Commentary

Rural surgeons who provide cancer care face a particular set of challenges. Rural patients tend to be older, sicker, less educated and economically disadvantaged. Rural areas have a higher prevalence of chronic diseases including heart disease and cancer. Rural patients present with more advanced cancers than their urban counterparts. Specific rural regions (i.e., Appalachia) have documented higher cancer incidences and mortality rates.

In addition, there are several barriers to providing cancer care for rural populations. These include poor access to health care services and specialists; geographic barriers preventing access to providers, services, and technology; minimal transportation options for either cancer screening or treatment; limited knowledge of cancer and low participation in screening and other healthy practices; prohibitive costs of screening and cancer treatment; and, in some cases, suboptimal care provided to cancer patients (J. Am. Coll. Surg. 2014;219:814-8; Gosschalk, A. and Carozza, S., “Cancer in rural areas: A literature review,” Rural Healthy People 2010, Vol. 2 [College Station: The Texas A&M University System Health Science Center, 2003]).

Several examples of suboptimal care for rural cancer patients have appeared in professional journals and meetings and in the lay press. Examples of rural cancer care inadequacies include lower use of needle biopsy and sentinel lymph node biopsy techniques for breast cancer patients (Am. J. Surg. 2014;208:382-90; Am. J. Surg. 2013;206:674-81; ACS Surgery News, “Use of minimally invasive biopsy lags in Texas,” February 2013, p. 15); significantly lower rates of radiation treatment in breast lumpectomy patients (USA Today, Nov. 18, 2012); lower rates of adequate lymph node dissection, appropriate chemotherapy, and higher death rates in colon cancer patients (Chow, C.J., ACS Clinical Congress Presentation 2012); higher mastectomy rates and later-stage cancers in breast cancer patients (Jethwa, K., AACR Annual Conference Presentation 2013); higher likelihood of discharge to a skilled nursing facility instead of home in colon cancer patients; and the list goes on and on. These articles all come from academic centers through database studies. It is rare indeed to see data collected and published by the rural centers and providers actually caring for rural cancer patients.

My personal bias is that rural surgeons provide very competent, compassionate, high quality care that allows the cancer patient to remain close to their homes and support systems. This opinion has been reinforced by my involvement with the ACS Advisory Council on Rural Surgery, the rural listserve /ACS Rural Community and through my interaction with surgeons across the country at ACS Chapter meetings and at the Congress.

A study done by Finlayson (Med. Care 1999;37:204-9) documented that nearly 100% of rural patients preferred to receive their care locally, especially if the quality of care was the same as the larger distant hospital. In fact, nearly half of the patients polled would choose to remain local even if the mortality rate at the local hospital was double that of a hospital requiring the patient to travel for care. More recent papers however suggest that patients may be bypassing their local hospitals for care because of concerns about the quality of care provided locally (J. Rural Health 1999;10:70-9; J. Rural Health 2007;23:17-24).

A 2013 ASCO presentation documented that General Surgeons perform a majority of cancer surgeries in the United States (Stizenberg, K.; SSO 66th Annual Cancer Symposium; Abstract 75, March 8, 2013). Only 303 (< 8%) counties in the United States even have a surgical oncologist. A 2014 ASCO presentation estimated a 43% increase in inpatient oncology procedures and a 25% increase in outpatient procedures between 2002 and 2020. By 2025 the total demand for oncology care will rise by 43% (ASCO, “The state of cancer care 2014,” J. Oncol. Prac. 2014;10:119-42). Another study (ACS Surgery News, “Surgeon supply to drop 18% by 2028,” January 2013, p. 1) has estimated that, with predicted future surgeon shortages, general surgeons will be called upon to perform 25% of cases now done by other surgical specialists. General surgeons, both rural and urban, are clearly providing the bulk of cancer care to patients and this trend is on the rise in coming years.

Rural surgeons have certain barriers that prevent them from measuring, documenting, and publicizing the specifics of the care provided to their patients. These surgeons often are in single or small group practices and manage their own businesses. They have no office or hospital staff dedicated to quality endeavors. Financial and time constraints prevent them from being champions of quality care in their communities. Additionally, small numbers of specific cases can result in high statistical complication and mortality rates even if these events happen infrequently. This inability to collect data and assess the quality of care provided can lead to patient outmigration and even “tiering” by third-party payers that forces patients away from their hometown hospitals and providers using financial disincentives.

Rural surgeons can and must now take the lead in collecting, assessing, and reporting data about the care they provide for their communities. This process can be in the form of standardized programs like ACS Rural National Surgical Quality Improvement Program (NSQIP), Surgical Care Improvement Project (SCIP), or Commission on Cancer (CoC) accreditation involvement. Smaller institutions with a single surgeon may not have the financial and staff resources to formally participate but each surgeon can assess what makes up the majority of his or her caseload, whether that is endoscopy or breast or colon cases, and find national benchmarks that can easily be measured. Every endoscopy department can collect data on cecal intubation rates, withdrawal times, adequacy of preps, adenoma detection rates, and appropriate follow-up intervals. Individual surgeons can pick and chose specific benchmarks from NSQIP, Commission on Cancer, National Accreditation Program for Breast Centers (NAPBC), or ACS Committee on Trauma standards documents and use these to evaluate the care they provide. Easy examples might include number of lymph nodes harvested at colon cancer surgery, percentage of breast cancer patients diagnosed with needle biopsy, and percentage treated with conservative surgery and appropriate postop radiation and or chemotherapy, or the percentage of melanoma patients treated per National Comprehensive Cancer Network guidelines. Other ways for institutions to document quality might be to partner with their tertiary referral center for CoC accreditation or just to participate in cancer conferences by videoconferencing. The Commission on Cancer has designated CoC Liason Program Chairs in each state that are available to aid in setting up these types of programs.

It is time for rural surgeons to partner with their hospitals and communities to carry out needs assessments and think of ways to fill those needs. An example might be to work with primary care providers to develop aggressive colon, breast, or lung cancer screening programs in communities with high numbers of late-stage cases. Transparency of the data collected and the care provided in the form of “Quality Reports to the Community” can improve local referral patterns, improve the financial viability of the local hospital, and prove to the community that quality care is being rendered. Pooling the data from a large base of rural surgeons could serve to disprove the academic community notion that rural patients receive suboptimal cancer care.

Dr. Sarap is a practicing general surgeon in Cambridge, Ohio. He is a member of the Advisory Council on Rural Surgery and has been appointed the Commission on Cancer Liaison Program Chair for Ohio.

Rural surgeons who provide cancer care face a particular set of challenges. Rural patients tend to be older, sicker, less educated and economically disadvantaged. Rural areas have a higher prevalence of chronic diseases including heart disease and cancer. Rural patients present with more advanced cancers than their urban counterparts. Specific rural regions (i.e., Appalachia) have documented higher cancer incidences and mortality rates.

In addition, there are several barriers to providing cancer care for rural populations. These include poor access to health care services and specialists; geographic barriers preventing access to providers, services, and technology; minimal transportation options for either cancer screening or treatment; limited knowledge of cancer and low participation in screening and other healthy practices; prohibitive costs of screening and cancer treatment; and, in some cases, suboptimal care provided to cancer patients (J. Am. Coll. Surg. 2014;219:814-8; Gosschalk, A. and Carozza, S., “Cancer in rural areas: A literature review,” Rural Healthy People 2010, Vol. 2 [College Station: The Texas A&M University System Health Science Center, 2003]).

Several examples of suboptimal care for rural cancer patients have appeared in professional journals and meetings and in the lay press. Examples of rural cancer care inadequacies include lower use of needle biopsy and sentinel lymph node biopsy techniques for breast cancer patients (Am. J. Surg. 2014;208:382-90; Am. J. Surg. 2013;206:674-81; ACS Surgery News, “Use of minimally invasive biopsy lags in Texas,” February 2013, p. 15); significantly lower rates of radiation treatment in breast lumpectomy patients (USA Today, Nov. 18, 2012); lower rates of adequate lymph node dissection, appropriate chemotherapy, and higher death rates in colon cancer patients (Chow, C.J., ACS Clinical Congress Presentation 2012); higher mastectomy rates and later-stage cancers in breast cancer patients (Jethwa, K., AACR Annual Conference Presentation 2013); higher likelihood of discharge to a skilled nursing facility instead of home in colon cancer patients; and the list goes on and on. These articles all come from academic centers through database studies. It is rare indeed to see data collected and published by the rural centers and providers actually caring for rural cancer patients.

My personal bias is that rural surgeons provide very competent, compassionate, high quality care that allows the cancer patient to remain close to their homes and support systems. This opinion has been reinforced by my involvement with the ACS Advisory Council on Rural Surgery, the rural listserve /ACS Rural Community and through my interaction with surgeons across the country at ACS Chapter meetings and at the Congress.

A study done by Finlayson (Med. Care 1999;37:204-9) documented that nearly 100% of rural patients preferred to receive their care locally, especially if the quality of care was the same as the larger distant hospital. In fact, nearly half of the patients polled would choose to remain local even if the mortality rate at the local hospital was double that of a hospital requiring the patient to travel for care. More recent papers however suggest that patients may be bypassing their local hospitals for care because of concerns about the quality of care provided locally (J. Rural Health 1999;10:70-9; J. Rural Health 2007;23:17-24).

A 2013 ASCO presentation documented that General Surgeons perform a majority of cancer surgeries in the United States (Stizenberg, K.; SSO 66th Annual Cancer Symposium; Abstract 75, March 8, 2013). Only 303 (< 8%) counties in the United States even have a surgical oncologist. A 2014 ASCO presentation estimated a 43% increase in inpatient oncology procedures and a 25% increase in outpatient procedures between 2002 and 2020. By 2025 the total demand for oncology care will rise by 43% (ASCO, “The state of cancer care 2014,” J. Oncol. Prac. 2014;10:119-42). Another study (ACS Surgery News, “Surgeon supply to drop 18% by 2028,” January 2013, p. 1) has estimated that, with predicted future surgeon shortages, general surgeons will be called upon to perform 25% of cases now done by other surgical specialists. General surgeons, both rural and urban, are clearly providing the bulk of cancer care to patients and this trend is on the rise in coming years.

Rural surgeons have certain barriers that prevent them from measuring, documenting, and publicizing the specifics of the care provided to their patients. These surgeons often are in single or small group practices and manage their own businesses. They have no office or hospital staff dedicated to quality endeavors. Financial and time constraints prevent them from being champions of quality care in their communities. Additionally, small numbers of specific cases can result in high statistical complication and mortality rates even if these events happen infrequently. This inability to collect data and assess the quality of care provided can lead to patient outmigration and even “tiering” by third-party payers that forces patients away from their hometown hospitals and providers using financial disincentives.

Rural surgeons can and must now take the lead in collecting, assessing, and reporting data about the care they provide for their communities. This process can be in the form of standardized programs like ACS Rural National Surgical Quality Improvement Program (NSQIP), Surgical Care Improvement Project (SCIP), or Commission on Cancer (CoC) accreditation involvement. Smaller institutions with a single surgeon may not have the financial and staff resources to formally participate but each surgeon can assess what makes up the majority of his or her caseload, whether that is endoscopy or breast or colon cases, and find national benchmarks that can easily be measured. Every endoscopy department can collect data on cecal intubation rates, withdrawal times, adequacy of preps, adenoma detection rates, and appropriate follow-up intervals. Individual surgeons can pick and chose specific benchmarks from NSQIP, Commission on Cancer, National Accreditation Program for Breast Centers (NAPBC), or ACS Committee on Trauma standards documents and use these to evaluate the care they provide. Easy examples might include number of lymph nodes harvested at colon cancer surgery, percentage of breast cancer patients diagnosed with needle biopsy, and percentage treated with conservative surgery and appropriate postop radiation and or chemotherapy, or the percentage of melanoma patients treated per National Comprehensive Cancer Network guidelines. Other ways for institutions to document quality might be to partner with their tertiary referral center for CoC accreditation or just to participate in cancer conferences by videoconferencing. The Commission on Cancer has designated CoC Liason Program Chairs in each state that are available to aid in setting up these types of programs.

It is time for rural surgeons to partner with their hospitals and communities to carry out needs assessments and think of ways to fill those needs. An example might be to work with primary care providers to develop aggressive colon, breast, or lung cancer screening programs in communities with high numbers of late-stage cases. Transparency of the data collected and the care provided in the form of “Quality Reports to the Community” can improve local referral patterns, improve the financial viability of the local hospital, and prove to the community that quality care is being rendered. Pooling the data from a large base of rural surgeons could serve to disprove the academic community notion that rural patients receive suboptimal cancer care.

Dr. Sarap is a practicing general surgeon in Cambridge, Ohio. He is a member of the Advisory Council on Rural Surgery and has been appointed the Commission on Cancer Liaison Program Chair for Ohio.

