WASHINGTON – Researchers have identified six new biomarkers of drug-induced liver injury (DILI) that, when combined with traditional measurements, seemed to better predict the disease course, compared with traditional biomarkers alone, according to a presentation at the annual meeting of the American Association for the Study of Liver Diseases.

In addition, some of these biomarkers may provide a “liquid biopsy” to assess degree of inflammation and mode of hepatocyte death, said Rachel Church, PhD, of the University of North Carolina, Chapel Hill.

“The motivation behind this research is that the standard biomarkers for DILI have several shortcomings,” Dr. Church said. “They’re not entirely liver specific, they’re not mechanistically informative, and they’re not sufficiently predictive of outcome.”

The researchers found that elevated levels of these six candidate biomarkers were predictive for adverse outcome in DILI: total keratin18 (K18); caspase-cleaved K18 (ccK18); alpha-fetoprotein (AFP); osteopontin (OPN); fatty acid–binding protein 1 (FABP1); and macrophage colony-stimulating factor receptor (MCSFR) determined by immunoassay. “We believe that using some of these candidate biomarkers in combination with the standard tests may be the best way to identify individuals at risk for an adverse outcome,” Dr. Church said.

While their analysis found that the traditional international normalized ratio had the overall best predictive value, measured as area under the curve (AUC) of 0.922, the candidate biomarker OPN was second best with an AUC of 0.871, “and actually performed better than total bilirubin,” Dr. Church said.

The study evaluated mechanistic candidate biomarkers by obtaining biopsies in a cohort of 27 patients within 2 weeks of diagnosis, focusing on three physiological reactions: inflammation, necrosis, and apoptosis.

With regard to inflammation, Dr. Church said, “What we found was that MCSFR actually was significantly elevated in patients who had a high score for inflammation; however, there was no significant difference in OPN, although there was a slight elevation.”

They evaluated necrosis using a semiquantitative confluent coagulative necrosis score, and found no difference in the typical biomarkers of cell necrosis, such as alanine transminase, aspartate aminotransferase, and K18. “So we also looked at the regenerative biomarkers, OPN and AFP, and indeed, we observed that both were significantly elevated with high confluent coagulative necrosis scores,” she said.

To evaluate apoptosis, the researchers used the semiquantitative apoptosis score. “We found there was a small but significant elevation in ccK18 in individuals with a high apoptosis score,” she said. They then evaluated the ratio of ccK18 to K18. “The closer the score is to 1, the more apoptosis you have; and the closer the score is to 0, the more necrosis you have,” Dr. Church said.

They also developed a predictive model that combined the traditional biomarkers INR, total bilirubin, and aspartate aminotransferase with the candidate biomarkers OPN and K18, which had an AUC of 0.97. “Some analysis of candidate biomarkers in combination with tests such as MELD score [Model for End-Stage Liver Disease] and ‘Hy’s Law’ saw that incorporating candidate biomarkers was useful,” Dr. Church said.

Dr. Church reported having no financial disclosures.

WASHINGTON – Researchers have identified six new biomarkers of drug-induced liver injury (DILI) that, when combined with traditional measurements, seemed to better predict the disease course, compared with traditional biomarkers alone, according to a presentation at the annual meeting of the American Association for the Study of Liver Diseases.

In addition, some of these biomarkers may provide a “liquid biopsy” to assess degree of inflammation and mode of hepatocyte death, said Rachel Church, PhD, of the University of North Carolina, Chapel Hill.

“The motivation behind this research is that the standard biomarkers for DILI have several shortcomings,” Dr. Church said. “They’re not entirely liver specific, they’re not mechanistically informative, and they’re not sufficiently predictive of outcome.”

The researchers found that elevated levels of these six candidate biomarkers were predictive for adverse outcome in DILI: total keratin18 (K18); caspase-cleaved K18 (ccK18); alpha-fetoprotein (AFP); osteopontin (OPN); fatty acid–binding protein 1 (FABP1); and macrophage colony-stimulating factor receptor (MCSFR) determined by immunoassay. “We believe that using some of these candidate biomarkers in combination with the standard tests may be the best way to identify individuals at risk for an adverse outcome,” Dr. Church said.

While their analysis found that the traditional international normalized ratio had the overall best predictive value, measured as area under the curve (AUC) of 0.922, the candidate biomarker OPN was second best with an AUC of 0.871, “and actually performed better than total bilirubin,” Dr. Church said.

The study evaluated mechanistic candidate biomarkers by obtaining biopsies in a cohort of 27 patients within 2 weeks of diagnosis, focusing on three physiological reactions: inflammation, necrosis, and apoptosis.

With regard to inflammation, Dr. Church said, “What we found was that MCSFR actually was significantly elevated in patients who had a high score for inflammation; however, there was no significant difference in OPN, although there was a slight elevation.”

They evaluated necrosis using a semiquantitative confluent coagulative necrosis score, and found no difference in the typical biomarkers of cell necrosis, such as alanine transminase, aspartate aminotransferase, and K18. “So we also looked at the regenerative biomarkers, OPN and AFP, and indeed, we observed that both were significantly elevated with high confluent coagulative necrosis scores,” she said.

To evaluate apoptosis, the researchers used the semiquantitative apoptosis score. “We found there was a small but significant elevation in ccK18 in individuals with a high apoptosis score,” she said. They then evaluated the ratio of ccK18 to K18. “The closer the score is to 1, the more apoptosis you have; and the closer the score is to 0, the more necrosis you have,” Dr. Church said.

They also developed a predictive model that combined the traditional biomarkers INR, total bilirubin, and aspartate aminotransferase with the candidate biomarkers OPN and K18, which had an AUC of 0.97. “Some analysis of candidate biomarkers in combination with tests such as MELD score [Model for End-Stage Liver Disease] and ‘Hy’s Law’ saw that incorporating candidate biomarkers was useful,” Dr. Church said.

Dr. Church reported having no financial disclosures.

WASHINGTON – Researchers have identified six new biomarkers of drug-induced liver injury (DILI) that, when combined with traditional measurements, seemed to better predict the disease course, compared with traditional biomarkers alone, according to a presentation at the annual meeting of the American Association for the Study of Liver Diseases.

In addition, some of these biomarkers may provide a “liquid biopsy” to assess degree of inflammation and mode of hepatocyte death, said Rachel Church, PhD, of the University of North Carolina, Chapel Hill.

“The motivation behind this research is that the standard biomarkers for DILI have several shortcomings,” Dr. Church said. “They’re not entirely liver specific, they’re not mechanistically informative, and they’re not sufficiently predictive of outcome.”

The researchers found that elevated levels of these six candidate biomarkers were predictive for adverse outcome in DILI: total keratin18 (K18); caspase-cleaved K18 (ccK18); alpha-fetoprotein (AFP); osteopontin (OPN); fatty acid–binding protein 1 (FABP1); and macrophage colony-stimulating factor receptor (MCSFR) determined by immunoassay. “We believe that using some of these candidate biomarkers in combination with the standard tests may be the best way to identify individuals at risk for an adverse outcome,” Dr. Church said.

