentations, diagnostic approach, medical management, and outpatient follow-up recommended in these 3 settings. We will summarize these areas and provide answers to commonly encountered clinical questions in the hospitalized patient with ILD.
CLINICAL PRESENTATION
Acute onset (or worsening) of dyspnea is the primary presenting symptom in most patients hospitalized for ILD. This symptom should be further characterized by assessing the degree of dyspnea and the extent of exercise limitation, as both impact overall disease severity and prognosis.4 Cough is the second most common symptom, and can be nonproductive, as is common in IPF, or be associated with secretions if parenchymal infection or acute bronchitis is present.5 Pleuritic chest pain, pleural effusion, and/or the presence of extrapulmonary features, including dysphagia, joint pain and swelling, or cutaneous thickening may suggest the presence of a CT-ILD. Because most forms of ILD present with only nonspecific symptoms, a careful history and physical examination are essential.
DIAGNOSIS
History
A comprehensive patient history is the backbone of diagnosing any ILD. History-taking should focus on severity and temporal progression of symptoms, presence of pre-existing systemic conditions associated with ILD, symptoms of extrapulmonary disease, and exposures to substances that can cause pulmonary injury, including a detailed history of occupations and hobbies, medications, smoking, and familial lung disease.6-9 Physicians must try to exclude other diagnoses that could result in a similar acute presentation, including congestive heart failure and infection. Considering the complex and extensive recommended history-taking, physicians may find it helpful to use a standardized questionnaire, as provided by the American College of Chest Physicians.10
Laboratory Testing
All patients presenting to the hospital with a suspected ILD should undergo careful assessment for the presence of connective tissue disease, including patients without clear symptoms because ILD can be the presenting manifestation. We routinely test for antinuclear antibody titer and pattern, rheumatoid factor, anticyclic citrullinated peptide, creatinine kinase, and aldolase as the initial screening panel in most patients, with further testing directed by the findings on history and physical examination. Pulmonary function tests are used routinely to monitor disease progression in the outpatient setting; however, in the hospitalized ILD patient, they are often difficult to perform and have no real diagnostic value. Similarly, arterial blood gas is not routinely used as part of the initial inpatient evaluation.
Table
Imaging
All hospitalized patients with a known or suspected ILD should undergo chest imaging, assuming they are stable enough to do so. While the chest radiograph can provide a low-cost initial assessment of the degree of lung involvement and presence of accompanying abnormalities, computed tomography (CT) scanning is the diagnostic test of choice.11 The pattern and distribution of abnormalities on CT scan can greatly assist with the differential diagnosis in patients presenting with a new ILD, while the presence and pattern of new opacities superimposed on chronic changes can inform the differential and the prognosis of an ILD exacerbation.12 High-resolution CT provides the most sensitive imaging modality for diffuse ILD. The addition of prone and expiratory images are helpful in differentiating mild lung disease from atelectasis and detecting air trapping, respectively.13 However, since pulmonary embolism is a common extraparenchymal finding routinely considered in the differential of a patient presenting with a known or suspected ILD, physicians should consider ordering a CT pulmonary angiogram with additional high-resolution images. Most important, radiographic evaluation should include a review of all available prior chest imaging to assess both the tempo and the nature of radiographic findings.
Bronchoscopy
Bronchoscopy (with bronchoalveolar lavage [BAL], transbronchial lung biopsy [TBLB] and/or transbronchial needle aspiration [TBNA]) is not a routinely used diagnostic tool in the hospitalized ILD patient. However, it should be considered in certain circumstances.7 Cell count and differential can be helpful in diagnosing AEP (greater than 40% eosinophilia) or acute HP (greater than 50% lymphocytosis), while the addition of microbiologic and cytologic analysis can assist with the diagnosis of infectious etiologies (including pneumocystis pneumonia) or malignancy.14,15 Bronchoscopy with BAL has limited sensitivity for many infections and the procedure is associated with a small risk of worsened hypoxemia. Transbronchial lung biopsy, and to a lesser extent TBNA, carry the added risk of pneumothorax and bleeding. In the majority of cases of ILD, TBLB and TBNA have limited diagnostic utility given the small amount of lung tissue sampled. In cases of suspected IPF, where the identification of the histologic pattern is needed for definitive diagnosis, tissue from TBLB cannot be used to make a conclusive diagnosis.16,17 However, both TBNA and TBLB are useful in the diagnosis of granulomatous disorders, such as sarcoidosis, where the diagnostic yield ranges from 80% to 90% and 50% to 75%, respectively.18,19
A newer bronchoscopic approach to sampling the lung using a bronchoscopically-placed cryoprobe (termed transbronchial cryobiopsy) has uncertain diagnostic utility and safety in the acute setting. This procedure involves intubation, sedation, and bronchoscopy allowing for the passage of an endobronchial cryoprobe through the bronchoscope and into the periphery of the lung. Several cryobiopies are generally taken from the same pulmonary subsegment. Despite a large number of recent publications on this topic, none of them have provided a clear sense of the diagnostic yield and safety.20,21 Transbronchial cryobiopsy remains a highly controversial procedure in the clinical setting, and we would not recommend its use until further data are available.22
Surgical Lung Biopsy
In the outpatient setting, a surgical lung biopsy is often useful when the ILD diagnosis cannot be made from the clinical context and imaging. However, patients presenting with acute respiratory failure from ILD are at greatly increased risk of complications from nonelective biopsy including pneumothorax, hemothorax, acute exacerbation of ILD, ICU admission, mechanical ventilation, and in-hospital mortality.23,24 Acute histological findings can also make it difficult to appreciate the underlying pattern of fibrosis, reducing the diagnostic utility.25-27 In our experience, surgical lung biopsy rarely alters the treatment of ILD patients presenting in acute respiratory failure. We believe that surgical lung biopsy should be reserved for the rare hospitalized patients in whom the clinician believes the results would clearly change management and that the substantial risk is worth taking.5,28
INPATIENT MANAGEMENT
The inpatient management of ILD is a large topic and difficult to comprehensively cover in a single review. Therefore, in this section, we will review 6 key management questions that address both general and specific treatment decisions that frequently arise in the care of hospitalized ILD patients (Figure).
Figure
When should hospitalized ILD patients be treated with antibiotics?
Infection and acute presentations of ILD have many similar clinical and radiographic features, making it difficult to distinguish between the two, or exclude infection as the causative role in an acute exacerbation.2 In many ILD patients, the risk of infection is higher than in the general population, due to the acute and chronic use of immunosuppression. Until firm guidelines on the use of antibiotics in hospitalized patients with acute respiratory symptoms are available, we recommend considering the empiric use of antibiotics in ILD patients in respiratory failure, in addition to a thorough infectious workup.
When should hospitalized ILD patients be treated with corticosteroids?
Clinical experience supports the use of corticosteroids in the acute management of most rapidly progressive ILDs presenting with respiratory failure, including AEP, COP, acute HP, drug-induced ILD, and some cases of CT-ILD. Patients with AEP tend to respond rapidly to corticosteroids. In a series of 137 patients with AEP, 127 (92%) received corticosteroids, with defervescence and improved dyspnea within 48 to 72 hours and resolution of all symptoms after a median of 7 (4 to 10) days.29 Cryptogenic organizing pneumonia is similarly corticosteroid-responsive, with patients typically started on doses of 1mg/kg of prednisone followed by a slow taper due to the risk of relapse.30 For the majority of acute CT-ILD, oral prednisone is the initial treatment, often in combination with a second immunosuppressive agent such as mycophenolate.
No proven therapies are available for acute exacerbations of IPF (AE-IPF), including the use of corticosteroids. The most recent international guidelines on the management of AE-IPF conditionally recommends the use of corticosteroids, although this recommendation is largely based on anecdotal reports and clearly states that randomized studies are needed.3 When corticosteroids are used, we recommend high doses (eg, 1 to 2 mg/kg of prednisone) with close clinical monitoring. Consider stopping corticosteroids after 3 to 5 days if there is no evidence of clinical improvement. Prolonged courses of corticosteroids should be avoided.