Rural surgeons who provide cancer care face a particular set of challenges. Rural patients tend to be older, sicker, less educated and economically disadvantaged. Rural areas have a higher prevalence of chronic diseases including heart disease and cancer. Rural patients present with more advanced cancers than their urban counterparts. Specific rural regions (i.e., Appalachia) have documented higher cancer incidences and mortality rates.

In addition, there are several barriers to providing cancer care for rural populations. These include poor access to health care services and specialists; geographic barriers preventing access to providers, services, and technology; minimal transportation options for either cancer screening or treatment; limited knowledge of cancer and low participation in screening and other healthy practices; prohibitive costs of screening and cancer treatment; and, in some cases, suboptimal care provided to cancer patients (J. Am. Coll. Surg. 2014;219:814-8; Gosschalk, A. and Carozza, S., “Cancer in rural areas: A literature review,” Rural Healthy People 2010, Vol. 2 [College Station: The Texas A&M University System Health Science Center, 2003]).

Several examples of suboptimal care for rural cancer patients have appeared in professional journals and meetings and in the lay press. Examples of rural cancer care inadequacies include lower use of needle biopsy and sentinel lymph node biopsy techniques for breast cancer patients (Am. J. Surg. 2014;208:382-90; Am. J. Surg. 2013;206:674-81; ACS Surgery News, “Use of minimally invasive biopsy lags in Texas,” February 2013, p. 15); significantly lower rates of radiation treatment in breast lumpectomy patients (USA Today, Nov. 18, 2012); lower rates of adequate lymph node dissection, appropriate chemotherapy, and higher death rates in colon cancer patients (Chow, C.J., ACS Clinical Congress Presentation 2012); higher mastectomy rates and later-stage cancers in breast cancer patients (Jethwa, K., AACR Annual Conference Presentation 2013); higher likelihood of discharge to a skilled nursing facility instead of home in colon cancer patients; and the list goes on and on. These articles all come from academic centers through database studies. It is rare indeed to see data collected and published by the rural centers and providers actually caring for rural cancer patients.

My personal bias is that rural surgeons provide very competent, compassionate, high quality care that allows the cancer patient to remain close to their homes and support systems. This opinion has been reinforced by my involvement with the ACS Advisory Council on Rural Surgery, the rural listserve /ACS Rural Community and through my interaction with surgeons across the country at ACS Chapter meetings and at the Congress.

A study done by Finlayson (Med. Care 1999;37:204-9) documented that nearly 100% of rural patients preferred to receive their care locally, especially if the quality of care was the same as the larger distant hospital. In fact, nearly half of the patients polled would choose to remain local even if the mortality rate at the local hospital was double that of a hospital requiring the patient to travel for care. More recent papers however suggest that patients may be bypassing their local hospitals for care because of concerns about the quality of care provided locally (J. Rural Health 1999;10:70-9; J. Rural Health 2007;23:17-24).

A 2013 ASCO presentation documented that General Surgeons perform a majority of cancer surgeries in the United States (Stizenberg, K.; SSO 66th Annual Cancer Symposium; Abstract 75, March 8, 2013). Only 303 (< 8%) counties in the United States even have a surgical oncologist. A 2014 ASCO presentation estimated a 43% increase in inpatient oncology procedures and a 25% increase in outpatient procedures between 2002 and 2020. By 2025 the total demand for oncology care will rise by 43% (ASCO, “The state of cancer care 2014,” J. Oncol. Prac. 2014;10:119-42). Another study (ACS Surgery News, “Surgeon supply to drop 18% by 2028,” January 2013, p. 1) has estimated that, with predicted future surgeon shortages, general surgeons will be called upon to perform 25% of cases now done by other surgical specialists. General surgeons, both rural and urban, are clearly providing the bulk of cancer care to patients and this trend is on the rise in coming years.

Rural surgeons have certain barriers that prevent them from measuring, documenting, and publicizing the specifics of the care provided to their patients. These surgeons often are in single or small group practices and manage their own businesses. They have no office or hospital staff dedicated to quality endeavors. Financial and time constraints prevent them from being champions of quality care in their communities. Additionally, small numbers of specific cases can result in high statistical complication and mortality rates even if these events happen infrequently. This inability to collect data and assess the quality of care provided can lead to patient outmigration and even “tiering” by third-party payers that forces patients away from their hometown hospitals and providers using financial disincentives.

Rural surgeons can and must now take the lead in collecting, assessing, and reporting data about the care they provide for their communities. This process can be in the form of standardized programs like ACS Rural National Surgical Quality Improvement Program (NSQIP), Surgical Care Improvement Project (SCIP), or Commission on Cancer (CoC) accreditation involvement. Smaller institutions with a single surgeon may not have the financial and staff resources to formally participate but each surgeon can assess what makes up the majority of his or her caseload, whether that is endoscopy or breast or colon cases, and find national benchmarks that can easily be measured. Every endoscopy department can collect data on cecal intubation rates, withdrawal times, adequacy of preps, adenoma detection rates, and appropriate follow-up intervals. Individual surgeons can pick and chose specific benchmarks from NSQIP, Commission on Cancer, National Accreditation Program for Breast Centers (NAPBC), or ACS Committee on Trauma standards documents and use these to evaluate the care they provide. Easy examples might include number of lymph nodes harvested at colon cancer surgery, percentage of breast cancer patients diagnosed with needle biopsy, and percentage treated with conservative surgery and appropriate postop radiation and or chemotherapy, or the percentage of melanoma patients treated per National Comprehensive Cancer Network guidelines. Other ways for institutions to document quality might be to partner with their tertiary referral center for CoC accreditation or just to participate in cancer conferences by videoconferencing. The Commission on Cancer has designated CoC Liason Program Chairs in each state that are available to aid in setting up these types of programs.

It is time for rural surgeons to partner with their hospitals and communities to carry out needs assessments and think of ways to fill those needs. An example might be to work with primary care providers to develop aggressive colon, breast, or lung cancer screening programs in communities with high numbers of late-stage cases. Transparency of the data collected and the care provided in the form of “Quality Reports to the Community” can improve local referral patterns, improve the financial viability of the local hospital, and prove to the community that quality care is being rendered. Pooling the data from a large base of rural surgeons could serve to disprove the academic community notion that rural patients receive suboptimal cancer care.

Dr. Sarap is a practicing general surgeon in Cambridge, Ohio. He is a member of the Advisory Council on Rural Surgery and has been appointed the Commission on Cancer Liaison Program Chair for Ohio.

The surgery chief resident texted me: “Patient in ED with peritonitis. Incarcerated hernia.”

I came to the ED; should be easy I thought. See the patient, have a short conversation since the chief resident would have done all the preop. Of course, things are rarely that simple.

First, she was a Jehovah’s Witness on warfarin with an INR of 4. More significantly, she had end-stage COPD. I reviewed her CT scan and labs and went to see her and could tell without any conversation she needed an operation. I needed more information, but not about her belly pain or when it started or whether she had peritonitis on exam. I needed to know how far she could walk, how much oxygen was she on at home, how much was she sleeping, how much weight had she lost, and could she leave the house.

It took 30 minutes to determine her functional status, whether she would survive the postoperative ICU care, whether she would come off the ventilator, and would she want a tracheostomy. It took another 15 minutes to discuss blood product use. Her husband was present, and I left them to decide what they wanted within the context of her goals for her life. She accepted some blood products, underwent surgery, and did well. She came off the ventilator quickly postop and returned home from the hospital. Although she did well, we had a plan for the ventilator and her goals of care defined should she have done poorly.

He was 72, had stage IV lung cancer, and was too weak for chemotherapy. Now he had free air and peritonitis. The referring institution called me and said he was too much for their surgeons. I suggested perhaps they needed to have “the talk” prior to transport. They were unwilling to do so and sent him by helicopter because he was hypotensive. He clearly needed an operation by all surgical standards. But I wanted to wait for his family and talk with them before taking him to the OR; he was in no condition for any component of informed consent.

The family arrived 30 minutes later. His wife, the daughters who had been helping to take care of him, and two more relatives that had just arrived in town. His wife was clear: The man was sleeping all the time, losing weight, barely eating a couple of bites, unsteady on his feet, and confused when he was awake. I discussed options: The surgeon part of me wanted to “fix the hole,” the ICU doc in me knew he would die in the ICU on a ventilator, and the palliative medicine part of me knew hospice was his best option. I told the family he needed surgery but would likely not leave the hospital alive. I recommended hospice.

The wife was thoughtful and looked at her daughters and said, “We need to send him to hospice.” The wife and daughters were the easiest family I have spoken with in a long time. She was clear about whet he wanted and how much he had declined in the past few months. We were able to get him to inpatient hospice from the ED.

Surgery has changed, at least in my practice. Oh, what would I give for a healthy 17-year-old with appendicitis who gets better within hours of the operating room and my conversation with the family that takes 10 seconds. Instead, I take care of the very old and the very sick and the very chronically ill. My conversations are not “you need surgery;” that is done by the chief resident. My conversations are “tell me your functional status and what do you want if/when things go poorly.” Much more complicated and much less fun. The surgeon wants to fix the hole. I can fix the hole. But have I really helped the patient and his or her family? Although it takes me longer and involves more of my emotions and skills, it really is better for the patients and their families to have “the talk.”

Next time you see a patient who is chronically ill, please have the conversation about functional status and goals of care, before you operate. Or transfer. Perhaps then we can save the patient a helicopter ride to hospice.

Dr. Toevs is a trauma critical care surgeon at Allegheny General Hospital in Pittsburgh. She has a master’s degree in bioethics and board certification in hospice and palliative medicine.

The surgery chief resident texted me: “Patient in ED with peritonitis. Incarcerated hernia.”

I came to the ED; should be easy I thought. See the patient, have a short conversation since the chief resident would have done all the preop. Of course, things are rarely that simple.

First, she was a Jehovah’s Witness on warfarin with an INR of 4. More significantly, she had end-stage COPD. I reviewed her CT scan and labs and went to see her and could tell without any conversation she needed an operation. I needed more information, but not about her belly pain or when it started or whether she had peritonitis on exam. I needed to know how far she could walk, how much oxygen was she on at home, how much was she sleeping, how much weight had she lost, and could she leave the house.

It took 30 minutes to determine her functional status, whether she would survive the postoperative ICU care, whether she would come off the ventilator, and would she want a tracheostomy. It took another 15 minutes to discuss blood product use. Her husband was present, and I left them to decide what they wanted within the context of her goals for her life. She accepted some blood products, underwent surgery, and did well. She came off the ventilator quickly postop and returned home from the hospital. Although she did well, we had a plan for the ventilator and her goals of care defined should she have done poorly.

He was 72, had stage IV lung cancer, and was too weak for chemotherapy. Now he had free air and peritonitis. The referring institution called me and said he was too much for their surgeons. I suggested perhaps they needed to have “the talk” prior to transport. They were unwilling to do so and sent him by helicopter because he was hypotensive. He clearly needed an operation by all surgical standards. But I wanted to wait for his family and talk with them before taking him to the OR; he was in no condition for any component of informed consent.

The family arrived 30 minutes later. His wife, the daughters who had been helping to take care of him, and two more relatives that had just arrived in town. His wife was clear: The man was sleeping all the time, losing weight, barely eating a couple of bites, unsteady on his feet, and confused when he was awake. I discussed options: The surgeon part of me wanted to “fix the hole,” the ICU doc in me knew he would die in the ICU on a ventilator, and the palliative medicine part of me knew hospice was his best option. I told the family he needed surgery but would likely not leave the hospital alive. I recommended hospice.

The wife was thoughtful and looked at her daughters and said, “We need to send him to hospice.” The wife and daughters were the easiest family I have spoken with in a long time. She was clear about whet he wanted and how much he had declined in the past few months. We were able to get him to inpatient hospice from the ED.

Surgery has changed, at least in my practice. Oh, what would I give for a healthy 17-year-old with appendicitis who gets better within hours of the operating room and my conversation with the family that takes 10 seconds. Instead, I take care of the very old and the very sick and the very chronically ill. My conversations are not “you need surgery;” that is done by the chief resident. My conversations are “tell me your functional status and what do you want if/when things go poorly.” Much more complicated and much less fun. The surgeon wants to fix the hole. I can fix the hole. But have I really helped the patient and his or her family? Although it takes me longer and involves more of my emotions and skills, it really is better for the patients and their families to have “the talk.”

Next time you see a patient who is chronically ill, please have the conversation about functional status and goals of care, before you operate. Or transfer. Perhaps then we can save the patient a helicopter ride to hospice.

Dr. Toevs is a trauma critical care surgeon at Allegheny General Hospital in Pittsburgh. She has a master’s degree in bioethics and board certification in hospice and palliative medicine.

The surgery chief resident texted me: “Patient in ED with peritonitis. Incarcerated hernia.”

I came to the ED; should be easy I thought. See the patient, have a short conversation since the chief resident would have done all the preop. Of course, things are rarely that simple.