While their analysis found that the traditional international normalized ratio had the overall best predictive value, measured as area under the curve (AUC) of 0.922, the candidate biomarker OPN was second best with an AUC of 0.871, “and actually performed better than total bilirubin,” Dr. Church said.

The study evaluated mechanistic candidate biomarkers by obtaining biopsies in a cohort of 27 patients within 2 weeks of diagnosis, focusing on three physiological reactions: inflammation, necrosis, and apoptosis.

With regard to inflammation, Dr. Church said, “What we found was that MCSFR actually was significantly elevated in patients who had a high score for inflammation; however, there was no significant difference in OPN, although there was a slight elevation.”

They evaluated necrosis using a semiquantitative confluent coagulative necrosis score, and found no difference in the typical biomarkers of cell necrosis, such as alanine transminase, aspartate aminotransferase, and K18. “So we also looked at the regenerative biomarkers, OPN and AFP, and indeed, we observed that both were significantly elevated with high confluent coagulative necrosis scores,” she said.

To evaluate apoptosis, the researchers used the semiquantitative apoptosis score. “We found there was a small but significant elevation in ccK18 in individuals with a high apoptosis score,” she said. They then evaluated the ratio of ccK18 to K18. “The closer the score is to 1, the more apoptosis you have; and the closer the score is to 0, the more necrosis you have,” Dr. Church said.

They also developed a predictive model that combined the traditional biomarkers INR, total bilirubin, and aspartate aminotransferase with the candidate biomarkers OPN and K18, which had an AUC of 0.97. “Some analysis of candidate biomarkers in combination with tests such as MELD score [Model for End-Stage Liver Disease] and ‘Hy’s Law’ saw that incorporating candidate biomarkers was useful,” Dr. Church said.

Dr. Church reported having no financial disclosures.

SAN DIEGO – The true impact of firearms injuries may be greatly underestimated, according to a study presented at the American College of Surgeons Clinical Congress.

An analysis released earlier this month estimated that firearms injuries cost nearly $3 billion a year in emergency department and inpatient treatment costs. The real cost is likely to be 10-20 times higher, said the lead author of the study, Faiz Gani, MD, a research fellow with the Johns Hopkins Surgery Center for Outcomes Research, Baltimore.

“This is just a drop in the bucket,” Dr. Gani said in an interview at the annual clinical congress of the American College of Surgeons.

SAN DIEGO – The true impact of firearms injuries may be greatly underestimated, according to a study presented at the American College of Surgeons Clinical Congress.

An analysis released earlier this month estimated that firearms injuries cost nearly $3 billion a year in emergency department and inpatient treatment costs. The real cost is likely to be 10-20 times higher, said the lead author of the study, Faiz Gani, MD, a research fellow with the Johns Hopkins Surgery Center for Outcomes Research, Baltimore.

“This is just a drop in the bucket,” Dr. Gani said in an interview at the annual clinical congress of the American College of Surgeons.

SAN DIEGO – The true impact of firearms injuries may be greatly underestimated, according to a study presented at the American College of Surgeons Clinical Congress.

An analysis released earlier this month estimated that firearms injuries cost nearly $3 billion a year in emergency department and inpatient treatment costs. The real cost is likely to be 10-20 times higher, said the lead author of the study, Faiz Gani, MD, a research fellow with the Johns Hopkins Surgery Center for Outcomes Research, Baltimore.

“This is just a drop in the bucket,” Dr. Gani said in an interview at the annual clinical congress of the American College of Surgeons.

SAN DIEGO – Surgery seems to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical-site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.

It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester, Minn. The path is not straightforward because the human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.

Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example), can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses. The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical-site infection.

Through diet or other presurgical interventions, Dr. Nelson said in a video interview, it might be possible to optimize the microbiome and reduce the chances of some of these occurrences.

She had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

SAN DIEGO – Surgery seems to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical-site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.

It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester, Minn. The path is not straightforward because the human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.

Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example), can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses. The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical-site infection.

Through diet or other presurgical interventions, Dr. Nelson said in a video interview, it might be possible to optimize the microbiome and reduce the chances of some of these occurrences.

She had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

SAN DIEGO – Surgery seems to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical-site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.

It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester, Minn. The path is not straightforward because the human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.

Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example), can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses. The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical-site infection.

Through diet or other presurgical interventions, Dr. Nelson said in a video interview, it might be possible to optimize the microbiome and reduce the chances of some of these occurrences.

She had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

The United States is in the midst of a public health crisis. Every day, 91 Americans die from opioid overdoses.¹ Opioid addiction has a tremendous negative effect on parents and children by destroying lives and breaking up families. When used appropriately, these drugs, such as morphine, hydrocodone, oxycodone, and fentanyl, provide much needed pain relief to patients, especially after a surgical procedure or during treatment for cancer. Unfortunately, opioids also have qualities that make them addictive and prone to overuse and abuse.

Heroin and other opioid drugs are affecting social, health, and economic welfare in communities throughout the United States. Opioid addiction does not discriminate among occupations, socioeconomic statuses, or ethnicities. Once addicted, users find it difficult to fight and overcome the habit. In this context, hospitalists who develop and use opioid policies and tactics are better equipped to deal with the increasing prevalence of opioid addiction and overdoses seen in the medical center environment.

Overview of opioid addiction

Opioids are more prevalent and easily available today in part because of the intense marketing campaigns by pharmaceutical companies. In fact, according to the 2014 National Survey on Drug Use and Health, almost 2 million Americans were dependent on or abused prescription opioids.² Opioids create artificial endorphins in the brain, amplifying positive feelings and euphoria. Once they become dependent, patients feel sick and become depressed when they aren’t using narcotics. They experience uncontrollable cravings, relieved only by increasing opioid use. Personal relationships and finances are severely affected because patients will do whatever they can to acquire more opioids. Some resort to doctor shopping to obtain more opioids, while others will engage in drug trafficking to purchase and sell narcotics. Most new heroin users report that they started with nonmedical use of opioid pain relievers.³

Unfortunately, in 2015, there were more than 20,000 prescription opioid overdose deaths and almost 13,000 overdose deaths related to heroin.⁴ In addition to addiction and death, overuse of narcotics can cause many medical issues, including dizziness, constipation, depression, and immune dysfunction.

As with any addiction, there are many problems related to opiate withdrawal. Some of these include anxiety, rhinorrhea, lacrimation, piloerection, mydriasis, nausea, vomiting, abdominal pain, diarrhea, tachycardia, and hypertension. Methadone, buprenorphine, and extended-release naltrexone typically are used to help alleviate cravings and the symptoms of withdrawal. With more than 1,000 patients treated daily by emergency departments for misuse of prescription opioids, it’s imperative for the medical community to address this health care crisis.⁵
 

Impact on first responders and hospitalists

The impact of this epidemic on the medical community is dramatic. Emergency system resources, already on overload, are further taxed and drained by the increased 911 calls for overdose incidents. This means that instead of responding to heart attacks, strokes, or other emergencies, first responders are spending time stabilizing overdose patients and taking them to hospitals. This resource drain spreads to emergency rooms and hospitals as they treat these patients. Eventually, the epidemic results in higher insurance costs to cover the impact on medical resources.