What additional pharmacologic therapies should be considered in the treatment of hospitalized ILD patients?
Immunomodulators. Patients presenting acutely with a new-onset ILD or with an acute exacerbation of a chronic ILD often receive corticosteroids, sometimes in concert with an immunomodulator. This is most commonly seen in the acute management of CTD- ILD and in chronic HP, where mycophenolate mofetil, and to a lesser extent, cyclophosphamide and azathioprine for CT-ILD are used in combination with corticosteroids. The rationale for this is both therapeutic synergy and a desire to limit the long-term exposure to corticosteroids. Similarly, multiple observational cohort studies have investigated the role of combination or tandem immunosuppression in the treatment AE-IPF. Although cyclosporine, cyclophosphamide, azathioprine, rituximab and tacrolimus have all been studied, their efficacy remains uncertain.3 Until these therapies are better studied, they have no routine role in the management of AE-IPF.
Antifibrotics. Nintedanib and pirfenidone are 2 antifibrotic agents approved for the treatment of IPF. Clinical trials suggest that, in addition to slowing disease progression, these therapies may help prevent AE-IPF. The data are most robust in studies of nintedanib. A phase 2 trial with 432 subjects demonstrated a delay in time to the first investigator-reported acute exacerbation.31 Two follow-up phase 3 trials showed a reduction in centrally adjudicated AE-IPF in the pooled nintedanib groups compared to placebo.32 An initial phase 2 trial of pirfenidone showed a reduction in acute exacerbations in patients on pirfenidone, but this finding was not replicated in follow-up studies.33-35 Because of their potential role in preventing acute exacerbations and emerging evidence to suggest that continuation of antifibrotics may lead to better outcomes during an acute exacerbation, these drugs should not generally be stopped during a hospitalization for ILD. However, no evidence supports their initiation during acute exacerbations, and we do not recommend starting antifibrotics in the hospitalized setting for newly diagnosed patients. Starting and stopping antifibrotics should be reserved for outpatient management.
When should noninvasive and mechanical ventilation be considered?
We recommend carefully considering the use of noninvasive ventilation (NIV) and intubation in every ILD patient in respiratory distress, as an acutely reversible process may be present. In patients requiring mechanical ventilation, every effort should be made to minimize potential damage by reducing the fraction of inspired oxygen (to prevent potential hyperoxic injury) and reducing tidal volumes (to minimize barotrauma). Patients with a chronic ILD, particularly IPF, who require NIV or mechanical ventilation will generally have poor outcomes.
Studies suggest that NIV prevents mechanical ventilation in only the minority of patients presenting with an AE-IPF and is associated with high in-hospital mortality and a median survival following hospital discharge of only 60 days.36-38 The majority of patients with IPF requiring mechanical ventilation will not survive the intensive care unit. In a series of 23 patients presenting with acute respiratory failure and IPF, 22 of the 23 patients died while receiving mechanical ventilation, with a median survival of 3 days. In a more recent study of 34 patients with acute respiratory failure and IPF, 15 subjects underwent mechanical ventilation with an in-hospital mortality rate of 100%.39 Given the overall poor survival associated with AE-IPF, mechanical ventilation should be carefully considered with the patient and family as part of an overall goals-of-care conversation prior to initiation.
When should hospitalized ILD patients be referred for inpatient lung transplant evaluation?
A subset of hospitalized patients with ILD will not respond to supportive and pharmacologic care, particularly those with advanced lung fibrosis. In these cases, lung transplantation may be the only remaining treatment option. This is particularly true for patients presenting with IPF, and it is 1 of the most common indications for lung transplantation. Patients with respiratory failure and ILD should be evaluated early in the hospital course for transplantation or considered for transfer to a transplant center. General contraindications to transplant are age older than 70 years, underweight or elevated BMI (generally higher than 30), malignancy within the last 2 years (with the exception of cutaneous squamous and basal cell tumors), untreatable major organ dysfunction other than the lung, noncurable chronic extrapulmonary infection (chronic active viral hepatitis B, hepatitis C, human immunodeficiency virus), significant chest wall deformity, untreatable psychiatric or psychologic disease, substance addiction within the last 6 months, or lack of dependable social support.40 In select patients with ILD and gas exchange abnormalities, mechanical ventilation or extracorporeal membrane oxygenation may be used to bridge a patient to lung transplantation.41
What should you tell your ILD patient to expect at discharge?
Accurate diagnosis is important not only for acute inpatient management, but for informing long-term prognosis. Acute-onset ILD tends to be more reversible, to be responsive to medical therapy, and to have a more favorable overall outcome. On the other hand, acute exacerbations of established ILD, particularly IPF, can have a more unfavorable and treatment-refractory course. Once a diagnosis is established, it is important both to provide patients with information and ensure appropriate outpatient follow-up. The Pulmonary Fibrosis Foundation (the largest U.S. advocacy and support organization for patients with ILD) provides information on ILD to patients and families and can serve as an important educational source.42 Prior to discharge, it is important to evaluate the oxygen needs of patients at rest and with exertion. Referral to an ILD center at discharge is important whenever possible, to monitor clinical symptoms and lung function, initiate or assess response to treatment, and provide supportive care, including oxygen therapy, pulmonary rehabilitation, and outpatient lung transplant referral.
CONCLUSION
ILD is a group of heterogeneous disorders characterized by lung inflammation and fibrosis. Although the onset of disease is typically insidious, patients can present acutely requiring hospitalization. Inpatient management varies significantly depending on ILD subtype, and, therefore, accurate diagnosis is key in determining treatment and prognosis. As we develop an improved understanding of the mechanisms of acute presentations of ILD, and our approaches to detection and treatment improve as a result of clinical trials, we anticipate continued modifications to this shared framework.
Disclosure
Dr. Collard reports personal fees from Alkermes, aTyr Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Global Blood Therapeutics, Genoa, ImmuneWorks, Moerae Matrix, Navitor, Parexel, Patara, Pharma Capital Partners, Prometic, Takeda, Toray, and Xfibra, outside the submitted work. Drs. Farrand and Shah report no financial conflicts of interest.