First, she was a Jehovah’s Witness on warfarin with an INR of 4. More significantly, she had end-stage COPD. I reviewed her CT scan and labs and went to see her and could tell without any conversation she needed an operation. I needed more information, but not about her belly pain or when it started or whether she had peritonitis on exam. I needed to know how far she could walk, how much oxygen was she on at home, how much was she sleeping, how much weight had she lost, and could she leave the house.

It took 30 minutes to determine her functional status, whether she would survive the postoperative ICU care, whether she would come off the ventilator, and would she want a tracheostomy. It took another 15 minutes to discuss blood product use. Her husband was present, and I left them to decide what they wanted within the context of her goals for her life. She accepted some blood products, underwent surgery, and did well. She came off the ventilator quickly postop and returned home from the hospital. Although she did well, we had a plan for the ventilator and her goals of care defined should she have done poorly.

He was 72, had stage IV lung cancer, and was too weak for chemotherapy. Now he had free air and peritonitis. The referring institution called me and said he was too much for their surgeons. I suggested perhaps they needed to have “the talk” prior to transport. They were unwilling to do so and sent him by helicopter because he was hypotensive. He clearly needed an operation by all surgical standards. But I wanted to wait for his family and talk with them before taking him to the OR; he was in no condition for any component of informed consent.

The family arrived 30 minutes later. His wife, the daughters who had been helping to take care of him, and two more relatives that had just arrived in town. His wife was clear: The man was sleeping all the time, losing weight, barely eating a couple of bites, unsteady on his feet, and confused when he was awake. I discussed options: The surgeon part of me wanted to “fix the hole,” the ICU doc in me knew he would die in the ICU on a ventilator, and the palliative medicine part of me knew hospice was his best option. I told the family he needed surgery but would likely not leave the hospital alive. I recommended hospice.

The wife was thoughtful and looked at her daughters and said, “We need to send him to hospice.” The wife and daughters were the easiest family I have spoken with in a long time. She was clear about whet he wanted and how much he had declined in the past few months. We were able to get him to inpatient hospice from the ED.

Surgery has changed, at least in my practice. Oh, what would I give for a healthy 17-year-old with appendicitis who gets better within hours of the operating room and my conversation with the family that takes 10 seconds. Instead, I take care of the very old and the very sick and the very chronically ill. My conversations are not “you need surgery;” that is done by the chief resident. My conversations are “tell me your functional status and what do you want if/when things go poorly.” Much more complicated and much less fun. The surgeon wants to fix the hole. I can fix the hole. But have I really helped the patient and his or her family? Although it takes me longer and involves more of my emotions and skills, it really is better for the patients and their families to have “the talk.”

Next time you see a patient who is chronically ill, please have the conversation about functional status and goals of care, before you operate. Or transfer. Perhaps then we can save the patient a helicopter ride to hospice.

Dr. Toevs is a trauma critical care surgeon at Allegheny General Hospital in Pittsburgh. She has a master’s degree in bioethics and board certification in hospice and palliative medicine.

After reading the Child Psychiatry Consult column “Aggression and angry outbursts” by Dr. Robert R. Althoff in the September 2014 issue of Pediatric News, I was disappointed that the differential diagnosis did not include an autism spectrum disorder such as DSM-IV Asperger syndrome.

The complex of symptoms described almost perfectly reflects the history of a child with autism. Typical autism spectrum disorder (ASD) issues of needing to direct the play, playing by their rules, and being adamant that things must be the way they see it are noted in the patient’s history. Aggression and outbursts also are typical of a patient with ASD.

Even though autistic behavior is typically predictable, parents are not always alert to the triggers. Most meltdowns are over transitions and denials. Parents of patients with autism often complain that they “walk on eggshells.”

Edward B. Aull, M.D.

Behavioral Pediatrics

St. Vincent Carmel Hospital

Carmel, Ind.

Dr. Althoff responds: I’d like to thank Dr. Aull for pointing out an oversight in my article. Certainly, children on the autistic spectrum can exhibit aggression, although it is not part of the diagnostic criteria for DSM-5 ASD, which include deficits in social interaction and communication, and restricted, repetitive patterns of behavior, interests, or activities. I was not intending for the case to give the impression that this child had difficulty with social communication and restricted interests, but the diagnosis of ASD should be considered on the differential. Similar to the situation in obsessive compulsive disorder or other anxiety disorders, when either the need for social communication becomes exceptionally high or the restricted behavior or interests are challenged, these children can become aggressive, although most do not. Interestingly enough, children with DSM-IV Asperger syndrome and high-functioning autism have co-occurring disorders up to 74% of the time, with the highest percentages in the disorders on the differential that I listed in the original article: behavior disorders, anxiety disorders, and mood disorders (J. Autism Dev. Disord. 2010;40:1080-93). Given these findings, one might consider that, while the diagnosis of an ASD should be considered in the differential, the aggressive behavior may not be associated with the autism symptoms, per se, but rather may be co-occurring symptoms.

After reading the Child Psychiatry Consult column “Aggression and angry outbursts” by Dr. Robert R. Althoff in the September 2014 issue of Pediatric News, I was disappointed that the differential diagnosis did not include an autism spectrum disorder such as DSM-IV Asperger syndrome.

The complex of symptoms described almost perfectly reflects the history of a child with autism. Typical autism spectrum disorder (ASD) issues of needing to direct the play, playing by their rules, and being adamant that things must be the way they see it are noted in the patient’s history. Aggression and outbursts also are typical of a patient with ASD.

Even though autistic behavior is typically predictable, parents are not always alert to the triggers. Most meltdowns are over transitions and denials. Parents of patients with autism often complain that they “walk on eggshells.”

Edward B. Aull, M.D.

Behavioral Pediatrics

St. Vincent Carmel Hospital

Carmel, Ind.

Dr. Althoff responds: I’d like to thank Dr. Aull for pointing out an oversight in my article. Certainly, children on the autistic spectrum can exhibit aggression, although it is not part of the diagnostic criteria for DSM-5 ASD, which include deficits in social interaction and communication, and restricted, repetitive patterns of behavior, interests, or activities. I was not intending for the case to give the impression that this child had difficulty with social communication and restricted interests, but the diagnosis of ASD should be considered on the differential. Similar to the situation in obsessive compulsive disorder or other anxiety disorders, when either the need for social communication becomes exceptionally high or the restricted behavior or interests are challenged, these children can become aggressive, although most do not. Interestingly enough, children with DSM-IV Asperger syndrome and high-functioning autism have co-occurring disorders up to 74% of the time, with the highest percentages in the disorders on the differential that I listed in the original article: behavior disorders, anxiety disorders, and mood disorders (J. Autism Dev. Disord. 2010;40:1080-93). Given these findings, one might consider that, while the diagnosis of an ASD should be considered in the differential, the aggressive behavior may not be associated with the autism symptoms, per se, but rather may be co-occurring symptoms.

After reading the Child Psychiatry Consult column “Aggression and angry outbursts” by Dr. Robert R. Althoff in the September 2014 issue of Pediatric News, I was disappointed that the differential diagnosis did not include an autism spectrum disorder such as DSM-IV Asperger syndrome.

The complex of symptoms described almost perfectly reflects the history of a child with autism. Typical autism spectrum disorder (ASD) issues of needing to direct the play, playing by their rules, and being adamant that things must be the way they see it are noted in the patient’s history. Aggression and outbursts also are typical of a patient with ASD.

Even though autistic behavior is typically predictable, parents are not always alert to the triggers. Most meltdowns are over transitions and denials. Parents of patients with autism often complain that they “walk on eggshells.”

Edward B. Aull, M.D.

Behavioral Pediatrics

St. Vincent Carmel Hospital

Carmel, Ind.

Dr. Althoff responds: I’d like to thank Dr. Aull for pointing out an oversight in my article. Certainly, children on the autistic spectrum can exhibit aggression, although it is not part of the diagnostic criteria for DSM-5 ASD, which include deficits in social interaction and communication, and restricted, repetitive patterns of behavior, interests, or activities. I was not intending for the case to give the impression that this child had difficulty with social communication and restricted interests, but the diagnosis of ASD should be considered on the differential. Similar to the situation in obsessive compulsive disorder or other anxiety disorders, when either the need for social communication becomes exceptionally high or the restricted behavior or interests are challenged, these children can become aggressive, although most do not. Interestingly enough, children with DSM-IV Asperger syndrome and high-functioning autism have co-occurring disorders up to 74% of the time, with the highest percentages in the disorders on the differential that I listed in the original article: behavior disorders, anxiety disorders, and mood disorders (J. Autism Dev. Disord. 2010;40:1080-93). Given these findings, one might consider that, while the diagnosis of an ASD should be considered in the differential, the aggressive behavior may not be associated with the autism symptoms, per se, but rather may be co-occurring symptoms.

The Centers for Disease Control and Prevention suggests that recurring pertussis outbreaks may be the “new normal.” Such outbreaks show that some of what we “know” about pertussis is still correct, but some things are evolving. So in this new year, what do we need to know about patient vulnerability post vaccine as well as the clinical course, diagnosis, and treatment of this stubborn persisting disease?

Vulnerability after acellular pertussis vaccine

The recent large 2014 California outbreak surpassed the record numbers for the previously highest incidence year, 2010 (MMWR 2014;63:1129-32). This is scary because more cases had been reported in California in 2010 than in any prior year since the 1940s. The overall 2014 California pertussis rate (26/100,000 population) was approximately 10 times the national average for the first 9 years of this century, Are there clues as to who is most vulnerable and why?

No age group was spared, but certain age groups did appear more vulnerable. Infants had a startling 174.6/100,000 incidence (six times the rate for the overall population). It is not surprising to any clinician that infants less than 1 year of age were hardest hit. Infants have the most evident symptoms with pertussis. Infants also have 5-7 months of their first year in which they are incompletely immunized. Therefore, many are not expected to be protected until about 7-9 months of age. This vulnerability could be partly remedied if all pregnant women got Tdap boosters as recommended during pregnancy.

Of note, 15-year-olds had an incidence similar to that of infants (137.8/100,000). Ethnically, non-Hispanic whites had the highest incidence among adolescents (166.2/100,000), compared with Hispanics (64.2/100,000), Asian/Pacific Islanders (43.9/100,000), and non-Hispanic blacks (23.7/100,000). Disturbingly, 87% of cases among 15-year-olds had received a prior Tdap booster dose (median time since booster Tdap = 3 years, range = 0-7 years). Previous data from the 2010 outbreak suggested that immunity to pertussis wanes 3-4 years after receipt of the last acellular pertussis (aP)–containing vaccine. This is likely part of the explanation in 2014 as well. However, waning immunity after the booster does not explain why non-Hispanic whites had two to six times the incidence of other ethnicities. Non-Hispanic whites are thought to be the demographic with the most vaccine refusal and vaccine delay in California, so this may partially explain excess cases. Racial differences in access to care or genetic differences in disease susceptibility also may play a role.

Why is this biphasic increase in incidence in California a microcosm of the new epidemiology of pertussis in the United States? A kinder, gentler DTaP vaccine replaced the whole-cell DTP in the late 1990s. This occurred in response to the public’s concern about potential central nervous system adverse effects associated with the whole-cell DTP vaccine. Immunogenicity studies seemed to show equivalent immune responses in infants and toddlers receiving DTaP, compared with those who received DTP. It has only been in the last 5 years that we now know that the new DTaP and Tdap are not working as well as we had hoped.

The two aspects to the lesser protection provided by aP vaccines are pertactin-deficient pertussis strains and quicker waning of aP vaccine–induced immunity. Antibody to pertactin appears to be important in protection against clinical pertussis. New circulating clinical strains of pertussis may not have pertactin (N. Engl. J. Med. 2013;368:583-4). The strains used in our current DTaP and Tdap were designed to protect against pertactin-containing strains and were tested for this. This means that a proportion of the antibodies induced by vaccine strains are not useful against pertactin-deficient strains. The aP vaccine still induces antibody to the pertussis toxin and other pertussis components in the vaccines, so they will likely still reduce the severity of disease. But the vaccines are not likely to prevent infections from pertactin-deficient strains. This is similar to the partial vaccine mismatch that we are seeing with the current seasonal H3N2 influenza vaccine strain.

The second aspect is that protection appears to wane approximately 3-5 years after the last dose of aP-containing vaccine. This contrasts sharply with expectations in the past of 7-10 years of protection from whole cell pertussis–containing vaccines. The less reactive aP vaccine produces fewer adverse effects by not producing as much inflammation as DPT. The problem is that part of the reason the DPT has such good protective responses is the amount of inflammation it produces. So with less aP vaccine–induced inflammation comes less robust antibody and T-cell responses.

Nevertheless, the current acellular pertussis vaccines remain the most effective available tools to reduce pertussis disease (Cochrane Database Syst. Rev. 2014;9:CD001478]). But until we have new versions of pertussis vaccines that address these two issues, we clinicians need to remain vigilant for signs and symptoms of pertussis.