Strategies for hospitalists

A multifaceted approach is required to combat this crisis, and hospitalists are one component of that solution. Here are strategies hospitalists can employ to combat the growing use and abuse of narcotics:

• Screen for high-risk conditions. Before prescribing opioids, screen patients for conditions that may be exacerbated by opioid use, including sleep apnea, obesity COPD, and heart failure, as well as whether they are using medications that cause sedation and respiratory depression.
• Develop and follow pain management clinical pathway protocols. For example, start with nonopioid analgesics, such as acetaminophen, ibuprofen, and naproxen, for patients with mild pain. If the patient is in moderate pain, or if the mild pain was unrelieved by the first type of medicine, continue with opioid analgesics including codeine, oxycodone, hydrocodone, or morphine. Finally, if the patient is experiencing severe pain, or if the mild to moderate pain was unrelieved by previous medications, prescribe higher doses of morphine, fentanyl, or hydromorphone or use a patient-controlled analgesia delivery of an intravenous opioid.
• Discuss other treatment options. Instead of prescribing narcotics, assess whether other treatment options are viable. These include physical and occupational therapy, steroid shots, massage, local nerve blocks, and muscle relaxers.
• Evaluate the reason(s) for current use of prescribed narcotics. It’s crucial to determine why patients are using opioids. The medical condition for which they were prescribed these medications may have resolved. If patients are using opioids without a medically indicated reason, offer alternative medications, such as methadone or naltrexone, and provide education to help them slowly taper off the drugs. Do not cease opioid use altogether unless the use is contraindicated because of other medical conditions or unstable vital signs (for example, low blood pressure).
• Train nurses on opioid use and addiction. Educate nurses about opioid addiction risk factors and symptoms of addiction. Instruct them on managing the Ramsay Sedation Scale and using an opioid sedation scale with patients receiving IV narcotics.
• Educate families on opioid use and addiction. Counsel patients and their families on the long-term effects of opioid use and about the warning signs of addiction. Teach them about alternatives to narcotics.
• Offer referrals to specialized clinics. Work with social workers, case managers, and local mental health professionals to refer patients to behavioral counseling, patient and family support groups, and monitored detoxification clinics qualified to treat opioid addiction.

Socioeconomic impact

The effects of the opioid epidemic are felt in all areas of the United States, especially in the health care industry. Emergency department visits are mounting while billions of dollars are spent on medical care for those addicted to opioids. Additionally, the socioeconomic effects of this crisis contribute to increasing depression, anxiety, missed days of work or school, unemployment, drop-out rates, and loss of productivity among those addicted to opioids. Also, the epidemic is adversely affecting families, leading to increased divorce rates, single parent families, and child abuse and neglect. By creating strategies and protocols for medical staff, patients, and families affected by opioid use, addiction, or overdose, hospitalists can have a positive influence on patients’ lives and ultimately the opioid epidemic.

Dr. Kasarla is a hospitalist with Apogee Physicians at Parkway Surgical & Cardiovascular Hospital in Fort Worth, Tex. He also works for Texas Health Physicians Group at Texas Health Harris Methodist Hospital and Texas Health Harris Methodist Hospital Southwest in Fort Worth, as well as at Texas Health Harris Methodist Hospital in Azle, Tex.

You can contact him at [email protected] or [email protected].

References

1. Understanding the Epidemic: Drug overdose deaths in the United States continue to increase in 2015. Accessed Sept. 11, 2017.

2. Behavioral health trends in the United States: Results from the 2014 national survey on drug use and health. Accessed Sept. 11, 2017.

3. Jones CM. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers – United States, 2002-2004 and 2008-2010. Drug Alcohol Depend. 2013;132(1-2):95-100.

4. Rudd RA et al. Increases in drug and opioid-involved overdose deaths – United States, 2010-2015. MMWR Morb Mortal Wkly Rep. 2016;65(50-51):1445-52.

5. Highlights of the 2011 Drug Abuse Warning Network (DAWN) findings on drug-related emergency department visits. Accessed Sept. 11, 2017.
 

The United States is in the midst of a public health crisis. Every day, 91 Americans die from opioid overdoses.¹ Opioid addiction has a tremendous negative effect on parents and children by destroying lives and breaking up families. When used appropriately, these drugs, such as morphine, hydrocodone, oxycodone, and fentanyl, provide much needed pain relief to patients, especially after a surgical procedure or during treatment for cancer. Unfortunately, opioids also have qualities that make them addictive and prone to overuse and abuse.

Heroin and other opioid drugs are affecting social, health, and economic welfare in communities throughout the United States. Opioid addiction does not discriminate among occupations, socioeconomic statuses, or ethnicities. Once addicted, users find it difficult to fight and overcome the habit. In this context, hospitalists who develop and use opioid policies and tactics are better equipped to deal with the increasing prevalence of opioid addiction and overdoses seen in the medical center environment.

Overview of opioid addiction

Opioids are more prevalent and easily available today in part because of the intense marketing campaigns by pharmaceutical companies. In fact, according to the 2014 National Survey on Drug Use and Health, almost 2 million Americans were dependent on or abused prescription opioids.² Opioids create artificial endorphins in the brain, amplifying positive feelings and euphoria. Once they become dependent, patients feel sick and become depressed when they aren’t using narcotics. They experience uncontrollable cravings, relieved only by increasing opioid use. Personal relationships and finances are severely affected because patients will do whatever they can to acquire more opioids. Some resort to doctor shopping to obtain more opioids, while others will engage in drug trafficking to purchase and sell narcotics. Most new heroin users report that they started with nonmedical use of opioid pain relievers.³

Unfortunately, in 2015, there were more than 20,000 prescription opioid overdose deaths and almost 13,000 overdose deaths related to heroin.⁴ In addition to addiction and death, overuse of narcotics can cause many medical issues, including dizziness, constipation, depression, and immune dysfunction.

As with any addiction, there are many problems related to opiate withdrawal. Some of these include anxiety, rhinorrhea, lacrimation, piloerection, mydriasis, nausea, vomiting, abdominal pain, diarrhea, tachycardia, and hypertension. Methadone, buprenorphine, and extended-release naltrexone typically are used to help alleviate cravings and the symptoms of withdrawal. With more than 1,000 patients treated daily by emergency departments for misuse of prescription opioids, it’s imperative for the medical community to address this health care crisis.⁵
 

Impact on first responders and hospitalists

The impact of this epidemic on the medical community is dramatic. Emergency system resources, already on overload, are further taxed and drained by the increased 911 calls for overdose incidents. This means that instead of responding to heart attacks, strokes, or other emergencies, first responders are spending time stabilizing overdose patients and taking them to hospitals. This resource drain spreads to emergency rooms and hospitals as they treat these patients. Eventually, the epidemic results in higher insurance costs to cover the impact on medical resources.