References
1. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748. PubMed 2. Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis. Clin Chest Med. 2012;33(1):59-68. PubMed 3. Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med. 2016;194(3):265-275. PubMed 4. King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med. 2001;164(7):1171-1181. PubMed 5. Behr J. Approach to the diagnosis of interstitial lung disease. Clin Chest Med. 2012;33(1):1-10. PubMed 6. Raghu G, Brown KK. Interstitial lung disease: clinical evaluation and keys to an accurate diagnosis. Clin Chest Med. 2004;25(3):409-419. PubMed 7. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58. PubMed 8. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis. 1986;133(2):321-340. PubMed 9. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs. Am Rev Respir Dis. 1986;133(3):488-505. PubMed 10. Diffuse Lung Disease Questionnaire for Patients. Available at: https://www.chestnet.org/~/media/chesnetorg/Foundation/Documents/Lung Disease Questionaire.ashx. Accessed August 15, 2016. 11. Pipavath S, Godwin JD. Imaging of interstitial lung disease. Clin Chest Med. 2004;25(3):455-465, v-vi. PubMed 12. Fujimoto K, Taniguchi H, Johkoh T, et al. Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. Eur Radiol. 2012;22(1):83-92. PubMed 13. Mayo JR. CT evaluation of diffuse infiltrative lung disease: dose considerations and optimal technique. J Thorac Imaging. 2009;24(4):252-259. PubMed 14. Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. New Engl J Med. 1989;321(9):569-574. PubMed 15. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med. 2012;186(4):314-324. PubMed 16. Churg A, Schwarz M. Transbronchial biopsy and usual interstitial pneumonia: a new paradigm? Chest. 2006;129(5):1117-1118. PubMed 17. Shim HS, Park MS, Park IK. Histopathologic findings of transbronchial biopsy in usual interstitial pneumonia. Pathol Int. 2010;60(5):373-377. PubMed 18. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. PubMed 19. Carmona EM, Kalra S, Ryu JH. Pulmonary sarcoidosis: diagnosis and treatment. Mayo Clin Proc. 2016;91(7):946-954. PubMed 20. Tomassetti S, Wells AU, Costabel U, et al. Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2016;193(7):745-752. PubMed 21. Johannson KA, Marcoux VS, Ronksley PE, Ryerson CJ. Diagnostic yield and complications of transbronchial lung cryobiopsy for interstitial lung disease. A systematic review and metaanalysis. Ann Am Thorac Soc. 2016;13(10):1828-1838. PubMed 22. Patel NM, Borczuk AC, Lederer DJ. Cryobiopsy in the diagnosis of interstitial lung disease. A step forward or back? Am J Respir Crit Care Med. 2016;193(7):707-709. PubMed 23. Rishi Raj M, Kirtee Raparia, MD, David A. Lynch, MD, Kevin K. Brown, MD. Surgical lung biopsy for interstitial lung diseases. Chest. 2016. 24. Kreider ME, Hansen-Flaschen J, Ahmad NN, et al. Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease. AnnAm Thor Surg. 2007;83(3):1140-1144. PubMed 25. Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial lung disease. Histopathology. 2011;58(4):525-530. PubMed 26. Churg A, Muller NL, Silva CI, Wright JL. Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. Am J Surg Pathol. 2007;31(2):277-284. PubMed 27. Jones KD, Urisman A. Histopathologic approach to the surgical lung biopsy in interstitial lung disease. Clin Chest Med. 2012;33(1):27-40. PubMed 28. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med. 2016;193(10):1161-1167. PubMed 29. Rhee CK, Min KH, Yim NY, et al. Clinical characteristics and corticosteroid treatment of acute eosinophilic pneumonia. Eur Respir J. 2013;41(2):402-409. PubMed 30. Lazor R, Vandevenne A, Pelletier A, Leclerc P, Court-Fortune I, Cordier JF. Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. The Groupe d’Etudes et de Recherche sur les Maladles “Orphelines” Pulmonaires (GERM”O”P). Am J Respir Crit Care Med. 2000;162(2 Pt 1):571-577. PubMed 31. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. New Engl J Med. 2011;365(12):1079-1087. PubMed 32. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. New Engl J Med. 2014;370(22):2071-2082. PubMed 33. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;171(9):1040-1047. PubMed 34. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-1769. PubMed 35. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. New Engl J Med. 2014;370(22):2083-2092. PubMed 36. Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med. 2002;166(6):839-842. PubMed 37. Vianello A, Arcaro G, Battistella L, et al. Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis. J Crit Care. 2014;29(4):562-567. PubMed 38. Blivet S, Philit F, Sab JM, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001;120(1):209-212. PubMed 39. Mollica C, Paone G, Conti V, et al. Mechanical ventilation in patients with endstage idiopathic pulmonary fibrosis. Respiration. 2010;79(3):209-215. PubMed 40. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25(7):745-755. PubMed 41. Hoopes CW, Kukreja J, Golden J, Davenport DL, Diaz-Guzman E, Zwischenberger JB. Extracorporeal membrane oxygenation as a bridge to pulmonary transplantation. J Thorac Cardiovasc Surg. 2013;145(3):862-867; discussion 867-868. PubMed 42. Pulmonary Fibrosis Foundation. http://pulmonaryfibrosis.org/. Accessed August 31, 2016.
Interstitial lung disease (ILD) encompasses a diverse group of disorders that cause inflammation and fibrosis of the lung parenchyma. The clinical manifestations, disease course, management and prognosis of ILD vary depending on the underlying subtype, making accurate classification and diagnosis an important initial step. While a comprehensive list of ILD contains dozens of disorders, the majority of patients will fall into 1 of 3 categories: exposure-related ILD, connective tissue disease-related ILD (CT-ILD), and the idiopathic interstitial pneumonias (Table).
An essential first step in the evaluation of every hospitalized patient with ILD is establishing a diagnosis. A common mistake among clinicians who diagnose patients with ILD is not realizing that ILD is a collection of diseases with different etiologies, natural histories, and treatments. A careful evaluation should be performed in every hospitalized patient with ILD to ensure an accurate diagnosis, ideally in the context of a multidisciplinary conference with pulmonary, radiology, pathology, and other specialties, as appropriate. A multidisciplinary panel of the American Thoracic Society/European Respiratory Society recently published a revised classification of ILD based on a combination of clinical, radiologic, and histopathologic findings, which may aid in refining the diagnosis.1
There are 3 main scenarios in which the hospital physician will encounter patients with ILD.
Acute presentation of new-onset disease. While many ILDs present insidiously, some cases present acutely and require hospitalization. The most common of these are acute hypersensitivity pneumonitis (HP), CT-ILD (in particular, myositis-related and systemic lupus erythematosus-related), drug-induced ILD (eg, amiodarone, nitrofurantoin), cryptogenic organizing pneumonia (COP), acute eosinophilic pneumonia (AEP), and acute interstitial pneumonia (AIP).
Acute presentation of established (chronic) disease. Patients with chronic forms of ILD can present to the hospital with an acute exacerbation of disease. This can be caused by extra-parenchymal complications, including pulmonary embolism, pneumothorax, and pleural effusion; parenchymal complications such as infectious pneumonia, aspiration pneumonitis, and congestive heart failure; or without an identifiable cause. This latter presentation is most commonly seen in idiopathic pulmonary fibrosis (IPF).2,3
Elective hospitalization for diagnostic surgical lung biopsy. Patients with ILD may be hospitalized electively for a laparoscopic surgical lung biopsy as part of their diagnostic evaluations.
Physicians caring for a hospitalized ILD patient must be familiar with the clinical presentations, diagnostic approach, medical management, and outpatient follow-up recommended in these 3 settings. We will summarize these areas and provide answers to commonly encountered clinical questions in the hospitalized patient with ILD.
CLINICAL PRESENTATION
Acute onset (or worsening) of dyspnea is the primary presenting symptom in most patients hospitalized for ILD. This symptom should be further characterized by assessing the degree of dyspnea and the extent of exercise limitation, as both impact overall disease severity and prognosis.4 Cough is the second most common symptom, and can be nonproductive, as is common in IPF, or be associated with secretions if parenchymal infection or acute bronchitis is present.5 Pleuritic chest pain, pleural effusion, and/or the presence of extrapulmonary features, including dysphagia, joint pain and swelling, or cutaneous thickening may suggest the presence of a CT-ILD. Because most forms of ILD present with only nonspecific symptoms, a careful history and physical examination are essential.
DIAGNOSIS
History
A comprehensive patient history is the backbone of diagnosing any ILD. History-taking should focus on severity and temporal progression of symptoms, presence of pre-existing systemic conditions associated with ILD, symptoms of extrapulmonary disease, and exposures to substances that can cause pulmonary injury, including a detailed history of occupations and hobbies, medications, smoking, and familial lung disease.6-9 Physicians must try to exclude other diagnoses that could result in a similar acute presentation, including congestive heart failure and infection. Considering the complex and extensive recommended history-taking, physicians may find it helpful to use a standardized questionnaire, as provided by the American College of Chest Physicians.10
Laboratory Testing
All patients presenting to the hospital with a suspected ILD should undergo careful assessment for the presence of connective tissue disease, including patients without clear symptoms because ILD can be the presenting manifestation. We routinely test for antinuclear antibody titer and pattern, rheumatoid factor, anticyclic citrullinated peptide, creatinine kinase, and aldolase as the initial screening panel in most patients, with further testing directed by the findings on history and physical examination. Pulmonary function tests are used routinely to monitor disease progression in the outpatient setting; however, in the hospitalized ILD patient, they are often difficult to perform and have no real diagnostic value. Similarly, arterial blood gas is not routinely used as part of the initial inpatient evaluation.