Clinical course

Remember that a whoop is rarely seen in young children and often also not seen when older patients present. The many outbreaks over the last 10 years have confirmed that paroxysmal cough with/without apnea in an infant/toddler should raise our index of suspicion. Likewise, older children, adolescents, and adults with persistent cough beyond 2 weeks are potential pertussis cases. Once the diagnosis is made, treatment is not expected to have a major impact on the clinical course, in part because the diagnosis is usually delayed (more than 10 days into symptoms). This delay allows more injury to the respiratory mucosa and cilia so that healing can require 6-12 weeks after bacterial replication ceases. This prolonged healing process is what is mostly responsible for the syndrome known as the “100-day cough.” So the clinical course of pertussis has not changed in the last 10 years. However, there have been changes in the commonly used diagnostic approach.

Pertussis diagnosis and contagion

During the last 5 years, polymerase chain reaction (PCR) testing has become the preferred technology to detect pertussis. This is due to the sensitivity and quick turnaround time of the assay. The gold standard for pertussis diagnosis remains culture, but it is expensive, cumbersome, and slow (up to a week to provide results). An ongoing debate arose about how long PCR testing remains positive after the onset of symptoms or treatment. This was not the problem when culture was the diagnostic tool of choice. Data from the 1970s and 1980s indicated that cultures were rarely positive after the third week of symptoms even without treatment. Furthermore, macrolides eliminated both contagion and positive culture results of infected patients after 5 days of treatment.

So now that we use PCR most often for diagnosis, what is the outer limit of positivity? A recent prospective cohort study from Salt Lake City suggests that PCR may detect pertussis DNA way beyond 3 weeks after symptom onset (J. Ped. Infect. Dis. 2014;3:347-9). Among patients hospitalized with laboratory-confirmed Bordetella pertussis infection, half had persistently positive pertussis PCR testing more than 50 days after symptom onset, despite antibiotic treatment and clinical improvement. The median (range) for the last day for a positive test after symptom onset was 58 days (4-172 days).

This raises the question as to whether there are viable pertussis organisms in the respiratory tract beyond the traditional 3 weeks defined by culture data. It is likely that DNA persists in the thick mucus of the respiratory tract way beyond viability of the last pertussis organisms. Put another way, PCR likely detects bacterial corpses or components way beyond the time that the patient is contagious. Unfortunately, current PCR data do not tell us how long patients remain contagious with the current strains of pertussis as infecting agents. Some institutions appear to be extending the isolation time for patients treated for pertussis beyond the traditional 5 days post initiation of effective treatment. Until more data are available, we are somewhat in the dark. But I would take comfort in the fact that it is unlikely the “new” data will be much different from those derived from the traditional studies that use culture to define infectivity. The American Academy of Pediatrics Committee on Infectious Diseases Red Book appears to agree.

For hospitalized pertussis patients, the AAP Committee on Infectious Diseases Red Book recommends standard and droplet precautions for 5 days after starting effective therapy, or 3 weeks after cough onset if appropriate antimicrobial therapy has not been given.

In addition, the CDC states: “PCR has optimal sensitivity during the first 3 weeks of cough when bacterial DNA is still present in the nasopharynx. After the fourth week of cough, the amount of bacterial DNA rapidly diminishes, which increases the risk of obtaining falsely negative results.” Later in the same document, the CDC says: “PCR testing following antibiotic therapy also can result in falsely negative findings. The exact duration of positivity following antibiotic use is not well understood, but PCR testing after 5 days of antibiotic use is unlikely to be of benefit and is generally not recommended.”

So what do we know? Not all PCR assays use the same primers, so some variance from the usual experience of up to 4 weeks of positive PCR results may be due to differences in the assays. But this raises concern that the PCR that you order may be positive at times when the patient is no longer contagious.

Pertussis treatment

If strains of pertussis have changed their pertactin antigen, are they changing their antibiotic susceptibility patterns? While there have been reports of macrolide resistance in a few pertussis strains, these still remain rare. The most recent comprehensive review of treatment efficacy was a Cochrane review performed in 2005 and published in 2007 (Cochrane Database Syst. Rev. 2007;3:CD004404). They evaluated 10 trials from 1969 to 2004 in which microbiologic eradication was defined by negative results from repeat pertussis culture. While meta-analysis of microbiologic eradication was not possible because of differences in antibiotic use, the investigators did conclude that antibiotic treatment “is effective in eliminating B. pertussis from patients with the disease to render them noninfectious, but does not alter the subsequent clinical course of the illness.”

Further, they state that “the best regimens for microbiologic clearance, with fewer side effects,” are 3 days of azithromycin (a single 10-mg/kg dose on 3 consecutive days) or 7 days of clarithromycin (7.5-mg/kg dose twice daily).

Another effective regimen is 14 days of erythromycin ethylsuccinate (60 mg/kg per day in 3 divided doses) .

CDC treatment recommendations include azithromycin or erythromycin, with trimethoprim-sulfamethoxazole as a possibility for macrolide-intolerant patients, although there are less data and success rates may not be as high.

Conclusion

So what do we know now about pertussis?

• Outbreaks are ongoing and likely will continue until newer more effective vaccines are produced, including those that circumvent the problem of pertactin-deficient strains.

• Pertussis is likely contagious up to 5 days on effective therapy, and for as long as 3 weeks if effective therapy has not been administered.

• PCR is a sensitive test that may remain positive for many weeks beyond contagion.

• Treatment with macrolides appears to be the most effective way to eradicate replicating pertussis pathogens.

• Treatment is not likely to have a major impact on the clinical course of disease because most of the damage to the respiratory tract is done prior to diagnosis and treatment. Treatment does reduce infectivity and subsequent cases.

• Current aP vaccines currently are our best preventative tools – including use in pregnant women to protect young infants.

As clinicians, our best course is to continue to immunize with the current vaccines, and remain vigilant for symptoms and signs of pertussis infection of patients so that early diagnosis and treatment can prevent further spread.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. Children’s Mercy Hospitals receives funds from GlaxoSmithKline for Dr. Harrison being principal investigator on a multicenter research study of a hexavalent pertussis-containing infant vaccine. E-mail Dr. Harrison at [email protected].

The Centers for Disease Control and Prevention suggests that recurring pertussis outbreaks may be the “new normal.” Such outbreaks show that some of what we “know” about pertussis is still correct, but some things are evolving. So in this new year, what do we need to know about patient vulnerability post vaccine as well as the clinical course, diagnosis, and treatment of this stubborn persisting disease?

Vulnerability after acellular pertussis vaccine

The recent large 2014 California outbreak surpassed the record numbers for the previously highest incidence year, 2010 (MMWR 2014;63:1129-32). This is scary because more cases had been reported in California in 2010 than in any prior year since the 1940s. The overall 2014 California pertussis rate (26/100,000 population) was approximately 10 times the national average for the first 9 years of this century, Are there clues as to who is most vulnerable and why?

No age group was spared, but certain age groups did appear more vulnerable. Infants had a startling 174.6/100,000 incidence (six times the rate for the overall population). It is not surprising to any clinician that infants less than 1 year of age were hardest hit. Infants have the most evident symptoms with pertussis. Infants also have 5-7 months of their first year in which they are incompletely immunized. Therefore, many are not expected to be protected until about 7-9 months of age. This vulnerability could be partly remedied if all pregnant women got Tdap boosters as recommended during pregnancy.

Of note, 15-year-olds had an incidence similar to that of infants (137.8/100,000). Ethnically, non-Hispanic whites had the highest incidence among adolescents (166.2/100,000), compared with Hispanics (64.2/100,000), Asian/Pacific Islanders (43.9/100,000), and non-Hispanic blacks (23.7/100,000). Disturbingly, 87% of cases among 15-year-olds had received a prior Tdap booster dose (median time since booster Tdap = 3 years, range = 0-7 years). Previous data from the 2010 outbreak suggested that immunity to pertussis wanes 3-4 years after receipt of the last acellular pertussis (aP)–containing vaccine. This is likely part of the explanation in 2014 as well. However, waning immunity after the booster does not explain why non-Hispanic whites had two to six times the incidence of other ethnicities. Non-Hispanic whites are thought to be the demographic with the most vaccine refusal and vaccine delay in California, so this may partially explain excess cases. Racial differences in access to care or genetic differences in disease susceptibility also may play a role.

Why is this biphasic increase in incidence in California a microcosm of the new epidemiology of pertussis in the United States? A kinder, gentler DTaP vaccine replaced the whole-cell DTP in the late 1990s. This occurred in response to the public’s concern about potential central nervous system adverse effects associated with the whole-cell DTP vaccine. Immunogenicity studies seemed to show equivalent immune responses in infants and toddlers receiving DTaP, compared with those who received DTP. It has only been in the last 5 years that we now know that the new DTaP and Tdap are not working as well as we had hoped.

The two aspects to the lesser protection provided by aP vaccines are pertactin-deficient pertussis strains and quicker waning of aP vaccine–induced immunity. Antibody to pertactin appears to be important in protection against clinical pertussis. New circulating clinical strains of pertussis may not have pertactin (N. Engl. J. Med. 2013;368:583-4). The strains used in our current DTaP and Tdap were designed to protect against pertactin-containing strains and were tested for this. This means that a proportion of the antibodies induced by vaccine strains are not useful against pertactin-deficient strains. The aP vaccine still induces antibody to the pertussis toxin and other pertussis components in the vaccines, so they will likely still reduce the severity of disease. But the vaccines are not likely to prevent infections from pertactin-deficient strains. This is similar to the partial vaccine mismatch that we are seeing with the current seasonal H3N2 influenza vaccine strain.

The second aspect is that protection appears to wane approximately 3-5 years after the last dose of aP-containing vaccine. This contrasts sharply with expectations in the past of 7-10 years of protection from whole cell pertussis–containing vaccines. The less reactive aP vaccine produces fewer adverse effects by not producing as much inflammation as DPT. The problem is that part of the reason the DPT has such good protective responses is the amount of inflammation it produces. So with less aP vaccine–induced inflammation comes less robust antibody and T-cell responses.

Nevertheless, the current acellular pertussis vaccines remain the most effective available tools to reduce pertussis disease (Cochrane Database Syst. Rev. 2014;9:CD001478]). But until we have new versions of pertussis vaccines that address these two issues, we clinicians need to remain vigilant for signs and symptoms of pertussis.

Clinical course

Remember that a whoop is rarely seen in young children and often also not seen when older patients present. The many outbreaks over the last 10 years have confirmed that paroxysmal cough with/without apnea in an infant/toddler should raise our index of suspicion. Likewise, older children, adolescents, and adults with persistent cough beyond 2 weeks are potential pertussis cases. Once the diagnosis is made, treatment is not expected to have a major impact on the clinical course, in part because the diagnosis is usually delayed (more than 10 days into symptoms). This delay allows more injury to the respiratory mucosa and cilia so that healing can require 6-12 weeks after bacterial replication ceases. This prolonged healing process is what is mostly responsible for the syndrome known as the “100-day cough.” So the clinical course of pertussis has not changed in the last 10 years. However, there have been changes in the commonly used diagnostic approach.

Pertussis diagnosis and contagion

During the last 5 years, polymerase chain reaction (PCR) testing has become the preferred technology to detect pertussis. This is due to the sensitivity and quick turnaround time of the assay. The gold standard for pertussis diagnosis remains culture, but it is expensive, cumbersome, and slow (up to a week to provide results). An ongoing debate arose about how long PCR testing remains positive after the onset of symptoms or treatment. This was not the problem when culture was the diagnostic tool of choice. Data from the 1970s and 1980s indicated that cultures were rarely positive after the third week of symptoms even without treatment. Furthermore, macrolides eliminated both contagion and positive culture results of infected patients after 5 days of treatment.

So now that we use PCR most often for diagnosis, what is the outer limit of positivity? A recent prospective cohort study from Salt Lake City suggests that PCR may detect pertussis DNA way beyond 3 weeks after symptom onset (J. Ped. Infect. Dis. 2014;3:347-9). Among patients hospitalized with laboratory-confirmed Bordetella pertussis infection, half had persistently positive pertussis PCR testing more than 50 days after symptom onset, despite antibiotic treatment and clinical improvement. The median (range) for the last day for a positive test after symptom onset was 58 days (4-172 days).

This raises the question as to whether there are viable pertussis organisms in the respiratory tract beyond the traditional 3 weeks defined by culture data. It is likely that DNA persists in the thick mucus of the respiratory tract way beyond viability of the last pertussis organisms. Put another way, PCR likely detects bacterial corpses or components way beyond the time that the patient is contagious. Unfortunately, current PCR data do not tell us how long patients remain contagious with the current strains of pertussis as infecting agents. Some institutions appear to be extending the isolation time for patients treated for pertussis beyond the traditional 5 days post initiation of effective treatment. Until more data are available, we are somewhat in the dark. But I would take comfort in the fact that it is unlikely the “new” data will be much different from those derived from the traditional studies that use culture to define infectivity. The American Academy of Pediatrics Committee on Infectious Diseases Red Book appears to agree.