Strategies for hospitalists

A multifaceted approach is required to combat this crisis, and hospitalists are one component of that solution. Here are strategies hospitalists can employ to combat the growing use and abuse of narcotics:

• Screen for high-risk conditions. Before prescribing opioids, screen patients for conditions that may be exacerbated by opioid use, including sleep apnea, obesity COPD, and heart failure, as well as whether they are using medications that cause sedation and respiratory depression.
• Develop and follow pain management clinical pathway protocols. For example, start with nonopioid analgesics, such as acetaminophen, ibuprofen, and naproxen, for patients with mild pain. If the patient is in moderate pain, or if the mild pain was unrelieved by the first type of medicine, continue with opioid analgesics including codeine, oxycodone, hydrocodone, or morphine. Finally, if the patient is experiencing severe pain, or if the mild to moderate pain was unrelieved by previous medications, prescribe higher doses of morphine, fentanyl, or hydromorphone or use a patient-controlled analgesia delivery of an intravenous opioid.
• Discuss other treatment options. Instead of prescribing narcotics, assess whether other treatment options are viable. These include physical and occupational therapy, steroid shots, massage, local nerve blocks, and muscle relaxers.
• Evaluate the reason(s) for current use of prescribed narcotics. It’s crucial to determine why patients are using opioids. The medical condition for which they were prescribed these medications may have resolved. If patients are using opioids without a medically indicated reason, offer alternative medications, such as methadone or naltrexone, and provide education to help them slowly taper off the drugs. Do not cease opioid use altogether unless the use is contraindicated because of other medical conditions or unstable vital signs (for example, low blood pressure).
• Train nurses on opioid use and addiction. Educate nurses about opioid addiction risk factors and symptoms of addiction. Instruct them on managing the Ramsay Sedation Scale and using an opioid sedation scale with patients receiving IV narcotics.
• Educate families on opioid use and addiction. Counsel patients and their families on the long-term effects of opioid use and about the warning signs of addiction. Teach them about alternatives to narcotics.
• Offer referrals to specialized clinics. Work with social workers, case managers, and local mental health professionals to refer patients to behavioral counseling, patient and family support groups, and monitored detoxification clinics qualified to treat opioid addiction.

Socioeconomic impact

The effects of the opioid epidemic are felt in all areas of the United States, especially in the health care industry. Emergency department visits are mounting while billions of dollars are spent on medical care for those addicted to opioids. Additionally, the socioeconomic effects of this crisis contribute to increasing depression, anxiety, missed days of work or school, unemployment, drop-out rates, and loss of productivity among those addicted to opioids. Also, the epidemic is adversely affecting families, leading to increased divorce rates, single parent families, and child abuse and neglect. By creating strategies and protocols for medical staff, patients, and families affected by opioid use, addiction, or overdose, hospitalists can have a positive influence on patients’ lives and ultimately the opioid epidemic.

Dr. Kasarla is a hospitalist with Apogee Physicians at Parkway Surgical & Cardiovascular Hospital in Fort Worth, Tex. He also works for Texas Health Physicians Group at Texas Health Harris Methodist Hospital and Texas Health Harris Methodist Hospital Southwest in Fort Worth, as well as at Texas Health Harris Methodist Hospital in Azle, Tex.

You can contact him at [email protected] or [email protected].

References

1. Understanding the Epidemic: Drug overdose deaths in the United States continue to increase in 2015. Accessed Sept. 11, 2017.

2. Behavioral health trends in the United States: Results from the 2014 national survey on drug use and health. Accessed Sept. 11, 2017.

3. Jones CM. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers – United States, 2002-2004 and 2008-2010. Drug Alcohol Depend. 2013;132(1-2):95-100.

4. Rudd RA et al. Increases in drug and opioid-involved overdose deaths – United States, 2010-2015. MMWR Morb Mortal Wkly Rep. 2016;65(50-51):1445-52.

5. Highlights of the 2011 Drug Abuse Warning Network (DAWN) findings on drug-related emergency department visits. Accessed Sept. 11, 2017.
 

The United States is in the midst of a public health crisis. Every day, 91 Americans die from opioid overdoses.¹ Opioid addiction has a tremendous negative effect on parents and children by destroying lives and breaking up families. When used appropriately, these drugs, such as morphine, hydrocodone, oxycodone, and fentanyl, provide much needed pain relief to patients, especially after a surgical procedure or during treatment for cancer. Unfortunately, opioids also have qualities that make them addictive and prone to overuse and abuse.

Heroin and other opioid drugs are affecting social, health, and economic welfare in communities throughout the United States. Opioid addiction does not discriminate among occupations, socioeconomic statuses, or ethnicities. Once addicted, users find it difficult to fight and overcome the habit. In this context, hospitalists who develop and use opioid policies and tactics are better equipped to deal with the increasing prevalence of opioid addiction and overdoses seen in the medical center environment.

Overview of opioid addiction

Opioids are more prevalent and easily available today in part because of the intense marketing campaigns by pharmaceutical companies. In fact, according to the 2014 National Survey on Drug Use and Health, almost 2 million Americans were dependent on or abused prescription opioids.² Opioids create artificial endorphins in the brain, amplifying positive feelings and euphoria. Once they become dependent, patients feel sick and become depressed when they aren’t using narcotics. They experience uncontrollable cravings, relieved only by increasing opioid use. Personal relationships and finances are severely affected because patients will do whatever they can to acquire more opioids. Some resort to doctor shopping to obtain more opioids, while others will engage in drug trafficking to purchase and sell narcotics. Most new heroin users report that they started with nonmedical use of opioid pain relievers.³

Unfortunately, in 2015, there were more than 20,000 prescription opioid overdose deaths and almost 13,000 overdose deaths related to heroin.⁴ In addition to addiction and death, overuse of narcotics can cause many medical issues, including dizziness, constipation, depression, and immune dysfunction.

As with any addiction, there are many problems related to opiate withdrawal. Some of these include anxiety, rhinorrhea, lacrimation, piloerection, mydriasis, nausea, vomiting, abdominal pain, diarrhea, tachycardia, and hypertension. Methadone, buprenorphine, and extended-release naltrexone typically are used to help alleviate cravings and the symptoms of withdrawal. With more than 1,000 patients treated daily by emergency departments for misuse of prescription opioids, it’s imperative for the medical community to address this health care crisis.⁵
 

Impact on first responders and hospitalists

The impact of this epidemic on the medical community is dramatic. Emergency system resources, already on overload, are further taxed and drained by the increased 911 calls for overdose incidents. This means that instead of responding to heart attacks, strokes, or other emergencies, first responders are spending time stabilizing overdose patients and taking them to hospitals. This resource drain spreads to emergency rooms and hospitals as they treat these patients. Eventually, the epidemic results in higher insurance costs to cover the impact on medical resources.