Table
Imaging
All hospitalized patients with a known or suspected ILD should undergo chest imaging, assuming they are stable enough to do so. While the chest radiograph can provide a low-cost initial assessment of the degree of lung involvement and presence of accompanying abnormalities, computed tomography (CT) scanning is the diagnostic test of choice.11 The pattern and distribution of abnormalities on CT scan can greatly assist with the differential diagnosis in patients presenting with a new ILD, while the presence and pattern of new opacities superimposed on chronic changes can inform the differential and the prognosis of an ILD exacerbation.12 High-resolution CT provides the most sensitive imaging modality for diffuse ILD. The addition of prone and expiratory images are helpful in differentiating mild lung disease from atelectasis and detecting air trapping, respectively.13 However, since pulmonary embolism is a common extraparenchymal finding routinely considered in the differential of a patient presenting with a known or suspected ILD, physicians should consider ordering a CT pulmonary angiogram with additional high-resolution images. Most important, radiographic evaluation should include a review of all available prior chest imaging to assess both the tempo and the nature of radiographic findings.
Bronchoscopy
Bronchoscopy (with bronchoalveolar lavage [BAL], transbronchial lung biopsy [TBLB] and/or transbronchial needle aspiration [TBNA]) is not a routinely used diagnostic tool in the hospitalized ILD patient. However, it should be considered in certain circumstances.7 Cell count and differential can be helpful in diagnosing AEP (greater than 40% eosinophilia) or acute HP (greater than 50% lymphocytosis), while the addition of microbiologic and cytologic analysis can assist with the diagnosis of infectious etiologies (including pneumocystis pneumonia) or malignancy.14,15 Bronchoscopy with BAL has limited sensitivity for many infections and the procedure is associated with a small risk of worsened hypoxemia. Transbronchial lung biopsy, and to a lesser extent TBNA, carry the added risk of pneumothorax and bleeding. In the majority of cases of ILD, TBLB and TBNA have limited diagnostic utility given the small amount of lung tissue sampled. In cases of suspected IPF, where the identification of the histologic pattern is needed for definitive diagnosis, tissue from TBLB cannot be used to make a conclusive diagnosis.16,17 However, both TBNA and TBLB are useful in the diagnosis of granulomatous disorders, such as sarcoidosis, where the diagnostic yield ranges from 80% to 90% and 50% to 75%, respectively.18,19
A newer bronchoscopic approach to sampling the lung using a bronchoscopically-placed cryoprobe (termed transbronchial cryobiopsy) has uncertain diagnostic utility and safety in the acute setting. This procedure involves intubation, sedation, and bronchoscopy allowing for the passage of an endobronchial cryoprobe through the bronchoscope and into the periphery of the lung. Several cryobiopies are generally taken from the same pulmonary subsegment. Despite a large number of recent publications on this topic, none of them have provided a clear sense of the diagnostic yield and safety.20,21 Transbronchial cryobiopsy remains a highly controversial procedure in the clinical setting, and we would not recommend its use until further data are available.22
Surgical Lung Biopsy
In the outpatient setting, a surgical lung biopsy is often useful when the ILD diagnosis cannot be made from the clinical context and imaging. However, patients presenting with acute respiratory failure from ILD are at greatly increased risk of complications from nonelective biopsy including pneumothorax, hemothorax, acute exacerbation of ILD, ICU admission, mechanical ventilation, and in-hospital mortality.23,24 Acute histological findings can also make it difficult to appreciate the underlying pattern of fibrosis, reducing the diagnostic utility.25-27 In our experience, surgical lung biopsy rarely alters the treatment of ILD patients presenting in acute respiratory failure. We believe that surgical lung biopsy should be reserved for the rare hospitalized patients in whom the clinician believes the results would clearly change management and that the substantial risk is worth taking.5,28
INPATIENT MANAGEMENT
The inpatient management of ILD is a large topic and difficult to comprehensively cover in a single review. Therefore, in this section, we will review 6 key management questions that address both general and specific treatment decisions that frequently arise in the care of hospitalized ILD patients (Figure).
Figure
When should hospitalized ILD patients be treated with antibiotics?
Infection and acute presentations of ILD have many similar clinical and radiographic features, making it difficult to distinguish between the two, or exclude infection as the causative role in an acute exacerbation.2 In many ILD patients, the risk of infection is higher than in the general population, due to the acute and chronic use of immunosuppression. Until firm guidelines on the use of antibiotics in hospitalized patients with acute respiratory symptoms are available, we recommend considering the empiric use of antibiotics in ILD patients in respiratory failure, in addition to a thorough infectious workup.
When should hospitalized ILD patients be treated with corticosteroids?
Clinical experience supports the use of corticosteroids in the acute management of most rapidly progressive ILDs presenting with respiratory failure, including AEP, COP, acute HP, drug-induced ILD, and some cases of CT-ILD. Patients with AEP tend to respond rapidly to corticosteroids. In a series of 137 patients with AEP, 127 (92%) received corticosteroids, with defervescence and improved dyspnea within 48 to 72 hours and resolution of all symptoms after a median of 7 (4 to 10) days.29 Cryptogenic organizing pneumonia is similarly corticosteroid-responsive, with patients typically started on doses of 1mg/kg of prednisone followed by a slow taper due to the risk of relapse.30 For the majority of acute CT-ILD, oral prednisone is the initial treatment, often in combination with a second immunosuppressive agent such as mycophenolate.
No proven therapies are available for acute exacerbations of IPF (AE-IPF), including the use of corticosteroids. The most recent international guidelines on the management of AE-IPF conditionally recommends the use of corticosteroids, although this recommendation is largely based on anecdotal reports and clearly states that randomized studies are needed.3 When corticosteroids are used, we recommend high doses (eg, 1 to 2 mg/kg of prednisone) with close clinical monitoring. Consider stopping corticosteroids after 3 to 5 days if there is no evidence of clinical improvement. Prolonged courses of corticosteroids should be avoided.
What additional pharmacologic therapies should be considered in the treatment of hospitalized ILD patients?
Immunomodulators. Patients presenting acutely with a new-onset ILD or with an acute exacerbation of a chronic ILD often receive corticosteroids, sometimes in concert with an immunomodulator. This is most commonly seen in the acute management of CTD- ILD and in chronic HP, where mycophenolate mofetil, and to a lesser extent, cyclophosphamide and azathioprine for CT-ILD are used in combination with corticosteroids. The rationale for this is both therapeutic synergy and a desire to limit the long-term exposure to corticosteroids. Similarly, multiple observational cohort studies have investigated the role of combination or tandem immunosuppression in the treatment AE-IPF. Although cyclosporine, cyclophosphamide, azathioprine, rituximab and tacrolimus have all been studied, their efficacy remains uncertain.3 Until these therapies are better studied, they have no routine role in the management of AE-IPF.
Antifibrotics. Nintedanib and pirfenidone are 2 antifibrotic agents approved for the treatment of IPF. Clinical trials suggest that, in addition to slowing disease progression, these therapies may help prevent AE-IPF. The data are most robust in studies of nintedanib. A phase 2 trial with 432 subjects demonstrated a delay in time to the first investigator-reported acute exacerbation.31 Two follow-up phase 3 trials showed a reduction in centrally adjudicated AE-IPF in the pooled nintedanib groups compared to placebo.32 An initial phase 2 trial of pirfenidone showed a reduction in acute exacerbations in patients on pirfenidone, but this finding was not replicated in follow-up studies.33-35 Because of their potential role in preventing acute exacerbations and emerging evidence to suggest that continuation of antifibrotics may lead to better outcomes during an acute exacerbation, these drugs should not generally be stopped during a hospitalization for ILD. However, no evidence supports their initiation during acute exacerbations, and we do not recommend starting antifibrotics in the hospitalized setting for newly diagnosed patients. Starting and stopping antifibrotics should be reserved for outpatient management.