For hospitalized pertussis patients, the AAP Committee on Infectious Diseases Red Book recommends standard and droplet precautions for 5 days after starting effective therapy, or 3 weeks after cough onset if appropriate antimicrobial therapy has not been given.

In addition, the CDC states: “PCR has optimal sensitivity during the first 3 weeks of cough when bacterial DNA is still present in the nasopharynx. After the fourth week of cough, the amount of bacterial DNA rapidly diminishes, which increases the risk of obtaining falsely negative results.” Later in the same document, the CDC says: “PCR testing following antibiotic therapy also can result in falsely negative findings. The exact duration of positivity following antibiotic use is not well understood, but PCR testing after 5 days of antibiotic use is unlikely to be of benefit and is generally not recommended.”

So what do we know? Not all PCR assays use the same primers, so some variance from the usual experience of up to 4 weeks of positive PCR results may be due to differences in the assays. But this raises concern that the PCR that you order may be positive at times when the patient is no longer contagious.

Pertussis treatment

If strains of pertussis have changed their pertactin antigen, are they changing their antibiotic susceptibility patterns? While there have been reports of macrolide resistance in a few pertussis strains, these still remain rare. The most recent comprehensive review of treatment efficacy was a Cochrane review performed in 2005 and published in 2007 (Cochrane Database Syst. Rev. 2007;3:CD004404). They evaluated 10 trials from 1969 to 2004 in which microbiologic eradication was defined by negative results from repeat pertussis culture. While meta-analysis of microbiologic eradication was not possible because of differences in antibiotic use, the investigators did conclude that antibiotic treatment “is effective in eliminating B. pertussis from patients with the disease to render them noninfectious, but does not alter the subsequent clinical course of the illness.”

Further, they state that “the best regimens for microbiologic clearance, with fewer side effects,” are 3 days of azithromycin (a single 10-mg/kg dose on 3 consecutive days) or 7 days of clarithromycin (7.5-mg/kg dose twice daily).

Another effective regimen is 14 days of erythromycin ethylsuccinate (60 mg/kg per day in 3 divided doses) .

CDC treatment recommendations include azithromycin or erythromycin, with trimethoprim-sulfamethoxazole as a possibility for macrolide-intolerant patients, although there are less data and success rates may not be as high.

Conclusion

So what do we know now about pertussis?

• Outbreaks are ongoing and likely will continue until newer more effective vaccines are produced, including those that circumvent the problem of pertactin-deficient strains.

• Pertussis is likely contagious up to 5 days on effective therapy, and for as long as 3 weeks if effective therapy has not been administered.

• PCR is a sensitive test that may remain positive for many weeks beyond contagion.

• Treatment with macrolides appears to be the most effective way to eradicate replicating pertussis pathogens.

• Treatment is not likely to have a major impact on the clinical course of disease because most of the damage to the respiratory tract is done prior to diagnosis and treatment. Treatment does reduce infectivity and subsequent cases.

• Current aP vaccines currently are our best preventative tools – including use in pregnant women to protect young infants.

As clinicians, our best course is to continue to immunize with the current vaccines, and remain vigilant for symptoms and signs of pertussis infection of patients so that early diagnosis and treatment can prevent further spread.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. Children’s Mercy Hospitals receives funds from GlaxoSmithKline for Dr. Harrison being principal investigator on a multicenter research study of a hexavalent pertussis-containing infant vaccine. E-mail Dr. Harrison at [email protected].

The Centers for Disease Control and Prevention suggests that recurring pertussis outbreaks may be the “new normal.” Such outbreaks show that some of what we “know” about pertussis is still correct, but some things are evolving. So in this new year, what do we need to know about patient vulnerability post vaccine as well as the clinical course, diagnosis, and treatment of this stubborn persisting disease?

Vulnerability after acellular pertussis vaccine

The recent large 2014 California outbreak surpassed the record numbers for the previously highest incidence year, 2010 (MMWR 2014;63:1129-32). This is scary because more cases had been reported in California in 2010 than in any prior year since the 1940s. The overall 2014 California pertussis rate (26/100,000 population) was approximately 10 times the national average for the first 9 years of this century, Are there clues as to who is most vulnerable and why?

No age group was spared, but certain age groups did appear more vulnerable. Infants had a startling 174.6/100,000 incidence (six times the rate for the overall population). It is not surprising to any clinician that infants less than 1 year of age were hardest hit. Infants have the most evident symptoms with pertussis. Infants also have 5-7 months of their first year in which they are incompletely immunized. Therefore, many are not expected to be protected until about 7-9 months of age. This vulnerability could be partly remedied if all pregnant women got Tdap boosters as recommended during pregnancy.

Of note, 15-year-olds had an incidence similar to that of infants (137.8/100,000). Ethnically, non-Hispanic whites had the highest incidence among adolescents (166.2/100,000), compared with Hispanics (64.2/100,000), Asian/Pacific Islanders (43.9/100,000), and non-Hispanic blacks (23.7/100,000). Disturbingly, 87% of cases among 15-year-olds had received a prior Tdap booster dose (median time since booster Tdap = 3 years, range = 0-7 years). Previous data from the 2010 outbreak suggested that immunity to pertussis wanes 3-4 years after receipt of the last acellular pertussis (aP)–containing vaccine. This is likely part of the explanation in 2014 as well. However, waning immunity after the booster does not explain why non-Hispanic whites had two to six times the incidence of other ethnicities. Non-Hispanic whites are thought to be the demographic with the most vaccine refusal and vaccine delay in California, so this may partially explain excess cases. Racial differences in access to care or genetic differences in disease susceptibility also may play a role.

Why is this biphasic increase in incidence in California a microcosm of the new epidemiology of pertussis in the United States? A kinder, gentler DTaP vaccine replaced the whole-cell DTP in the late 1990s. This occurred in response to the public’s concern about potential central nervous system adverse effects associated with the whole-cell DTP vaccine. Immunogenicity studies seemed to show equivalent immune responses in infants and toddlers receiving DTaP, compared with those who received DTP. It has only been in the last 5 years that we now know that the new DTaP and Tdap are not working as well as we had hoped.

The two aspects to the lesser protection provided by aP vaccines are pertactin-deficient pertussis strains and quicker waning of aP vaccine–induced immunity. Antibody to pertactin appears to be important in protection against clinical pertussis. New circulating clinical strains of pertussis may not have pertactin (N. Engl. J. Med. 2013;368:583-4). The strains used in our current DTaP and Tdap were designed to protect against pertactin-containing strains and were tested for this. This means that a proportion of the antibodies induced by vaccine strains are not useful against pertactin-deficient strains. The aP vaccine still induces antibody to the pertussis toxin and other pertussis components in the vaccines, so they will likely still reduce the severity of disease. But the vaccines are not likely to prevent infections from pertactin-deficient strains. This is similar to the partial vaccine mismatch that we are seeing with the current seasonal H3N2 influenza vaccine strain.

The second aspect is that protection appears to wane approximately 3-5 years after the last dose of aP-containing vaccine. This contrasts sharply with expectations in the past of 7-10 years of protection from whole cell pertussis–containing vaccines. The less reactive aP vaccine produces fewer adverse effects by not producing as much inflammation as DPT. The problem is that part of the reason the DPT has such good protective responses is the amount of inflammation it produces. So with less aP vaccine–induced inflammation comes less robust antibody and T-cell responses.

Nevertheless, the current acellular pertussis vaccines remain the most effective available tools to reduce pertussis disease (Cochrane Database Syst. Rev. 2014;9:CD001478]). But until we have new versions of pertussis vaccines that address these two issues, we clinicians need to remain vigilant for signs and symptoms of pertussis.

Clinical course

Remember that a whoop is rarely seen in young children and often also not seen when older patients present. The many outbreaks over the last 10 years have confirmed that paroxysmal cough with/without apnea in an infant/toddler should raise our index of suspicion. Likewise, older children, adolescents, and adults with persistent cough beyond 2 weeks are potential pertussis cases. Once the diagnosis is made, treatment is not expected to have a major impact on the clinical course, in part because the diagnosis is usually delayed (more than 10 days into symptoms). This delay allows more injury to the respiratory mucosa and cilia so that healing can require 6-12 weeks after bacterial replication ceases. This prolonged healing process is what is mostly responsible for the syndrome known as the “100-day cough.” So the clinical course of pertussis has not changed in the last 10 years. However, there have been changes in the commonly used diagnostic approach.

Pertussis diagnosis and contagion

During the last 5 years, polymerase chain reaction (PCR) testing has become the preferred technology to detect pertussis. This is due to the sensitivity and quick turnaround time of the assay. The gold standard for pertussis diagnosis remains culture, but it is expensive, cumbersome, and slow (up to a week to provide results). An ongoing debate arose about how long PCR testing remains positive after the onset of symptoms or treatment. This was not the problem when culture was the diagnostic tool of choice. Data from the 1970s and 1980s indicated that cultures were rarely positive after the third week of symptoms even without treatment. Furthermore, macrolides eliminated both contagion and positive culture results of infected patients after 5 days of treatment.

So now that we use PCR most often for diagnosis, what is the outer limit of positivity? A recent prospective cohort study from Salt Lake City suggests that PCR may detect pertussis DNA way beyond 3 weeks after symptom onset (J. Ped. Infect. Dis. 2014;3:347-9). Among patients hospitalized with laboratory-confirmed Bordetella pertussis infection, half had persistently positive pertussis PCR testing more than 50 days after symptom onset, despite antibiotic treatment and clinical improvement. The median (range) for the last day for a positive test after symptom onset was 58 days (4-172 days).

This raises the question as to whether there are viable pertussis organisms in the respiratory tract beyond the traditional 3 weeks defined by culture data. It is likely that DNA persists in the thick mucus of the respiratory tract way beyond viability of the last pertussis organisms. Put another way, PCR likely detects bacterial corpses or components way beyond the time that the patient is contagious. Unfortunately, current PCR data do not tell us how long patients remain contagious with the current strains of pertussis as infecting agents. Some institutions appear to be extending the isolation time for patients treated for pertussis beyond the traditional 5 days post initiation of effective treatment. Until more data are available, we are somewhat in the dark. But I would take comfort in the fact that it is unlikely the “new” data will be much different from those derived from the traditional studies that use culture to define infectivity. The American Academy of Pediatrics Committee on Infectious Diseases Red Book appears to agree.

For hospitalized pertussis patients, the AAP Committee on Infectious Diseases Red Book recommends standard and droplet precautions for 5 days after starting effective therapy, or 3 weeks after cough onset if appropriate antimicrobial therapy has not been given.

In addition, the CDC states: “PCR has optimal sensitivity during the first 3 weeks of cough when bacterial DNA is still present in the nasopharynx. After the fourth week of cough, the amount of bacterial DNA rapidly diminishes, which increases the risk of obtaining falsely negative results.” Later in the same document, the CDC says: “PCR testing following antibiotic therapy also can result in falsely negative findings. The exact duration of positivity following antibiotic use is not well understood, but PCR testing after 5 days of antibiotic use is unlikely to be of benefit and is generally not recommended.”

So what do we know? Not all PCR assays use the same primers, so some variance from the usual experience of up to 4 weeks of positive PCR results may be due to differences in the assays. But this raises concern that the PCR that you order may be positive at times when the patient is no longer contagious.

Pertussis treatment

If strains of pertussis have changed their pertactin antigen, are they changing their antibiotic susceptibility patterns? While there have been reports of macrolide resistance in a few pertussis strains, these still remain rare. The most recent comprehensive review of treatment efficacy was a Cochrane review performed in 2005 and published in 2007 (Cochrane Database Syst. Rev. 2007;3:CD004404). They evaluated 10 trials from 1969 to 2004 in which microbiologic eradication was defined by negative results from repeat pertussis culture. While meta-analysis of microbiologic eradication was not possible because of differences in antibiotic use, the investigators did conclude that antibiotic treatment “is effective in eliminating B. pertussis from patients with the disease to render them noninfectious, but does not alter the subsequent clinical course of the illness.”

Further, they state that “the best regimens for microbiologic clearance, with fewer side effects,” are 3 days of azithromycin (a single 10-mg/kg dose on 3 consecutive days) or 7 days of clarithromycin (7.5-mg/kg dose twice daily).

Another effective regimen is 14 days of erythromycin ethylsuccinate (60 mg/kg per day in 3 divided doses) .

CDC treatment recommendations include azithromycin or erythromycin, with trimethoprim-sulfamethoxazole as a possibility for macrolide-intolerant patients, although there are less data and success rates may not be as high.