Strategies for hospitalists

A multifaceted approach is required to combat this crisis, and hospitalists are one component of that solution. Here are strategies hospitalists can employ to combat the growing use and abuse of narcotics:

• Screen for high-risk conditions. Before prescribing opioids, screen patients for conditions that may be exacerbated by opioid use, including sleep apnea, obesity COPD, and heart failure, as well as whether they are using medications that cause sedation and respiratory depression.
• Develop and follow pain management clinical pathway protocols. For example, start with nonopioid analgesics, such as acetaminophen, ibuprofen, and naproxen, for patients with mild pain. If the patient is in moderate pain, or if the mild pain was unrelieved by the first type of medicine, continue with opioid analgesics including codeine, oxycodone, hydrocodone, or morphine. Finally, if the patient is experiencing severe pain, or if the mild to moderate pain was unrelieved by previous medications, prescribe higher doses of morphine, fentanyl, or hydromorphone or use a patient-controlled analgesia delivery of an intravenous opioid.
• Discuss other treatment options. Instead of prescribing narcotics, assess whether other treatment options are viable. These include physical and occupational therapy, steroid shots, massage, local nerve blocks, and muscle relaxers.
• Evaluate the reason(s) for current use of prescribed narcotics. It’s crucial to determine why patients are using opioids. The medical condition for which they were prescribed these medications may have resolved. If patients are using opioids without a medically indicated reason, offer alternative medications, such as methadone or naltrexone, and provide education to help them slowly taper off the drugs. Do not cease opioid use altogether unless the use is contraindicated because of other medical conditions or unstable vital signs (for example, low blood pressure).
• Train nurses on opioid use and addiction. Educate nurses about opioid addiction risk factors and symptoms of addiction. Instruct them on managing the Ramsay Sedation Scale and using an opioid sedation scale with patients receiving IV narcotics.
• Educate families on opioid use and addiction. Counsel patients and their families on the long-term effects of opioid use and about the warning signs of addiction. Teach them about alternatives to narcotics.
• Offer referrals to specialized clinics. Work with social workers, case managers, and local mental health professionals to refer patients to behavioral counseling, patient and family support groups, and monitored detoxification clinics qualified to treat opioid addiction.

Socioeconomic impact

The effects of the opioid epidemic are felt in all areas of the United States, especially in the health care industry. Emergency department visits are mounting while billions of dollars are spent on medical care for those addicted to opioids. Additionally, the socioeconomic effects of this crisis contribute to increasing depression, anxiety, missed days of work or school, unemployment, drop-out rates, and loss of productivity among those addicted to opioids. Also, the epidemic is adversely affecting families, leading to increased divorce rates, single parent families, and child abuse and neglect. By creating strategies and protocols for medical staff, patients, and families affected by opioid use, addiction, or overdose, hospitalists can have a positive influence on patients’ lives and ultimately the opioid epidemic.

Dr. Kasarla is a hospitalist with Apogee Physicians at Parkway Surgical & Cardiovascular Hospital in Fort Worth, Tex. He also works for Texas Health Physicians Group at Texas Health Harris Methodist Hospital and Texas Health Harris Methodist Hospital Southwest in Fort Worth, as well as at Texas Health Harris Methodist Hospital in Azle, Tex.

You can contact him at [email protected] or [email protected].

References

1. Understanding the Epidemic: Drug overdose deaths in the United States continue to increase in 2015. Accessed Sept. 11, 2017.

2. Behavioral health trends in the United States: Results from the 2014 national survey on drug use and health. Accessed Sept. 11, 2017.

3. Jones CM. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers – United States, 2002-2004 and 2008-2010. Drug Alcohol Depend. 2013;132(1-2):95-100.

4. Rudd RA et al. Increases in drug and opioid-involved overdose deaths – United States, 2010-2015. MMWR Morb Mortal Wkly Rep. 2016;65(50-51):1445-52.

5. Highlights of the 2011 Drug Abuse Warning Network (DAWN) findings on drug-related emergency department visits. Accessed Sept. 11, 2017.
 

The suicide rate in the United States rose over 19% from 2001 to 2015, with an increasing gap separating rural areas from those with large urban populations, according to the Centers for Disease Control and Prevention.

Suicide rates in nonmetropolitan/rural counties for those aged 10 years and older have been consistently higher, and increased more, than those in large metropolitan counties, the CDC said.

[email protected]

The suicide rate in the United States rose over 19% from 2001 to 2015, with an increasing gap separating rural areas from those with large urban populations, according to the Centers for Disease Control and Prevention.

Suicide rates in nonmetropolitan/rural counties for those aged 10 years and older have been consistently higher, and increased more, than those in large metropolitan counties, the CDC said.

[email protected]

The suicide rate in the United States rose over 19% from 2001 to 2015, with an increasing gap separating rural areas from those with large urban populations, according to the Centers for Disease Control and Prevention.

Suicide rates in nonmetropolitan/rural counties for those aged 10 years and older have been consistently higher, and increased more, than those in large metropolitan counties, the CDC said.

[email protected]

A patient with Merkel cell carcinoma (MCC) came to Sir Charles Gairdner Hospital in Perth, Australia, after 2 weeks of dyspnea. He was diagnosed with cardiac tamponade and received urgent pericardiocentesis. An echocardiogram and computer tomography scan showed a large infiltrating mass in the heart. Immunohistochemistry of the pericardial fluid revealed MCC. The MCC had metastasized to his heart—the tenth such reported case, and the second case reported of MCC causing cardiac tamponade.

The clinicians report on several “important illustrative aspects” that appeared while they were unraveling the clues to the patient’s condition. One aspect was the challenge of the histopathologic diagnosis itself. The majority of patients with MCC present with localized disease, they note. Only 4% of patients have distant metastases, usually to lymph nodes, lung, central nervous system, and bone. MCC metastases to the heart are extremely rare. Most commonly, a cancer that spreads to the heart has started in the lungs, esophagus, or breast, or has begun as lymphoma, melanoma, or leukemia.  

However, it’s “exponentially more likely,” the clinicians say, for a cardiac tumor to be a metastasis than a primary cardiac tumor, and it is uncommon for the heart to be the only site of metastatic disease from a noncardiac malignancy. Thus, the patient represented a unique case: apart from an internal mammary lymph node, the heart was the only site of distant metastatic spread.  

This patient’s case highlights the importance of early and accurate diagnosis of MCC with aggressive surgical treatment for localized disease, the clinicians say. New cardiac symptoms in the setting of malignancy should raise suspicion of cardiac metastasis.

Source:
Di Loreto M, Francis R. BMJ Case Rep. 2017. pii: bcr-2017-221311.
doi: 10.1136/bcr-2017-221311.