When should noninvasive and mechanical ventilation be considered?
We recommend carefully considering the use of noninvasive ventilation (NIV) and intubation in every ILD patient in respiratory distress, as an acutely reversible process may be present. In patients requiring mechanical ventilation, every effort should be made to minimize potential damage by reducing the fraction of inspired oxygen (to prevent potential hyperoxic injury) and reducing tidal volumes (to minimize barotrauma). Patients with a chronic ILD, particularly IPF, who require NIV or mechanical ventilation will generally have poor outcomes.
Studies suggest that NIV prevents mechanical ventilation in only the minority of patients presenting with an AE-IPF and is associated with high in-hospital mortality and a median survival following hospital discharge of only 60 days.36-38 The majority of patients with IPF requiring mechanical ventilation will not survive the intensive care unit. In a series of 23 patients presenting with acute respiratory failure and IPF, 22 of the 23 patients died while receiving mechanical ventilation, with a median survival of 3 days. In a more recent study of 34 patients with acute respiratory failure and IPF, 15 subjects underwent mechanical ventilation with an in-hospital mortality rate of 100%.39 Given the overall poor survival associated with AE-IPF, mechanical ventilation should be carefully considered with the patient and family as part of an overall goals-of-care conversation prior to initiation.
When should hospitalized ILD patients be referred for inpatient lung transplant evaluation?
A subset of hospitalized patients with ILD will not respond to supportive and pharmacologic care, particularly those with advanced lung fibrosis. In these cases, lung transplantation may be the only remaining treatment option. This is particularly true for patients presenting with IPF, and it is 1 of the most common indications for lung transplantation. Patients with respiratory failure and ILD should be evaluated early in the hospital course for transplantation or considered for transfer to a transplant center. General contraindications to transplant are age older than 70 years, underweight or elevated BMI (generally higher than 30), malignancy within the last 2 years (with the exception of cutaneous squamous and basal cell tumors), untreatable major organ dysfunction other than the lung, noncurable chronic extrapulmonary infection (chronic active viral hepatitis B, hepatitis C, human immunodeficiency virus), significant chest wall deformity, untreatable psychiatric or psychologic disease, substance addiction within the last 6 months, or lack of dependable social support.40 In select patients with ILD and gas exchange abnormalities, mechanical ventilation or extracorporeal membrane oxygenation may be used to bridge a patient to lung transplantation.41
What should you tell your ILD patient to expect at discharge?
Accurate diagnosis is important not only for acute inpatient management, but for informing long-term prognosis. Acute-onset ILD tends to be more reversible, to be responsive to medical therapy, and to have a more favorable overall outcome. On the other hand, acute exacerbations of established ILD, particularly IPF, can have a more unfavorable and treatment-refractory course. Once a diagnosis is established, it is important both to provide patients with information and ensure appropriate outpatient follow-up. The Pulmonary Fibrosis Foundation (the largest U.S. advocacy and support organization for patients with ILD) provides information on ILD to patients and families and can serve as an important educational source.42 Prior to discharge, it is important to evaluate the oxygen needs of patients at rest and with exertion. Referral to an ILD center at discharge is important whenever possible, to monitor clinical symptoms and lung function, initiate or assess response to treatment, and provide supportive care, including oxygen therapy, pulmonary rehabilitation, and outpatient lung transplant referral.
CONCLUSION
ILD is a group of heterogeneous disorders characterized by lung inflammation and fibrosis. Although the onset of disease is typically insidious, patients can present acutely requiring hospitalization. Inpatient management varies significantly depending on ILD subtype, and, therefore, accurate diagnosis is key in determining treatment and prognosis. As we develop an improved understanding of the mechanisms of acute presentations of ILD, and our approaches to detection and treatment improve as a result of clinical trials, we anticipate continued modifications to this shared framework.
Disclosure
Dr. Collard reports personal fees from Alkermes, aTyr Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Global Blood Therapeutics, Genoa, ImmuneWorks, Moerae Matrix, Navitor, Parexel, Patara, Pharma Capital Partners, Prometic, Takeda, Toray, and Xfibra, outside the submitted work. Drs. Farrand and Shah report no financial conflicts of interest.
Interstitial lung disease (ILD) encompasses a diverse group of disorders that cause inflammation and fibrosis of the lung parenchyma. The clinical manifestations, disease course, management and prognosis of ILD vary depending on the underlying subtype, making accurate classification and diagnosis an important initial step. While a comprehensive list of ILD contains dozens of disorders, the majority of patients will fall into 1 of 3 categories: exposure-related ILD, connective tissue disease-related ILD (CT-ILD), and the idiopathic interstitial pneumonias (Table).
An essential first step in the evaluation of every hospitalized patient with ILD is establishing a diagnosis. A common mistake among clinicians who diagnose patients with ILD is not realizing that ILD is a collection of diseases with different etiologies, natural histories, and treatments. A careful evaluation should be performed in every hospitalized patient with ILD to ensure an accurate diagnosis, ideally in the context of a multidisciplinary conference with pulmonary, radiology, pathology, and other specialties, as appropriate. A multidisciplinary panel of the American Thoracic Society/European Respiratory Society recently published a revised classification of ILD based on a combination of clinical, radiologic, and histopathologic findings, which may aid in refining the diagnosis.1
There are 3 main scenarios in which the hospital physician will encounter patients with ILD.
Acute presentation of new-onset disease. While many ILDs present insidiously, some cases present acutely and require hospitalization. The most common of these are acute hypersensitivity pneumonitis (HP), CT-ILD (in particular, myositis-related and systemic lupus erythematosus-related), drug-induced ILD (eg, amiodarone, nitrofurantoin), cryptogenic organizing pneumonia (COP), acute eosinophilic pneumonia (AEP), and acute interstitial pneumonia (AIP).
Acute presentation of established (chronic) disease. Patients with chronic forms of ILD can present to the hospital with an acute exacerbation of disease. This can be caused by extra-parenchymal complications, including pulmonary embolism, pneumothorax, and pleural effusion; parenchymal complications such as infectious pneumonia, aspiration pneumonitis, and congestive heart failure; or without an identifiable cause. This latter presentation is most commonly seen in idiopathic pulmonary fibrosis (IPF).2,3
Elective hospitalization for diagnostic surgical lung biopsy. Patients with ILD may be hospitalized electively for a laparoscopic surgical lung biopsy as part of their diagnostic evaluations.
Physicians caring for a hospitalized ILD patient must be familiar with the clinical presentations, diagnostic approach, medical management, and outpatient follow-up recommended in these 3 settings. We will summarize these areas and provide answers to commonly encountered clinical questions in the hospitalized patient with ILD.
CLINICAL PRESENTATION
Acute onset (or worsening) of dyspnea is the primary presenting symptom in most patients hospitalized for ILD. This symptom should be further characterized by assessing the degree of dyspnea and the extent of exercise limitation, as both impact overall disease severity and prognosis.4 Cough is the second most common symptom, and can be nonproductive, as is common in IPF, or be associated with secretions if parenchymal infection or acute bronchitis is present.5 Pleuritic chest pain, pleural effusion, and/or the presence of extrapulmonary features, including dysphagia, joint pain and swelling, or cutaneous thickening may suggest the presence of a CT-ILD. Because most forms of ILD present with only nonspecific symptoms, a careful history and physical examination are essential.