Conclusion

So what do we know now about pertussis?

• Outbreaks are ongoing and likely will continue until newer more effective vaccines are produced, including those that circumvent the problem of pertactin-deficient strains.

• Pertussis is likely contagious up to 5 days on effective therapy, and for as long as 3 weeks if effective therapy has not been administered.

• PCR is a sensitive test that may remain positive for many weeks beyond contagion.

• Treatment with macrolides appears to be the most effective way to eradicate replicating pertussis pathogens.

• Treatment is not likely to have a major impact on the clinical course of disease because most of the damage to the respiratory tract is done prior to diagnosis and treatment. Treatment does reduce infectivity and subsequent cases.

• Current aP vaccines currently are our best preventative tools – including use in pregnant women to protect young infants.

As clinicians, our best course is to continue to immunize with the current vaccines, and remain vigilant for symptoms and signs of pertussis infection of patients so that early diagnosis and treatment can prevent further spread.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. Children’s Mercy Hospitals receives funds from GlaxoSmithKline for Dr. Harrison being principal investigator on a multicenter research study of a hexavalent pertussis-containing infant vaccine. E-mail Dr. Harrison at [email protected].

Introduction

In the last 20 years there has been a marked rise in the number of children and adolescents receiving the diagnosis of bipolar disorder (BD) – a mood disorder that, classically, involves cycling between episodes of elevated mood and episodes of low mood (Arch. Gen. Psychiatry 2207;64:1032-9). The increase in diagnosis is partly explained by the inclusion of children with chronic irritability being diagnosed with BD. This has led to concern about the subsequent use of approved second-generation antipsychotics for chronically irritable children, with the resultant side effects.

A new diagnosis called disruptive mood dysregulation disorder (DMDD) was introduced into the DSM-5 to describe these chronically irritable children and, in part, to reduce the number of children receiving a bipolar diagnosis. So, how does one know whether a child has BD, DMDD, or something else? The two brief cases that follow distinguish the difference between BD and DMDD.

Case 1 summary

Joseph is a 15-year-old boy with a history of childhood depression. About 1 year ago, he began to appear more irritable and anxious. Despite his parents’ prohibition, he was going out at night and was intoxicated on several occasions when he came home – something he had never done before. After about 2 weeks of this, he began going to bed at midnight, but would be up again by 4 a.m. talking to himself, playing music, or exercising. He was hanging out with a different crowd. He began to talk about the possibility of becoming part of a motorcycle gang – at some point perhaps the leader of Hells Angels. Slowly, this resolved. However, these symptoms recurred about 1 month ago with progressive worsening, again, and 2 days ago he stopped sleeping at all. He has been locking himself in his room, talking rapidly and excessively about motorcycles, complaining that he “just needed to get his thoughts together.” He was very distractible and was not eating. His mother called his primary care clinician who advised her to bring him to the ED, which she could do only by police because he refused to leave the home, complaining of the “noises” outside.

Case 1 discussion

Joseph most likely has bipolar I disorder, although a substance-induced mania will have to be ruled out. His symptoms are classic for what we think of as “narrow phenotypic” mania – elated and irritable mood, grandiosity, flight of ideas, decreased need for sleep, hypertalkativeness, increase in goal-directed activity, severe distractibility, and excessive involvement in activities that are likely to have painful consequences. These episodes are a clear change from baseline. Here, Joseph has been previously depressed, but never had symptoms like this that came, went, and then returned. If these manic symptoms continue for 1 week or longer, or are so severe as to require him to be hospitalized, these are a manic episode, which, essentially, makes the diagnosis of bipolar I disorder. Most clinicians have seen mania in late adolescence and early adulthood and can distinguish when these episodes occur in childhood. There is less ambiguity about this diagnosis when it occurs with frank mania.

Case 2 summary

Henry is a 12-year-old boy. His parents say that he’s been difficult since he was “in the womb.” Starting at about the age of 4 years, they started to notice that he would frequently become moody – lasting almost all day in a way that was noticed by everyone. He remains almost constantly irritable. He responds extremely to negative emotional stimuli, like when he got so upset about striking out at a Little League game last year that he had a 15-minute temper outburst that couldn’t be stopped. When his father removed him from the field to the car, he kicked out a window. These types of events are not uncommon, occurring four to five times per week, and are associated with verbal and physical aggression. There have been no symptom-free periods since age 4 years. There have been no clear episodes, and nothing that could be described as elation.

Case 2 discussion

Henry would very likely meet the criteria for the DSM-5 diagnosis of disruptive mood dysregulation disorder. DMDD requires that there be severe and recurrent temper outbursts that can be verbal or physical and are grossly out of proportion to the situation, happening at least three times a week for the past year. In between these outbursts, the child’s mood is angry or irritable, most of the day, nearly every day with no time longer than 3 months in the last year without symptoms. There cannot be symptoms of mania or hypomania. DMDD should be distinguished from oppositional-defiant disorder (ODD), which cannot be diagnosed concurrently. ODD has similar characteristics, but the temper outbursts are not as severe, frequent, or chronic. The mood symptoms in DMDD predominate, while oppositionality predominates in ODD. Note the chronicity of irritable mood in DMDD. This is the distinguishing characteristic of the disorder – chronic, nonepisodic irritability.

General discussion

The distinction between BD and DMDD does matter, but it is sometimes quite hard to draw a clear line – even for the experts. It can be easy to be frustrated with yourself as a clinician when you’re unable to come to a clear decision about the diagnosis. With mood disorders in children, however, it’s important not to attribute the field’s lack of clarity to your own lack of knowledge. In these difficult cases, it’s highly likely that even the experts would disagree. Making the distinction between bipolar disorder and DMDD becomes even more complex in the situation of “other specified bipolar and related disorders,” which allows for short or subsyndromal hypomanic episodes with major depression, hypomania without depression, or short-duration cyclothymia. These cases, formerly called “bipolar, not otherwise specified,” are more likely to progress to adult bipolar disorder I or II. DMDD, on the other hand, is more likely to progress to adult depression (Biol. Psychiatry 2006;60:991-7).

Why does the distinction matter? Because the treatment for bipolar disorder is likely to involve one of the traditional mood stabilizers or the second-generation antipsychotics that are Food and Drug Administration–approved for bipolar disorder along with family education and cognitive-behavioral therapy. However, there is no evidence at this time that the management of DMDD should consist of these same treatments. In fact, a trial of lithium for DMDD (actually, its research predecessor severe mood dysregulation) was negative (J. Child. Adolesc. Psychopharmacol. 2009;19:61-73). While we are still working out how to help children with DMDD, the current trials being done are examining the use of antidepressants and psychostimulants (either serially or in combination) along with family-based interventions similar to those used for ODD. These are tough cases, and frequently a consult with a child psychiatrist or psychologist will be helpful.

Dr. Althoff is an associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Dr. Althoff has received grants/research support from the National Institute of Mental Health, the National Institute of General Medical Sciences, the Research Center for Children, Youth, and Families, and the Klingenstein Third Generation Foundation, and honoraria from the Oakstone General Publishing for CME presentations. E-mail him at [email protected].

Introduction

In the last 20 years there has been a marked rise in the number of children and adolescents receiving the diagnosis of bipolar disorder (BD) – a mood disorder that, classically, involves cycling between episodes of elevated mood and episodes of low mood (Arch. Gen. Psychiatry 2207;64:1032-9). The increase in diagnosis is partly explained by the inclusion of children with chronic irritability being diagnosed with BD. This has led to concern about the subsequent use of approved second-generation antipsychotics for chronically irritable children, with the resultant side effects.

A new diagnosis called disruptive mood dysregulation disorder (DMDD) was introduced into the DSM-5 to describe these chronically irritable children and, in part, to reduce the number of children receiving a bipolar diagnosis. So, how does one know whether a child has BD, DMDD, or something else? The two brief cases that follow distinguish the difference between BD and DMDD.

Case 1 summary

Joseph is a 15-year-old boy with a history of childhood depression. About 1 year ago, he began to appear more irritable and anxious. Despite his parents’ prohibition, he was going out at night and was intoxicated on several occasions when he came home – something he had never done before. After about 2 weeks of this, he began going to bed at midnight, but would be up again by 4 a.m. talking to himself, playing music, or exercising. He was hanging out with a different crowd. He began to talk about the possibility of becoming part of a motorcycle gang – at some point perhaps the leader of Hells Angels. Slowly, this resolved. However, these symptoms recurred about 1 month ago with progressive worsening, again, and 2 days ago he stopped sleeping at all. He has been locking himself in his room, talking rapidly and excessively about motorcycles, complaining that he “just needed to get his thoughts together.” He was very distractible and was not eating. His mother called his primary care clinician who advised her to bring him to the ED, which she could do only by police because he refused to leave the home, complaining of the “noises” outside.

Case 1 discussion

Joseph most likely has bipolar I disorder, although a substance-induced mania will have to be ruled out. His symptoms are classic for what we think of as “narrow phenotypic” mania – elated and irritable mood, grandiosity, flight of ideas, decreased need for sleep, hypertalkativeness, increase in goal-directed activity, severe distractibility, and excessive involvement in activities that are likely to have painful consequences. These episodes are a clear change from baseline. Here, Joseph has been previously depressed, but never had symptoms like this that came, went, and then returned. If these manic symptoms continue for 1 week or longer, or are so severe as to require him to be hospitalized, these are a manic episode, which, essentially, makes the diagnosis of bipolar I disorder. Most clinicians have seen mania in late adolescence and early adulthood and can distinguish when these episodes occur in childhood. There is less ambiguity about this diagnosis when it occurs with frank mania.

Case 2 summary

Henry is a 12-year-old boy. His parents say that he’s been difficult since he was “in the womb.” Starting at about the age of 4 years, they started to notice that he would frequently become moody – lasting almost all day in a way that was noticed by everyone. He remains almost constantly irritable. He responds extremely to negative emotional stimuli, like when he got so upset about striking out at a Little League game last year that he had a 15-minute temper outburst that couldn’t be stopped. When his father removed him from the field to the car, he kicked out a window. These types of events are not uncommon, occurring four to five times per week, and are associated with verbal and physical aggression. There have been no symptom-free periods since age 4 years. There have been no clear episodes, and nothing that could be described as elation.

Case 2 discussion

Henry would very likely meet the criteria for the DSM-5 diagnosis of disruptive mood dysregulation disorder. DMDD requires that there be severe and recurrent temper outbursts that can be verbal or physical and are grossly out of proportion to the situation, happening at least three times a week for the past year. In between these outbursts, the child’s mood is angry or irritable, most of the day, nearly every day with no time longer than 3 months in the last year without symptoms. There cannot be symptoms of mania or hypomania. DMDD should be distinguished from oppositional-defiant disorder (ODD), which cannot be diagnosed concurrently. ODD has similar characteristics, but the temper outbursts are not as severe, frequent, or chronic. The mood symptoms in DMDD predominate, while oppositionality predominates in ODD. Note the chronicity of irritable mood in DMDD. This is the distinguishing characteristic of the disorder – chronic, nonepisodic irritability.

General discussion

The distinction between BD and DMDD does matter, but it is sometimes quite hard to draw a clear line – even for the experts. It can be easy to be frustrated with yourself as a clinician when you’re unable to come to a clear decision about the diagnosis. With mood disorders in children, however, it’s important not to attribute the field’s lack of clarity to your own lack of knowledge. In these difficult cases, it’s highly likely that even the experts would disagree. Making the distinction between bipolar disorder and DMDD becomes even more complex in the situation of “other specified bipolar and related disorders,” which allows for short or subsyndromal hypomanic episodes with major depression, hypomania without depression, or short-duration cyclothymia. These cases, formerly called “bipolar, not otherwise specified,” are more likely to progress to adult bipolar disorder I or II. DMDD, on the other hand, is more likely to progress to adult depression (Biol. Psychiatry 2006;60:991-7).

Why does the distinction matter? Because the treatment for bipolar disorder is likely to involve one of the traditional mood stabilizers or the second-generation antipsychotics that are Food and Drug Administration–approved for bipolar disorder along with family education and cognitive-behavioral therapy. However, there is no evidence at this time that the management of DMDD should consist of these same treatments. In fact, a trial of lithium for DMDD (actually, its research predecessor severe mood dysregulation) was negative (J. Child. Adolesc. Psychopharmacol. 2009;19:61-73). While we are still working out how to help children with DMDD, the current trials being done are examining the use of antidepressants and psychostimulants (either serially or in combination) along with family-based interventions similar to those used for ODD. These are tough cases, and frequently a consult with a child psychiatrist or psychologist will be helpful.

Dr. Althoff is an associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Dr. Althoff has received grants/research support from the National Institute of Mental Health, the National Institute of General Medical Sciences, the Research Center for Children, Youth, and Families, and the Klingenstein Third Generation Foundation, and honoraria from the Oakstone General Publishing for CME presentations. E-mail him at [email protected].