A patient with Merkel cell carcinoma (MCC) came to Sir Charles Gairdner Hospital in Perth, Australia, after 2 weeks of dyspnea. He was diagnosed with cardiac tamponade and received urgent pericardiocentesis. An echocardiogram and computer tomography scan showed a large infiltrating mass in the heart. Immunohistochemistry of the pericardial fluid revealed MCC. The MCC had metastasized to his heart—the tenth such reported case, and the second case reported of MCC causing cardiac tamponade.

The clinicians report on several “important illustrative aspects” that appeared while they were unraveling the clues to the patient’s condition. One aspect was the challenge of the histopathologic diagnosis itself. The majority of patients with MCC present with localized disease, they note. Only 4% of patients have distant metastases, usually to lymph nodes, lung, central nervous system, and bone. MCC metastases to the heart are extremely rare. Most commonly, a cancer that spreads to the heart has started in the lungs, esophagus, or breast, or has begun as lymphoma, melanoma, or leukemia.  

However, it’s “exponentially more likely,” the clinicians say, for a cardiac tumor to be a metastasis than a primary cardiac tumor, and it is uncommon for the heart to be the only site of metastatic disease from a noncardiac malignancy. Thus, the patient represented a unique case: apart from an internal mammary lymph node, the heart was the only site of distant metastatic spread.  

This patient’s case highlights the importance of early and accurate diagnosis of MCC with aggressive surgical treatment for localized disease, the clinicians say. New cardiac symptoms in the setting of malignancy should raise suspicion of cardiac metastasis.

Source:
Di Loreto M, Francis R. BMJ Case Rep. 2017. pii: bcr-2017-221311.
doi: 10.1136/bcr-2017-221311.

A patient with Merkel cell carcinoma (MCC) came to Sir Charles Gairdner Hospital in Perth, Australia, after 2 weeks of dyspnea. He was diagnosed with cardiac tamponade and received urgent pericardiocentesis. An echocardiogram and computer tomography scan showed a large infiltrating mass in the heart. Immunohistochemistry of the pericardial fluid revealed MCC. The MCC had metastasized to his heart—the tenth such reported case, and the second case reported of MCC causing cardiac tamponade.

The clinicians report on several “important illustrative aspects” that appeared while they were unraveling the clues to the patient’s condition. One aspect was the challenge of the histopathologic diagnosis itself. The majority of patients with MCC present with localized disease, they note. Only 4% of patients have distant metastases, usually to lymph nodes, lung, central nervous system, and bone. MCC metastases to the heart are extremely rare. Most commonly, a cancer that spreads to the heart has started in the lungs, esophagus, or breast, or has begun as lymphoma, melanoma, or leukemia.  

However, it’s “exponentially more likely,” the clinicians say, for a cardiac tumor to be a metastasis than a primary cardiac tumor, and it is uncommon for the heart to be the only site of metastatic disease from a noncardiac malignancy. Thus, the patient represented a unique case: apart from an internal mammary lymph node, the heart was the only site of distant metastatic spread.  

This patient’s case highlights the importance of early and accurate diagnosis of MCC with aggressive surgical treatment for localized disease, the clinicians say. New cardiac symptoms in the setting of malignancy should raise suspicion of cardiac metastasis.

Source:
Di Loreto M, Francis R. BMJ Case Rep. 2017. pii: bcr-2017-221311.
doi: 10.1136/bcr-2017-221311.

Photo by Rhoda Baer

New research indicates that hospitalized patients with advanced cancer have a high burden of physical and psychological symptoms, and this burden is linked to longer hospital stays and a greater risk for unplanned hospital readmissions and death.

Researchers said these findings highlight the need to develop and test interventions to lessen patients’ symptoms.

Ryan Nipp, MD, of Massachusetts General Hospital in Boston, and his colleagues reported the findings in Cancer.

The researchers noted that patients with advanced cancer often experience frequent and prolonged hospitalizations for reasons that have not been fully explored.

To investigate, the team collected information from 1036 patients with advanced cancer as they were being admitted for an unplanned hospitalization.

The Edmonton Symptom Assessment System (ESAS) was used to assess patients’ physical symptoms, and the Patient Health Questionnaire 4 (PHQ-4) was used to assess their psychological symptoms.

The researchers examined the relationship between patients’ symptom burden and the duration of their hospital stay, risk of readmission, and death.

Many patients reported moderate or severe fatigue (86.7%), poor well-being (74.2%), drowsiness (71.7%), pain (67.7%), and lack of appetite (67.3%). Nearly 30% of patients had clinically significant symptoms of depression (28.8%) and anxiety (28.0%).

The patients’ mean hospital stay was 6.3 days, the readmission rate within 90 days of discharge was 43.1%, and the 90-day mortality rate was 41.6%.

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P=0.040), and depression symptoms (P=0.017) were significantly associated with longer hospital stays, but anxiety symptoms were not (P=0.190).

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P=0.072), and anxiety symptoms (P=0.045) were significantly associated with a higher likelihood of readmission within 90 days, but depression symptoms were not (P=0.219).

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P<0.001), depression symptoms (P<0.001), and anxiety symptoms (P=0.012) were all significantly associated with a higher likelihood of death or readmission within 90 days.

“We demonstrated that many hospitalized patients with advanced cancer experience an immense physical and psychological symptom burden,” Dr Nipp said.

“Interventions to identify and treat symptomatic patients hold great potential for improving patients’ experience with their illness, enhancing their quality of life, and reducing their healthcare utilization.”

Photo by Rhoda Baer

New research indicates that hospitalized patients with advanced cancer have a high burden of physical and psychological symptoms, and this burden is linked to longer hospital stays and a greater risk for unplanned hospital readmissions and death.

Researchers said these findings highlight the need to develop and test interventions to lessen patients’ symptoms.

Ryan Nipp, MD, of Massachusetts General Hospital in Boston, and his colleagues reported the findings in Cancer.

The researchers noted that patients with advanced cancer often experience frequent and prolonged hospitalizations for reasons that have not been fully explored.

To investigate, the team collected information from 1036 patients with advanced cancer as they were being admitted for an unplanned hospitalization.

The Edmonton Symptom Assessment System (ESAS) was used to assess patients’ physical symptoms, and the Patient Health Questionnaire 4 (PHQ-4) was used to assess their psychological symptoms.

The researchers examined the relationship between patients’ symptom burden and the duration of their hospital stay, risk of readmission, and death.

Many patients reported moderate or severe fatigue (86.7%), poor well-being (74.2%), drowsiness (71.7%), pain (67.7%), and lack of appetite (67.3%). Nearly 30% of patients had clinically significant symptoms of depression (28.8%) and anxiety (28.0%).

The patients’ mean hospital stay was 6.3 days, the readmission rate within 90 days of discharge was 43.1%, and the 90-day mortality rate was 41.6%.