DIAGNOSIS
History
A comprehensive patient history is the backbone of diagnosing any ILD. History-taking should focus on severity and temporal progression of symptoms, presence of pre-existing systemic conditions associated with ILD, symptoms of extrapulmonary disease, and exposures to substances that can cause pulmonary injury, including a detailed history of occupations and hobbies, medications, smoking, and familial lung disease.6-9 Physicians must try to exclude other diagnoses that could result in a similar acute presentation, including congestive heart failure and infection. Considering the complex and extensive recommended history-taking, physicians may find it helpful to use a standardized questionnaire, as provided by the American College of Chest Physicians.10
Laboratory Testing
All patients presenting to the hospital with a suspected ILD should undergo careful assessment for the presence of connective tissue disease, including patients without clear symptoms because ILD can be the presenting manifestation. We routinely test for antinuclear antibody titer and pattern, rheumatoid factor, anticyclic citrullinated peptide, creatinine kinase, and aldolase as the initial screening panel in most patients, with further testing directed by the findings on history and physical examination. Pulmonary function tests are used routinely to monitor disease progression in the outpatient setting; however, in the hospitalized ILD patient, they are often difficult to perform and have no real diagnostic value. Similarly, arterial blood gas is not routinely used as part of the initial inpatient evaluation.
Table
Imaging
All hospitalized patients with a known or suspected ILD should undergo chest imaging, assuming they are stable enough to do so. While the chest radiograph can provide a low-cost initial assessment of the degree of lung involvement and presence of accompanying abnormalities, computed tomography (CT) scanning is the diagnostic test of choice.11 The pattern and distribution of abnormalities on CT scan can greatly assist with the differential diagnosis in patients presenting with a new ILD, while the presence and pattern of new opacities superimposed on chronic changes can inform the differential and the prognosis of an ILD exacerbation.12 High-resolution CT provides the most sensitive imaging modality for diffuse ILD. The addition of prone and expiratory images are helpful in differentiating mild lung disease from atelectasis and detecting air trapping, respectively.13 However, since pulmonary embolism is a common extraparenchymal finding routinely considered in the differential of a patient presenting with a known or suspected ILD, physicians should consider ordering a CT pulmonary angiogram with additional high-resolution images. Most important, radiographic evaluation should include a review of all available prior chest imaging to assess both the tempo and the nature of radiographic findings.
Bronchoscopy
Bronchoscopy (with bronchoalveolar lavage [BAL], transbronchial lung biopsy [TBLB] and/or transbronchial needle aspiration [TBNA]) is not a routinely used diagnostic tool in the hospitalized ILD patient. However, it should be considered in certain circumstances.7 Cell count and differential can be helpful in diagnosing AEP (greater than 40% eosinophilia) or acute HP (greater than 50% lymphocytosis), while the addition of microbiologic and cytologic analysis can assist with the diagnosis of infectious etiologies (including pneumocystis pneumonia) or malignancy.14,15 Bronchoscopy with BAL has limited sensitivity for many infections and the procedure is associated with a small risk of worsened hypoxemia. Transbronchial lung biopsy, and to a lesser extent TBNA, carry the added risk of pneumothorax and bleeding. In the majority of cases of ILD, TBLB and TBNA have limited diagnostic utility given the small amount of lung tissue sampled. In cases of suspected IPF, where the identification of the histologic pattern is needed for definitive diagnosis, tissue from TBLB cannot be used to make a conclusive diagnosis.16,17 However, both TBNA and TBLB are useful in the diagnosis of granulomatous disorders, such as sarcoidosis, where the diagnostic yield ranges from 80% to 90% and 50% to 75%, respectively.18,19
A newer bronchoscopic approach to sampling the lung using a bronchoscopically-placed cryoprobe (termed transbronchial cryobiopsy) has uncertain diagnostic utility and safety in the acute setting. This procedure involves intubation, sedation, and bronchoscopy allowing for the passage of an endobronchial cryoprobe through the bronchoscope and into the periphery of the lung. Several cryobiopies are generally taken from the same pulmonary subsegment. Despite a large number of recent publications on this topic, none of them have provided a clear sense of the diagnostic yield and safety.20,21 Transbronchial cryobiopsy remains a highly controversial procedure in the clinical setting, and we would not recommend its use until further data are available.22
Surgical Lung Biopsy
In the outpatient setting, a surgical lung biopsy is often useful when the ILD diagnosis cannot be made from the clinical context and imaging. However, patients presenting with acute respiratory failure from ILD are at greatly increased risk of complications from nonelective biopsy including pneumothorax, hemothorax, acute exacerbation of ILD, ICU admission, mechanical ventilation, and in-hospital mortality.23,24 Acute histological findings can also make it difficult to appreciate the underlying pattern of fibrosis, reducing the diagnostic utility.25-27 In our experience, surgical lung biopsy rarely alters the treatment of ILD patients presenting in acute respiratory failure. We believe that surgical lung biopsy should be reserved for the rare hospitalized patients in whom the clinician believes the results would clearly change management and that the substantial risk is worth taking.5,28
INPATIENT MANAGEMENT
The inpatient management of ILD is a large topic and difficult to comprehensively cover in a single review. Therefore, in this section, we will review 6 key management questions that address both general and specific treatment decisions that frequently arise in the care of hospitalized ILD patients (Figure).
Figure
When should hospitalized ILD patients be treated with antibiotics?
Infection and acute presentations of ILD have many similar clinical and radiographic features, making it difficult to distinguish between the two, or exclude infection as the causative role in an acute exacerbation.2 In many ILD patients, the risk of infection is higher than in the general population, due to the acute and chronic use of immunosuppression. Until firm guidelines on the use of antibiotics in hospitalized patients with acute respiratory symptoms are available, we recommend considering the empiric use of antibiotics in ILD patients in respiratory failure, in addition to a thorough infectious workup.
When should hospitalized ILD patients be treated with corticosteroids?
Clinical experience supports the use of corticosteroids in the acute management of most rapidly progressive ILDs presenting with respiratory failure, including AEP, COP, acute HP, drug-induced ILD, and some cases of CT-ILD. Patients with AEP tend to respond rapidly to corticosteroids. In a series of 137 patients with AEP, 127 (92%) received corticosteroids, with defervescence and improved dyspnea within 48 to 72 hours and resolution of all symptoms after a median of 7 (4 to 10) days.29 Cryptogenic organizing pneumonia is similarly corticosteroid-responsive, with patients typically started on doses of 1mg/kg of prednisone followed by a slow taper due to the risk of relapse.30 For the majority of acute CT-ILD, oral prednisone is the initial treatment, often in combination with a second immunosuppressive agent such as mycophenolate.
No proven therapies are available for acute exacerbations of IPF (AE-IPF), including the use of corticosteroids. The most recent international guidelines on the management of AE-IPF conditionally recommends the use of corticosteroids, although this recommendation is largely based on anecdotal reports and clearly states that randomized studies are needed.3 When corticosteroids are used, we recommend high doses (eg, 1 to 2 mg/kg of prednisone) with close clinical monitoring. Consider stopping corticosteroids after 3 to 5 days if there is no evidence of clinical improvement. Prolonged courses of corticosteroids should be avoided.
What additional pharmacologic therapies should be considered in the treatment of hospitalized ILD patients?
Immunomodulators. Patients presenting acutely with a new-onset ILD or with an acute exacerbation of a chronic ILD often receive corticosteroids, sometimes in concert with an immunomodulator. This is most commonly seen in the acute management of CTD- ILD and in chronic HP, where mycophenolate mofetil, and to a lesser extent, cyclophosphamide and azathioprine for CT-ILD are used in combination with corticosteroids. The rationale for this is both therapeutic synergy and a desire to limit the long-term exposure to corticosteroids. Similarly, multiple observational cohort studies have investigated the role of combination or tandem immunosuppression in the treatment AE-IPF. Although cyclosporine, cyclophosphamide, azathioprine, rituximab and tacrolimus have all been studied, their efficacy remains uncertain.3 Until these therapies are better studied, they have no routine role in the management of AE-IPF.