Introduction

In the last 20 years there has been a marked rise in the number of children and adolescents receiving the diagnosis of bipolar disorder (BD) – a mood disorder that, classically, involves cycling between episodes of elevated mood and episodes of low mood (Arch. Gen. Psychiatry 2207;64:1032-9). The increase in diagnosis is partly explained by the inclusion of children with chronic irritability being diagnosed with BD. This has led to concern about the subsequent use of approved second-generation antipsychotics for chronically irritable children, with the resultant side effects.

A new diagnosis called disruptive mood dysregulation disorder (DMDD) was introduced into the DSM-5 to describe these chronically irritable children and, in part, to reduce the number of children receiving a bipolar diagnosis. So, how does one know whether a child has BD, DMDD, or something else? The two brief cases that follow distinguish the difference between BD and DMDD.

Case 1 summary

Joseph is a 15-year-old boy with a history of childhood depression. About 1 year ago, he began to appear more irritable and anxious. Despite his parents’ prohibition, he was going out at night and was intoxicated on several occasions when he came home – something he had never done before. After about 2 weeks of this, he began going to bed at midnight, but would be up again by 4 a.m. talking to himself, playing music, or exercising. He was hanging out with a different crowd. He began to talk about the possibility of becoming part of a motorcycle gang – at some point perhaps the leader of Hells Angels. Slowly, this resolved. However, these symptoms recurred about 1 month ago with progressive worsening, again, and 2 days ago he stopped sleeping at all. He has been locking himself in his room, talking rapidly and excessively about motorcycles, complaining that he “just needed to get his thoughts together.” He was very distractible and was not eating. His mother called his primary care clinician who advised her to bring him to the ED, which she could do only by police because he refused to leave the home, complaining of the “noises” outside.

Case 1 discussion

Joseph most likely has bipolar I disorder, although a substance-induced mania will have to be ruled out. His symptoms are classic for what we think of as “narrow phenotypic” mania – elated and irritable mood, grandiosity, flight of ideas, decreased need for sleep, hypertalkativeness, increase in goal-directed activity, severe distractibility, and excessive involvement in activities that are likely to have painful consequences. These episodes are a clear change from baseline. Here, Joseph has been previously depressed, but never had symptoms like this that came, went, and then returned. If these manic symptoms continue for 1 week or longer, or are so severe as to require him to be hospitalized, these are a manic episode, which, essentially, makes the diagnosis of bipolar I disorder. Most clinicians have seen mania in late adolescence and early adulthood and can distinguish when these episodes occur in childhood. There is less ambiguity about this diagnosis when it occurs with frank mania.

Case 2 summary

Henry is a 12-year-old boy. His parents say that he’s been difficult since he was “in the womb.” Starting at about the age of 4 years, they started to notice that he would frequently become moody – lasting almost all day in a way that was noticed by everyone. He remains almost constantly irritable. He responds extremely to negative emotional stimuli, like when he got so upset about striking out at a Little League game last year that he had a 15-minute temper outburst that couldn’t be stopped. When his father removed him from the field to the car, he kicked out a window. These types of events are not uncommon, occurring four to five times per week, and are associated with verbal and physical aggression. There have been no symptom-free periods since age 4 years. There have been no clear episodes, and nothing that could be described as elation.

Case 2 discussion

Henry would very likely meet the criteria for the DSM-5 diagnosis of disruptive mood dysregulation disorder. DMDD requires that there be severe and recurrent temper outbursts that can be verbal or physical and are grossly out of proportion to the situation, happening at least three times a week for the past year. In between these outbursts, the child’s mood is angry or irritable, most of the day, nearly every day with no time longer than 3 months in the last year without symptoms. There cannot be symptoms of mania or hypomania. DMDD should be distinguished from oppositional-defiant disorder (ODD), which cannot be diagnosed concurrently. ODD has similar characteristics, but the temper outbursts are not as severe, frequent, or chronic. The mood symptoms in DMDD predominate, while oppositionality predominates in ODD. Note the chronicity of irritable mood in DMDD. This is the distinguishing characteristic of the disorder – chronic, nonepisodic irritability.

General discussion

The distinction between BD and DMDD does matter, but it is sometimes quite hard to draw a clear line – even for the experts. It can be easy to be frustrated with yourself as a clinician when you’re unable to come to a clear decision about the diagnosis. With mood disorders in children, however, it’s important not to attribute the field’s lack of clarity to your own lack of knowledge. In these difficult cases, it’s highly likely that even the experts would disagree. Making the distinction between bipolar disorder and DMDD becomes even more complex in the situation of “other specified bipolar and related disorders,” which allows for short or subsyndromal hypomanic episodes with major depression, hypomania without depression, or short-duration cyclothymia. These cases, formerly called “bipolar, not otherwise specified,” are more likely to progress to adult bipolar disorder I or II. DMDD, on the other hand, is more likely to progress to adult depression (Biol. Psychiatry 2006;60:991-7).

Why does the distinction matter? Because the treatment for bipolar disorder is likely to involve one of the traditional mood stabilizers or the second-generation antipsychotics that are Food and Drug Administration–approved for bipolar disorder along with family education and cognitive-behavioral therapy. However, there is no evidence at this time that the management of DMDD should consist of these same treatments. In fact, a trial of lithium for DMDD (actually, its research predecessor severe mood dysregulation) was negative (J. Child. Adolesc. Psychopharmacol. 2009;19:61-73). While we are still working out how to help children with DMDD, the current trials being done are examining the use of antidepressants and psychostimulants (either serially or in combination) along with family-based interventions similar to those used for ODD. These are tough cases, and frequently a consult with a child psychiatrist or psychologist will be helpful.

Dr. Althoff is an associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Dr. Althoff has received grants/research support from the National Institute of Mental Health, the National Institute of General Medical Sciences, the Research Center for Children, Youth, and Families, and the Klingenstein Third Generation Foundation, and honoraria from the Oakstone General Publishing for CME presentations. E-mail him at [email protected].

Like many groups, our practice shares backup call on a rotational basis. This week-long pleasure cruise is characterized by phone calls throughout the night (“Why are we checking a temperature on a comfortably sleeping 85-year-old at 2 a.m. again?”), dubious requests (“I am still unclear why you were cleaning out your medicine cabinet at 4 a.m. Even so, I cannot refill the oxycodone you just flushed down the toilet.”), and fragmented sleep associated with clinically significant carbohydrate cravings.

In the old days, this indispensable community service could be handled without the need for remoting into the practice. But most calls these days require that our computers be close at hand. As such, we find ourselves in the wee hours of morning staring at computer screens that, we are increasingly aware, emit melatonin-killing blue wavelengths of light. This makes it that much harder to go back to sleep after triaging colonoscopy-preps-gone-wrong calls.

Several months ago, one of my patients gave me orange-tinted, blue light–blocking (BB) glasses as a gift. These glasses are designed to filter out the blue wavelength (480 nm), which most strongly impacts alertness, cognitive performance, and circadian physiology.

They have collected dust on my desk. … until last week while on call.

In a recently published study, Stéphanie van der Lely of the University of Basel, Switzerland, and colleagues evaluated the impact of blue-blocker glasses as a countermeasure to evening computer screen time among adolescents (J. Adolesc. Health 2015;56:113-9). Thirteen adolescents with a mean age of 16 years participated in this crossover study over 16 days. Blue blockers were provided from 6 p.m. to sleep onset. Glasses reduced the blue light transmission to 30%.

Compared with clear lenses, BB significantly attenuated LED-induced melatonin suppression in the evening. BB glasses also decreased vigilant attention and subjective alertness before bedtime.

This article would suggest that my melatonin is not being suppressed while I wear the glasses as I do my evening article writing and answer phone calls. The color shifts take some getting used to, but the glasses are comfortable. In addition to sleeping in the attic, my backup call routine will include these glasses.

Now, if we can just find something to filter out midnight acetaminophen requests. At least I’ll fall back asleep quickly after telling them to take two and call me in the morning.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

Like many groups, our practice shares backup call on a rotational basis. This week-long pleasure cruise is characterized by phone calls throughout the night (“Why are we checking a temperature on a comfortably sleeping 85-year-old at 2 a.m. again?”), dubious requests (“I am still unclear why you were cleaning out your medicine cabinet at 4 a.m. Even so, I cannot refill the oxycodone you just flushed down the toilet.”), and fragmented sleep associated with clinically significant carbohydrate cravings.

In the old days, this indispensable community service could be handled without the need for remoting into the practice. But most calls these days require that our computers be close at hand. As such, we find ourselves in the wee hours of morning staring at computer screens that, we are increasingly aware, emit melatonin-killing blue wavelengths of light. This makes it that much harder to go back to sleep after triaging colonoscopy-preps-gone-wrong calls.

Several months ago, one of my patients gave me orange-tinted, blue light–blocking (BB) glasses as a gift. These glasses are designed to filter out the blue wavelength (480 nm), which most strongly impacts alertness, cognitive performance, and circadian physiology.

They have collected dust on my desk. … until last week while on call.

In a recently published study, Stéphanie van der Lely of the University of Basel, Switzerland, and colleagues evaluated the impact of blue-blocker glasses as a countermeasure to evening computer screen time among adolescents (J. Adolesc. Health 2015;56:113-9). Thirteen adolescents with a mean age of 16 years participated in this crossover study over 16 days. Blue blockers were provided from 6 p.m. to sleep onset. Glasses reduced the blue light transmission to 30%.

Compared with clear lenses, BB significantly attenuated LED-induced melatonin suppression in the evening. BB glasses also decreased vigilant attention and subjective alertness before bedtime.

This article would suggest that my melatonin is not being suppressed while I wear the glasses as I do my evening article writing and answer phone calls. The color shifts take some getting used to, but the glasses are comfortable. In addition to sleeping in the attic, my backup call routine will include these glasses.

Now, if we can just find something to filter out midnight acetaminophen requests. At least I’ll fall back asleep quickly after telling them to take two and call me in the morning.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

Like many groups, our practice shares backup call on a rotational basis. This week-long pleasure cruise is characterized by phone calls throughout the night (“Why are we checking a temperature on a comfortably sleeping 85-year-old at 2 a.m. again?”), dubious requests (“I am still unclear why you were cleaning out your medicine cabinet at 4 a.m. Even so, I cannot refill the oxycodone you just flushed down the toilet.”), and fragmented sleep associated with clinically significant carbohydrate cravings.

In the old days, this indispensable community service could be handled without the need for remoting into the practice. But most calls these days require that our computers be close at hand. As such, we find ourselves in the wee hours of morning staring at computer screens that, we are increasingly aware, emit melatonin-killing blue wavelengths of light. This makes it that much harder to go back to sleep after triaging colonoscopy-preps-gone-wrong calls.

Several months ago, one of my patients gave me orange-tinted, blue light–blocking (BB) glasses as a gift. These glasses are designed to filter out the blue wavelength (480 nm), which most strongly impacts alertness, cognitive performance, and circadian physiology.

They have collected dust on my desk. … until last week while on call.

In a recently published study, Stéphanie van der Lely of the University of Basel, Switzerland, and colleagues evaluated the impact of blue-blocker glasses as a countermeasure to evening computer screen time among adolescents (J. Adolesc. Health 2015;56:113-9). Thirteen adolescents with a mean age of 16 years participated in this crossover study over 16 days. Blue blockers were provided from 6 p.m. to sleep onset. Glasses reduced the blue light transmission to 30%.

Compared with clear lenses, BB significantly attenuated LED-induced melatonin suppression in the evening. BB glasses also decreased vigilant attention and subjective alertness before bedtime.

This article would suggest that my melatonin is not being suppressed while I wear the glasses as I do my evening article writing and answer phone calls. The color shifts take some getting used to, but the glasses are comfortable. In addition to sleeping in the attic, my backup call routine will include these glasses.

Now, if we can just find something to filter out midnight acetaminophen requests. At least I’ll fall back asleep quickly after telling them to take two and call me in the morning.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses the limitations of the system that has been in place for more than 30 years, which ascribed a pregnancy risk category of A,B,C,D, or X to drugs, with the purpose of informing the clinician and patient about the reproductive safety of medications during pregnancy. Though well intentioned, criticisms of this system have been abundant.

The system certainly simplified the interaction between physicians and patients, who presumably would be reassured that the risk of a certain medicine had been quantified by a regulatory body and therefore could be used as a basis for making a decision about whether or not to take a medicine during pregnancy. While the purpose of the labeling system was to provide some overarching guidance about available reproductive safety information of a medicine, it was ultimately used by clinicians and patients either to somehow garner reassurance about a medicine, or to heighten concern about a medicine.

From the outset, the system could not take into account the accruing reproductive safety information regarding compounds across therapeutic categories, and as a result, the risk category could be inadvertently reassuring or even misleading to patients with respect to medicines they might decide to stop or to continue.