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P=0.040), and depression symptoms (P=0.017) were significantly associated with longer hospital stays, but anxiety symptoms were not (P=0.190).

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P=0.072), and anxiety symptoms (P=0.045) were significantly associated with a higher likelihood of readmission within 90 days, but depression symptoms were not (P=0.219).

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P<0.001), depression symptoms (P<0.001), and anxiety symptoms (P=0.012) were all significantly associated with a higher likelihood of death or readmission within 90 days.

“We demonstrated that many hospitalized patients with advanced cancer experience an immense physical and psychological symptom burden,” Dr Nipp said.

“Interventions to identify and treat symptomatic patients hold great potential for improving patients’ experience with their illness, enhancing their quality of life, and reducing their healthcare utilization.”

Photo by Rhoda Baer

New research indicates that hospitalized patients with advanced cancer have a high burden of physical and psychological symptoms, and this burden is linked to longer hospital stays and a greater risk for unplanned hospital readmissions and death.

Researchers said these findings highlight the need to develop and test interventions to lessen patients’ symptoms.

Ryan Nipp, MD, of Massachusetts General Hospital in Boston, and his colleagues reported the findings in Cancer.

The researchers noted that patients with advanced cancer often experience frequent and prolonged hospitalizations for reasons that have not been fully explored.

To investigate, the team collected information from 1036 patients with advanced cancer as they were being admitted for an unplanned hospitalization.

The Edmonton Symptom Assessment System (ESAS) was used to assess patients’ physical symptoms, and the Patient Health Questionnaire 4 (PHQ-4) was used to assess their psychological symptoms.

The researchers examined the relationship between patients’ symptom burden and the duration of their hospital stay, risk of readmission, and death.

Many patients reported moderate or severe fatigue (86.7%), poor well-being (74.2%), drowsiness (71.7%), pain (67.7%), and lack of appetite (67.3%). Nearly 30% of patients had clinically significant symptoms of depression (28.8%) and anxiety (28.0%).

The patients’ mean hospital stay was 6.3 days, the readmission rate within 90 days of discharge was 43.1%, and the 90-day mortality rate was 41.6%.

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P=0.040), and depression symptoms (P=0.017) were significantly associated with longer hospital stays, but anxiety symptoms were not (P=0.190).

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P=0.072), and anxiety symptoms (P=0.045) were significantly associated with a higher likelihood of readmission within 90 days, but depression symptoms were not (P=0.219).

Physical symptoms (P<0.001), total ESAS score (P<0.001), total PHQ-4 score (P<0.001), depression symptoms (P<0.001), and anxiety symptoms (P=0.012) were all significantly associated with a higher likelihood of death or readmission within 90 days.

“We demonstrated that many hospitalized patients with advanced cancer experience an immense physical and psychological symptom burden,” Dr Nipp said.

“Interventions to identify and treat symptomatic patients hold great potential for improving patients’ experience with their illness, enhancing their quality of life, and reducing their healthcare utilization.”

Photo by Chad McNeeley

GRANADA, SPAIN—A monoclonal antibody can resolve co-existing hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GVHD), according to a case study.

The antibody is OMS721, and it targets MASP-2, a pro-inflammatory protein target involved in activation of the complement system.

The case of OMS721 ameliorating HSCT-TMA and GVHD was presented at the European Society for Blood and Marrow Transplantation Crash Course on Diagnosis and Treatment of Noninfectious Complications after HCT.

The patient was a participant in an ongoing phase 2 trial of thrombotic microangiopathies, including HSCT-TMA. The trial is sponsored by Omeros Corporation, the company developing OMS721.

The patient was an adult male with post-transplant TMA persisting at least 2 weeks following calcineurin inhibitor modification.

The patient had undergone HSCT for T-cell acute lymphoblastic leukemia. His post-transplant course was complicated by multiple episodes of steroid-refractory grade 4 GVHD, cytomegalovirus infection, and HSCT-TMA.

After 2 prior episodes of GVHD, the patient presented with bloody diarrhea. Intestinal biopsy demonstrated both HSCT-TMA and GVHD. No infections were identified.

The patient also had new-onset neurological symptoms of paresthesias, tetraparesis, and a neurogenic bladder, which have been reported as neurological manifestations of GVHD and TMA.

The patient was unable to walk due to the tetraparesis and required blood transfusions at least once daily. Hematological markers demonstrated HSCT-TMA with thrombocytopenia, elevated lactate dehydrogenase, and schistocytes.

Two weeks prior to starting OMS721, the patient’s immunosuppression (cyclosporine) had been decreased, and, given his history of steroid-refractory GVHD, he was receiving only low-dose corticosteroids. He received no other GVHD treatment.

After 2 OMS721 doses, the patient’s bloody diarrhea resolved, and his hematological markers improved. After 4 OMS721 doses, he was able to walk with help.

The patient completed 8 weeks of OMS721 treatment and has been doing well at home. All signs and symptoms of HSCT-TMA and all clinical symptoms of GVHD have resolved. His neurological symptoms have continued to improve.

“This patient’s marked response to OMS721 treatment was very gratifying,” said Anna Grassi, MD, of Azienda Ospedaliera Papa Giovanni XXIII in Bergamo, Italy.

“The cause of his neurological symptoms is not clear but may be a manifestation of GVHD or other endothelial injury. Prior to OMS721 treatment, this patient was deteriorating and at high risk for early death. The improvement of GVHD, H[S]CT-TMA, and the neurological symptoms following OMS721 treatment is promising.”

Photo by Chad McNeeley

GRANADA, SPAIN—A monoclonal antibody can resolve co-existing hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GVHD), according to a case study.

The antibody is OMS721, and it targets MASP-2, a pro-inflammatory protein target involved in activation of the complement system.

The case of OMS721 ameliorating HSCT-TMA and GVHD was presented at the European Society for Blood and Marrow Transplantation Crash Course on Diagnosis and Treatment of Noninfectious Complications after HCT.

The patient was a participant in an ongoing phase 2 trial of thrombotic microangiopathies, including HSCT-TMA. The trial is sponsored by Omeros Corporation, the company developing OMS721.

The patient was an adult male with post-transplant TMA persisting at least 2 weeks following calcineurin inhibitor modification.

The patient had undergone HSCT for T-cell acute lymphoblastic leukemia. His post-transplant course was complicated by multiple episodes of steroid-refractory grade 4 GVHD, cytomegalovirus infection, and HSCT-TMA.

After 2 prior episodes of GVHD, the patient presented with bloody diarrhea. Intestinal biopsy demonstrated both HSCT-TMA and GVHD. No infections were identified.

The patient also had new-onset neurological symptoms of paresthesias, tetraparesis, and a neurogenic bladder, which have been reported as neurological manifestations of GVHD and TMA.

The patient was unable to walk due to the tetraparesis and required blood transfusions at least once daily. Hematological markers demonstrated HSCT-TMA with thrombocytopenia, elevated lactate dehydrogenase, and schistocytes.