Antifibrotics. Nintedanib and pirfenidone are 2 antifibrotic agents approved for the treatment of IPF. Clinical trials suggest that, in addition to slowing disease progression, these therapies may help prevent AE-IPF. The data are most robust in studies of nintedanib. A phase 2 trial with 432 subjects demonstrated a delay in time to the first investigator-reported acute exacerbation.31 Two follow-up phase 3 trials showed a reduction in centrally adjudicated AE-IPF in the pooled nintedanib groups compared to placebo.32 An initial phase 2 trial of pirfenidone showed a reduction in acute exacerbations in patients on pirfenidone, but this finding was not replicated in follow-up studies.33-35 Because of their potential role in preventing acute exacerbations and emerging evidence to suggest that continuation of antifibrotics may lead to better outcomes during an acute exacerbation, these drugs should not generally be stopped during a hospitalization for ILD. However, no evidence supports their initiation during acute exacerbations, and we do not recommend starting antifibrotics in the hospitalized setting for newly diagnosed patients. Starting and stopping antifibrotics should be reserved for outpatient management.
When should noninvasive and mechanical ventilation be considered?
We recommend carefully considering the use of noninvasive ventilation (NIV) and intubation in every ILD patient in respiratory distress, as an acutely reversible process may be present. In patients requiring mechanical ventilation, every effort should be made to minimize potential damage by reducing the fraction of inspired oxygen (to prevent potential hyperoxic injury) and reducing tidal volumes (to minimize barotrauma). Patients with a chronic ILD, particularly IPF, who require NIV or mechanical ventilation will generally have poor outcomes.
Studies suggest that NIV prevents mechanical ventilation in only the minority of patients presenting with an AE-IPF and is associated with high in-hospital mortality and a median survival following hospital discharge of only 60 days.36-38 The majority of patients with IPF requiring mechanical ventilation will not survive the intensive care unit. In a series of 23 patients presenting with acute respiratory failure and IPF, 22 of the 23 patients died while receiving mechanical ventilation, with a median survival of 3 days. In a more recent study of 34 patients with acute respiratory failure and IPF, 15 subjects underwent mechanical ventilation with an in-hospital mortality rate of 100%.39 Given the overall poor survival associated with AE-IPF, mechanical ventilation should be carefully considered with the patient and family as part of an overall goals-of-care conversation prior to initiation.
When should hospitalized ILD patients be referred for inpatient lung transplant evaluation?
A subset of hospitalized patients with ILD will not respond to supportive and pharmacologic care, particularly those with advanced lung fibrosis. In these cases, lung transplantation may be the only remaining treatment option. This is particularly true for patients presenting with IPF, and it is 1 of the most common indications for lung transplantation. Patients with respiratory failure and ILD should be evaluated early in the hospital course for transplantation or considered for transfer to a transplant center. General contraindications to transplant are age older than 70 years, underweight or elevated BMI (generally higher than 30), malignancy within the last 2 years (with the exception of cutaneous squamous and basal cell tumors), untreatable major organ dysfunction other than the lung, noncurable chronic extrapulmonary infection (chronic active viral hepatitis B, hepatitis C, human immunodeficiency virus), significant chest wall deformity, untreatable psychiatric or psychologic disease, substance addiction within the last 6 months, or lack of dependable social support.40 In select patients with ILD and gas exchange abnormalities, mechanical ventilation or extracorporeal membrane oxygenation may be used to bridge a patient to lung transplantation.41
What should you tell your ILD patient to expect at discharge?
Accurate diagnosis is important not only for acute inpatient management, but for informing long-term prognosis. Acute-onset ILD tends to be more reversible, to be responsive to medical therapy, and to have a more favorable overall outcome. On the other hand, acute exacerbations of established ILD, particularly IPF, can have a more unfavorable and treatment-refractory course. Once a diagnosis is established, it is important both to provide patients with information and ensure appropriate outpatient follow-up. The Pulmonary Fibrosis Foundation (the largest U.S. advocacy and support organization for patients with ILD) provides information on ILD to patients and families and can serve as an important educational source.42 Prior to discharge, it is important to evaluate the oxygen needs of patients at rest and with exertion. Referral to an ILD center at discharge is important whenever possible, to monitor clinical symptoms and lung function, initiate or assess response to treatment, and provide supportive care, including oxygen therapy, pulmonary rehabilitation, and outpatient lung transplant referral.
CONCLUSION
ILD is a group of heterogeneous disorders characterized by lung inflammation and fibrosis. Although the onset of disease is typically insidious, patients can present acutely requiring hospitalization. Inpatient management varies significantly depending on ILD subtype, and, therefore, accurate diagnosis is key in determining treatment and prognosis. As we develop an improved understanding of the mechanisms of acute presentations of ILD, and our approaches to detection and treatment improve as a result of clinical trials, we anticipate continued modifications to this shared framework.
Disclosure
Dr. Collard reports personal fees from Alkermes, aTyr Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Global Blood Therapeutics, Genoa, ImmuneWorks, Moerae Matrix, Navitor, Parexel, Patara, Pharma Capital Partners, Prometic, Takeda, Toray, and Xfibra, outside the submitted work. Drs. Farrand and Shah report no financial conflicts of interest.
References
1. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748. PubMed 2. Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis. Clin Chest Med. 2012;33(1):59-68. PubMed 3. Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med. 2016;194(3):265-275. PubMed 4. King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med. 2001;164(7):1171-1181. PubMed 5. Behr J. Approach to the diagnosis of interstitial lung disease. Clin Chest Med. 2012;33(1):1-10. PubMed 6. Raghu G, Brown KK. Interstitial lung disease: clinical evaluation and keys to an accurate diagnosis. Clin Chest Med. 2004;25(3):409-419. PubMed 7. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58. PubMed 8. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis. 1986;133(2):321-340. PubMed 9. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs. Am Rev Respir Dis. 1986;133(3):488-505. PubMed 10. Diffuse Lung Disease Questionnaire for Patients. Available at: https://www.chestnet.org/~/media/chesnetorg/Foundation/Documents/Lung Disease Questionaire.ashx. Accessed August 15, 2016. 11. Pipavath S, Godwin JD. Imaging of interstitial lung disease. Clin Chest Med. 2004;25(3):455-465, v-vi. PubMed 12. Fujimoto K, Taniguchi H, Johkoh T, et al. Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. Eur Radiol. 2012;22(1):83-92. PubMed 13. Mayo JR. CT evaluation of diffuse infiltrative lung disease: dose considerations and optimal technique. J Thorac Imaging. 2009;24(4):252-259. PubMed 14. Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. New Engl J Med. 1989;321(9):569-574. PubMed 15. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med. 2012;186(4):314-324. PubMed 16. Churg A, Schwarz M. Transbronchial biopsy and usual interstitial pneumonia: a new paradigm? Chest. 2006;129(5):1117-1118. PubMed 17. Shim HS, Park MS, Park IK. Histopathologic findings of transbronchial biopsy in usual interstitial pneumonia. Pathol Int. 2010;60(5):373-377. PubMed 18. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. PubMed 19. Carmona EM, Kalra S, Ryu JH. Pulmonary sarcoidosis: diagnosis and treatment. Mayo Clin Proc. 2016;91(7):946-954. PubMed 20. Tomassetti S, Wells AU, Costabel U, et al. Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2016;193(7):745-752. PubMed 21. Johannson KA, Marcoux VS, Ronksley PE, Ryerson CJ. Diagnostic yield and complications of transbronchial lung cryobiopsy for interstitial lung disease. A systematic review and metaanalysis. Ann Am Thorac Soc. 2016;13(10):1828-1838. PubMed 22. Patel NM, Borczuk AC, Lederer DJ. Cryobiopsy in the diagnosis of interstitial lung disease. A step forward or back? Am J Respir Crit Care Med. 2016;193(7):707-709. PubMed 23. Rishi Raj M, Kirtee Raparia, MD, David A. Lynch, MD, Kevin K. Brown, MD. Surgical lung biopsy for interstitial lung diseases. Chest. 2016. 24. Kreider ME, Hansen-Flaschen J, Ahmad NN, et al. Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease. AnnAm Thor Surg. 2007;83(3):1140-1144. PubMed 25. Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial lung disease. Histopathology. 2011;58(4):525-530. PubMed 26. Churg A, Muller NL, Silva CI, Wright JL. Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. Am J Surg Pathol. 2007;31(2):277-284. PubMed 27. Jones KD, Urisman A. Histopathologic approach to the surgical lung biopsy in interstitial lung disease. Clin Chest Med. 2012;33(1):27-40. PubMed 28. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med. 2016;193(10):1161-1167. PubMed 29. Rhee CK, Min KH, Yim NY, et al. Clinical characteristics and corticosteroid treatment of acute eosinophilic pneumonia. Eur Respir J. 2013;41(2):402-409. PubMed 30. Lazor R, Vandevenne A, Pelletier A, Leclerc P, Court-Fortune I, Cordier JF. Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. The Groupe d’Etudes et de Recherche sur les Maladles “Orphelines” Pulmonaires (GERM”O”P). Am J Respir Crit Care Med. 2000;162(2 Pt 1):571-577. PubMed 31. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. New Engl J Med. 2011;365(12):1079-1087. PubMed 32. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. New Engl J Med. 2014;370(22):2071-2082. PubMed 33. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;171(9):1040-1047. PubMed 34. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-1769. PubMed 35. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. New Engl J Med. 2014;370(22):2083-2092. PubMed 36. Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med. 2002;166(6):839-842. PubMed 37. Vianello A, Arcaro G, Battistella L, et al. Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis. J Crit Care. 2014;29(4):562-567. PubMed 38. Blivet S, Philit F, Sab JM, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001;120(1):209-212. PubMed 39. Mollica C, Paone G, Conti V, et al. Mechanical ventilation in patients with endstage idiopathic pulmonary fibrosis. Respiration. 2010;79(3):209-215. PubMed 40. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25(7):745-755. PubMed 41. Hoopes CW, Kukreja J, Golden J, Davenport DL, Diaz-Guzman E, Zwischenberger JB. Extracorporeal membrane oxygenation as a bridge to pulmonary transplantation. J Thorac Cardiovasc Surg. 2013;145(3):862-867; discussion 867-868. PubMed 42. Pulmonary Fibrosis Foundation. http://pulmonaryfibrosis.org/. Accessed August 31, 2016.
References
1. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748. PubMed 2. Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis. Clin Chest Med. 2012;33(1):59-68. PubMed 3. Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med. 2016;194(3):265-275. PubMed 4. King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med. 2001;164(7):1171-1181. PubMed 5. Behr J. Approach to the diagnosis of interstitial lung disease. Clin Chest Med. 2012;33(1):1-10. PubMed 6. Raghu G, Brown KK. Interstitial lung disease: clinical evaluation and keys to an accurate diagnosis. Clin Chest Med. 2004;25(3):409-419. PubMed 7. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58. PubMed 8. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis. 1986;133(2):321-340. PubMed 9. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs. Am Rev Respir Dis. 1986;133(3):488-505. PubMed 10. Diffuse Lung Disease Questionnaire for Patients. Available at: https://www.chestnet.org/~/media/chesnetorg/Foundation/Documents/Lung Disease Questionaire.ashx. Accessed August 15, 2016. 11. Pipavath S, Godwin JD. Imaging of interstitial lung disease. Clin Chest Med. 2004;25(3):455-465, v-vi. PubMed 12. Fujimoto K, Taniguchi H, Johkoh T, et al. Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. Eur Radiol. 2012;22(1):83-92. PubMed 13. Mayo JR. CT evaluation of diffuse infiltrative lung disease: dose considerations and optimal technique. J Thorac Imaging. 2009;24(4):252-259. PubMed 14. Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. New Engl J Med. 1989;321(9):569-574. PubMed 15. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med. 2012;186(4):314-324. PubMed 16. Churg A, Schwarz M. Transbronchial biopsy and usual interstitial pneumonia: a new paradigm? Chest. 2006;129(5):1117-1118. PubMed 17. Shim HS, Park MS, Park IK. Histopathologic findings of transbronchial biopsy in usual interstitial pneumonia. Pathol Int. 2010;60(5):373-377. PubMed 18. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. PubMed 19. Carmona EM, Kalra S, Ryu JH. Pulmonary sarcoidosis: diagnosis and treatment. Mayo Clin Proc. 2016;91(7):946-954. PubMed 20. Tomassetti S, Wells AU, Costabel U, et al. Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2016;193(7):745-752. PubMed 21. Johannson KA, Marcoux VS, Ronksley PE, Ryerson CJ. Diagnostic yield and complications of transbronchial lung cryobiopsy for interstitial lung disease. A systematic review and metaanalysis. Ann Am Thorac Soc. 2016;13(10):1828-1838. PubMed 22. Patel NM, Borczuk AC, Lederer DJ. Cryobiopsy in the diagnosis of interstitial lung disease. A step forward or back? Am J Respir Crit Care Med. 2016;193(7):707-709. PubMed 23. Rishi Raj M, Kirtee Raparia, MD, David A. Lynch, MD, Kevin K. Brown, MD. Surgical lung biopsy for interstitial lung diseases. Chest. 2016. 24. Kreider ME, Hansen-Flaschen J, Ahmad NN, et al. Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease. AnnAm Thor Surg. 2007;83(3):1140-1144. PubMed 25. Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial lung disease. Histopathology. 2011;58(4):525-530. PubMed 26. Churg A, Muller NL, Silva CI, Wright JL. Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. Am J Surg Pathol. 2007;31(2):277-284. PubMed 27. Jones KD, Urisman A. Histopathologic approach to the surgical lung biopsy in interstitial lung disease. Clin Chest Med. 2012;33(1):27-40. PubMed 28. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med. 2016;193(10):1161-1167. PubMed 29. Rhee CK, Min KH, Yim NY, et al. Clinical characteristics and corticosteroid treatment of acute eosinophilic pneumonia. Eur Respir J. 2013;41(2):402-409. PubMed 30. Lazor R, Vandevenne A, Pelletier A, Leclerc P, Court-Fortune I, Cordier JF. Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. The Groupe d’Etudes et de Recherche sur les Maladles “Orphelines” Pulmonaires (GERM”O”P). Am J Respir Crit Care Med. 2000;162(2 Pt 1):571-577. PubMed 31. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. New Engl J Med. 2011;365(12):1079-1087. PubMed 32. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. New Engl J Med. 2014;370(22):2071-2082. PubMed 33. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;171(9):1040-1047. PubMed 34. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-1769. PubMed 35. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. New Engl J Med. 2014;370(22):2083-2092. PubMed 36. Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med. 2002;166(6):839-842. PubMed 37. Vianello A, Arcaro G, Battistella L, et al. Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis. J Crit Care. 2014;29(4):562-567. PubMed 38. Blivet S, Philit F, Sab JM, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001;120(1):209-212. PubMed 39. Mollica C, Paone G, Conti V, et al. Mechanical ventilation in patients with endstage idiopathic pulmonary fibrosis. Respiration. 2010;79(3):209-215. PubMed 40. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25(7):745-755. PubMed 41. Hoopes CW, Kukreja J, Golden J, Davenport DL, Diaz-Guzman E, Zwischenberger JB. Extracorporeal membrane oxygenation as a bridge to pulmonary transplantation. J Thorac Cardiovasc Surg. 2013;145(3):862-867; discussion 867-868. PubMed 42. Pulmonary Fibrosis Foundation. http://pulmonaryfibrosis.org/. Accessed August 31, 2016.