Two weeks prior to starting OMS721, the patient’s immunosuppression (cyclosporine) had been decreased, and, given his history of steroid-refractory GVHD, he was receiving only low-dose corticosteroids. He received no other GVHD treatment.

After 2 OMS721 doses, the patient’s bloody diarrhea resolved, and his hematological markers improved. After 4 OMS721 doses, he was able to walk with help.

The patient completed 8 weeks of OMS721 treatment and has been doing well at home. All signs and symptoms of HSCT-TMA and all clinical symptoms of GVHD have resolved. His neurological symptoms have continued to improve.

“This patient’s marked response to OMS721 treatment was very gratifying,” said Anna Grassi, MD, of Azienda Ospedaliera Papa Giovanni XXIII in Bergamo, Italy.

“The cause of his neurological symptoms is not clear but may be a manifestation of GVHD or other endothelial injury. Prior to OMS721 treatment, this patient was deteriorating and at high risk for early death. The improvement of GVHD, H[S]CT-TMA, and the neurological symptoms following OMS721 treatment is promising.”

Photo by Chad McNeeley

GRANADA, SPAIN—A monoclonal antibody can resolve co-existing hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GVHD), according to a case study.

The antibody is OMS721, and it targets MASP-2, a pro-inflammatory protein target involved in activation of the complement system.

The case of OMS721 ameliorating HSCT-TMA and GVHD was presented at the European Society for Blood and Marrow Transplantation Crash Course on Diagnosis and Treatment of Noninfectious Complications after HCT.

The patient was a participant in an ongoing phase 2 trial of thrombotic microangiopathies, including HSCT-TMA. The trial is sponsored by Omeros Corporation, the company developing OMS721.

The patient was an adult male with post-transplant TMA persisting at least 2 weeks following calcineurin inhibitor modification.

The patient had undergone HSCT for T-cell acute lymphoblastic leukemia. His post-transplant course was complicated by multiple episodes of steroid-refractory grade 4 GVHD, cytomegalovirus infection, and HSCT-TMA.

After 2 prior episodes of GVHD, the patient presented with bloody diarrhea. Intestinal biopsy demonstrated both HSCT-TMA and GVHD. No infections were identified.

The patient also had new-onset neurological symptoms of paresthesias, tetraparesis, and a neurogenic bladder, which have been reported as neurological manifestations of GVHD and TMA.

The patient was unable to walk due to the tetraparesis and required blood transfusions at least once daily. Hematological markers demonstrated HSCT-TMA with thrombocytopenia, elevated lactate dehydrogenase, and schistocytes.

Two weeks prior to starting OMS721, the patient’s immunosuppression (cyclosporine) had been decreased, and, given his history of steroid-refractory GVHD, he was receiving only low-dose corticosteroids. He received no other GVHD treatment.

After 2 OMS721 doses, the patient’s bloody diarrhea resolved, and his hematological markers improved. After 4 OMS721 doses, he was able to walk with help.

The patient completed 8 weeks of OMS721 treatment and has been doing well at home. All signs and symptoms of HSCT-TMA and all clinical symptoms of GVHD have resolved. His neurological symptoms have continued to improve.

“This patient’s marked response to OMS721 treatment was very gratifying,” said Anna Grassi, MD, of Azienda Ospedaliera Papa Giovanni XXIII in Bergamo, Italy.

“The cause of his neurological symptoms is not clear but may be a manifestation of GVHD or other endothelial injury. Prior to OMS721 treatment, this patient was deteriorating and at high risk for early death. The improvement of GVHD, H[S]CT-TMA, and the neurological symptoms following OMS721 treatment is promising.”

follicular lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).

G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.

G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.

Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.

Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.

Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.

The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).

Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.

An additional 13 patients treated at the 10 μg dose were evaluable for safety.  There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.

Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.

Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

follicular lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).

G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.

G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.

Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.

Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.

Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.

The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).

Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.

An additional 13 patients treated at the 10 μg dose were evaluable for safety.  There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.

Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.

Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

follicular lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).

G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.

G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.

Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.

Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.

Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.

The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).

Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.

An additional 13 patients treated at the 10 μg dose were evaluable for safety.  There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.

Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.

Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission. 

Infants with congenital cytomegalovirus (cCMV) who were asymptomatic at birth with normal hearing by age 2 years were not at higher risk of intellectual impairment or low academic achievement, compared with controls, but patients with sensorineural hearing loss may experience more difficulty, according to a longitudinal study.

Full-scale intelligence, language, and academic achievement was evaluated in 78 adolescents with cCMV and normal hearing, 11 with cCMV and sensorineural hearing loss (SNHL) by age 2 years, and 40 controls. Mean full-scale intelligence scores did not vary among the patients with normal hearing and the controls, said Adriana S. Lopez of the National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, and her coauthors. Each group scored a mean 108 (95% confidence interval, 105-110 and 104-111, respectively) at age 5 years and 111 (95% CI, 108-114 and 107-104, respectively) at age 18 years (P = .96). The scores of the patients with SNHL, however, were 7 points lower at both times (P less than .05).

CDC/Craig Lyerla

[email protected]

Infants with congenital cytomegalovirus (cCMV) who were asymptomatic at birth with normal hearing by age 2 years were not at higher risk of intellectual impairment or low academic achievement, compared with controls, but patients with sensorineural hearing loss may experience more difficulty, according to a longitudinal study.

Full-scale intelligence, language, and academic achievement was evaluated in 78 adolescents with cCMV and normal hearing, 11 with cCMV and sensorineural hearing loss (SNHL) by age 2 years, and 40 controls. Mean full-scale intelligence scores did not vary among the patients with normal hearing and the controls, said Adriana S. Lopez of the National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, and her coauthors. Each group scored a mean 108 (95% confidence interval, 105-110 and 104-111, respectively) at age 5 years and 111 (95% CI, 108-114 and 107-104, respectively) at age 18 years (P = .96). The scores of the patients with SNHL, however, were 7 points lower at both times (P less than .05).

CDC/Craig Lyerla

[email protected]

Infants with congenital cytomegalovirus (cCMV) who were asymptomatic at birth with normal hearing by age 2 years were not at higher risk of intellectual impairment or low academic achievement, compared with controls, but patients with sensorineural hearing loss may experience more difficulty, according to a longitudinal study.

Full-scale intelligence, language, and academic achievement was evaluated in 78 adolescents with cCMV and normal hearing, 11 with cCMV and sensorineural hearing loss (SNHL) by age 2 years, and 40 controls. Mean full-scale intelligence scores did not vary among the patients with normal hearing and the controls, said Adriana S. Lopez of the National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, and her coauthors. Each group scored a mean 108 (95% confidence interval, 105-110 and 104-111, respectively) at age 5 years and 111 (95% CI, 108-114 and 107-104, respectively) at age 18 years (P = .96). The scores of the patients with SNHL, however, were 7 points lower at both times (P less than .05).

CDC/Craig Lyerla

[email protected]