With the older labeling system, some medicines are in the same category, despite very different amounts of reproductive safety information available on the drugs. In the 1990s, there were more reproductive safety data available on certain selective serotonin reuptake inhibitors (SSRIs), compared with others, but now the amount of such data available across SSRIs is fairly consistent. Yet SSRI labels have not been updated with the abundance of new reproductive safety information that has become available.

Almost 10 years ago, paroxetine (Paxil) was switched from a category C to D, when first-trimester exposure was linked to an increased risk of birth defects, particularly heart defects. But it was not switched back to category C when data became available that did not support that level of concern. Because of some of its side effects, paroxetine may not be considered by many to be a first-line treatment for major depression, but it certainly would not be absolutely contraindicated during pregnancy as might be presumed by the assignment of a category D label.

Lithium and sodium valproate provide another example of the limitations of the old system, which will be addressed in the new system. While the teratogenicity of both agents has been well described, the absolute risk of malformations with fetal exposure to lithium is approximately 0.05%- 0.1%, but the risk of neural tube defects with sodium valproate is estimated at 8%. Complicating the issue further, in 2013, the FDA announced that sodium valproate had been changed from a category D to X for migraine prevention, but retained the category D classification for other indications.

Placing lithium in category D suggests a relative contraindication and yet discontinuing that medication during pregnancy can put the mother and her baby at risk, given the data supporting the rapid onset of relapse in women who stop mood stabilizers during pregnancy.

For women maintained on lithium for recurrent or brittle bipolar disorder, the drug would certainly not be contraindicated and may afford critical emotional well-being and protection from relapse during pregnancy; the clinical scenario of discontinuation of lithium proximate to or during pregnancy and subsequent relapse of underlying illness is a serious clinical matter frequently demanding urgent intervention.

Still another example of the incomplete informative value of the older system is found in the assignment of atypical antipsychotics into different risk categories. Lurasidone (Latuda), approved in 2010, is in category B, but other atypical antipsychotics are in category C. One might assume that this implies that there are more reproductive safety data available on lurasidone supporting safety, but in fact, reproductive safety data for this molecule are extremely limited, and the absence of adverse event information resulted in a category B. This is a great example of the clinical maxim that incomplete or sparse data is just that; it does not imply safety, it implies that we do not know a lot about the safety of a medication.

If the old system of pregnancy labeling was arbitrary, the PLLR will be more descriptive. Safety information during pregnancy and lactation in the drug label will appear in a section on pregnancy, reformatted to include a risk summary, clinical considerations, and data subsections, as well as a section on lactation, and a section on females and males of reproductive potential.

Ongoing revision of the label as information becomes outdated is a requirement, and manufacturers will be obligated to include information on whether there is a pregnancy registry for the given drug. The goal of the PLLR is thus to provide the patient and clinician with information which addresses both sides of the risk-benefit decision for a given medicine – risks of fetal drug exposure and the risk of untreated illness for the woman and baby, a factor that is not addressed at all with the current system.

Certainly, the new label system will be a charge to industry to establish, support, and encourage enrollment in well-designed pregnancy registries across therapeutic areas to provide ample amounts of good quality data that can then be used by patients along with their physicians to make the most appropriate clinical decisions.

Much of the currently available reproductive safety information on drugs is derived from spontaneous reports, where there has been inconsistent information and variable levels of scrutiny with respect to outcomes assessment, and from small, underpowered cohort studies or large administrative databases. Postmarketing surveillance efforts have been rather modest and have not been a priority for manufacturers in most cases. Hopefully, this will change as pregnancy registries become part of routine postmarketing surveillance.

The new system will not be a panacea, and I expect there will be growing pains, considering the huge challenge of reducing the available data of varying quality into distinct paragraphs. It may also be difficult to synthesize the volume of data and the nuanced differences between certain studies into a paragraph on risk assessment. The task will be simpler for some agents and more challenging for others where the data are less consistent. Questions also remain as to how data will be revised over time.

But despite these challenges, the new system represents a monumental change, and in my mind, will bring a focus to the importance of the issue of quantifying reproductive safety of medications used by women either planning to get pregnant or who are pregnant or breastfeeding, across therapeutic areas. Of particular importance, the new system will hopefully lead to more discussion between physician and patient about what is and is not known about the reproductive safety of a medication, versus a cursory reference to some previously assigned category label.

Our group has shown that when it comes to making decisions about using medication during pregnancy, even when given the same information, women will make different decisions. This is critical since people make personal decisions about the use of these medications in collaboration with their doctors on a case-by-case basis, based on personal preference, available information, and clinical conditions across a spectrum of severity.

As the FDA requirements shift from the arbitrary category label assignment to a more descriptive explanation of risk, based on available data, an important question will be what mechanism will be used by regulators collaborating with industry to update labels with the growing amounts of information on reproductive safety, particularly if there is a commitment from industry to enhance postmarketing surveillance with more pregnancy registries.

Better data can catalyze thoughtful discussions between doctor and patient regarding decisions to use or defer treatment with a given medicine. One might wonder if the new system will open a Pandora’s box. But I believe in this case, opening Pandora’s box would be welcome because it will hopefully lead to a more careful examination of the available information regarding reproductive safety and more informed decisions on the part of patients.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health. He has been a consultant to manufacturers of antidepressant medications and is the principal investigator of the National Pregnancy Registry for Atypical Antipsychotics, which receives support from the manufacturers of those drugs. To comment, e-mail him at [email protected]. Scan this QR code or go to obgynnews.com to view similar columns.

As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses the limitations of the system that has been in place for more than 30 years, which ascribed a pregnancy risk category of A,B,C,D, or X to drugs, with the purpose of informing the clinician and patient about the reproductive safety of medications during pregnancy. Though well intentioned, criticisms of this system have been abundant.

The system certainly simplified the interaction between physicians and patients, who presumably would be reassured that the risk of a certain medicine had been quantified by a regulatory body and therefore could be used as a basis for making a decision about whether or not to take a medicine during pregnancy. While the purpose of the labeling system was to provide some overarching guidance about available reproductive safety information of a medicine, it was ultimately used by clinicians and patients either to somehow garner reassurance about a medicine, or to heighten concern about a medicine.

From the outset, the system could not take into account the accruing reproductive safety information regarding compounds across therapeutic categories, and as a result, the risk category could be inadvertently reassuring or even misleading to patients with respect to medicines they might decide to stop or to continue.

With the older labeling system, some medicines are in the same category, despite very different amounts of reproductive safety information available on the drugs. In the 1990s, there were more reproductive safety data available on certain selective serotonin reuptake inhibitors (SSRIs), compared with others, but now the amount of such data available across SSRIs is fairly consistent. Yet SSRI labels have not been updated with the abundance of new reproductive safety information that has become available.

Almost 10 years ago, paroxetine (Paxil) was switched from a category C to D, when first-trimester exposure was linked to an increased risk of birth defects, particularly heart defects. But it was not switched back to category C when data became available that did not support that level of concern. Because of some of its side effects, paroxetine may not be considered by many to be a first-line treatment for major depression, but it certainly would not be absolutely contraindicated during pregnancy as might be presumed by the assignment of a category D label.

Lithium and sodium valproate provide another example of the limitations of the old system, which will be addressed in the new system. While the teratogenicity of both agents has been well described, the absolute risk of malformations with fetal exposure to lithium is approximately 0.05%- 0.1%, but the risk of neural tube defects with sodium valproate is estimated at 8%. Complicating the issue further, in 2013, the FDA announced that sodium valproate had been changed from a category D to X for migraine prevention, but retained the category D classification for other indications.

Placing lithium in category D suggests a relative contraindication and yet discontinuing that medication during pregnancy can put the mother and her baby at risk, given the data supporting the rapid onset of relapse in women who stop mood stabilizers during pregnancy.

For women maintained on lithium for recurrent or brittle bipolar disorder, the drug would certainly not be contraindicated and may afford critical emotional well-being and protection from relapse during pregnancy; the clinical scenario of discontinuation of lithium proximate to or during pregnancy and subsequent relapse of underlying illness is a serious clinical matter frequently demanding urgent intervention.

Still another example of the incomplete informative value of the older system is found in the assignment of atypical antipsychotics into different risk categories. Lurasidone (Latuda), approved in 2010, is in category B, but other atypical antipsychotics are in category C. One might assume that this implies that there are more reproductive safety data available on lurasidone supporting safety, but in fact, reproductive safety data for this molecule are extremely limited, and the absence of adverse event information resulted in a category B. This is a great example of the clinical maxim that incomplete or sparse data is just that; it does not imply safety, it implies that we do not know a lot about the safety of a medication.

If the old system of pregnancy labeling was arbitrary, the PLLR will be more descriptive. Safety information during pregnancy and lactation in the drug label will appear in a section on pregnancy, reformatted to include a risk summary, clinical considerations, and data subsections, as well as a section on lactation, and a section on females and males of reproductive potential.

Ongoing revision of the label as information becomes outdated is a requirement, and manufacturers will be obligated to include information on whether there is a pregnancy registry for the given drug. The goal of the PLLR is thus to provide the patient and clinician with information which addresses both sides of the risk-benefit decision for a given medicine – risks of fetal drug exposure and the risk of untreated illness for the woman and baby, a factor that is not addressed at all with the current system.

Certainly, the new label system will be a charge to industry to establish, support, and encourage enrollment in well-designed pregnancy registries across therapeutic areas to provide ample amounts of good quality data that can then be used by patients along with their physicians to make the most appropriate clinical decisions.

Much of the currently available reproductive safety information on drugs is derived from spontaneous reports, where there has been inconsistent information and variable levels of scrutiny with respect to outcomes assessment, and from small, underpowered cohort studies or large administrative databases. Postmarketing surveillance efforts have been rather modest and have not been a priority for manufacturers in most cases. Hopefully, this will change as pregnancy registries become part of routine postmarketing surveillance.

The new system will not be a panacea, and I expect there will be growing pains, considering the huge challenge of reducing the available data of varying quality into distinct paragraphs. It may also be difficult to synthesize the volume of data and the nuanced differences between certain studies into a paragraph on risk assessment. The task will be simpler for some agents and more challenging for others where the data are less consistent. Questions also remain as to how data will be revised over time.

But despite these challenges, the new system represents a monumental change, and in my mind, will bring a focus to the importance of the issue of quantifying reproductive safety of medications used by women either planning to get pregnant or who are pregnant or breastfeeding, across therapeutic areas. Of particular importance, the new system will hopefully lead to more discussion between physician and patient about what is and is not known about the reproductive safety of a medication, versus a cursory reference to some previously assigned category label.

Our group has shown that when it comes to making decisions about using medication during pregnancy, even when given the same information, women will make different decisions. This is critical since people make personal decisions about the use of these medications in collaboration with their doctors on a case-by-case basis, based on personal preference, available information, and clinical conditions across a spectrum of severity.

As the FDA requirements shift from the arbitrary category label assignment to a more descriptive explanation of risk, based on available data, an important question will be what mechanism will be used by regulators collaborating with industry to update labels with the growing amounts of information on reproductive safety, particularly if there is a commitment from industry to enhance postmarketing surveillance with more pregnancy registries.

Better data can catalyze thoughtful discussions between doctor and patient regarding decisions to use or defer treatment with a given medicine. One might wonder if the new system will open a Pandora’s box. But I believe in this case, opening Pandora’s box would be welcome because it will hopefully lead to a more careful examination of the available information regarding reproductive safety and more informed decisions on the part of patients.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health. He has been a consultant to manufacturers of antidepressant medications and is the principal investigator of the National Pregnancy Registry for Atypical Antipsychotics, which receives support from the manufacturers of those drugs. To comment, e-mail him at [email protected]. Scan this QR code or go to obgynnews.com to view similar columns.

As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses the limitations of the system that has been in place for more than 30 years, which ascribed a pregnancy risk category of A,B,C,D, or X to drugs, with the purpose of informing the clinician and patient about the reproductive safety of medications during pregnancy. Though well intentioned, criticisms of this system have been abundant.

The system certainly simplified the interaction between physicians and patients, who presumably would be reassured that the risk of a certain medicine had been quantified by a regulatory body and therefore could be used as a basis for making a decision about whether or not to take a medicine during pregnancy. While the purpose of the labeling system was to provide some overarching guidance about available reproductive safety information of a medicine, it was ultimately used by clinicians and patients either to somehow garner reassurance about a medicine, or to heighten concern about a medicine.

From the outset, the system could not take into account the accruing reproductive safety information regarding compounds across therapeutic categories, and as a result, the risk category could be inadvertently reassuring or even misleading to patients with respect to medicines they might decide to stop or to continue.

With the older labeling system, some medicines are in the same category, despite very different amounts of reproductive safety information available on the drugs. In the 1990s, there were more reproductive safety data available on certain selective serotonin reuptake inhibitors (SSRIs), compared with others, but now the amount of such data available across SSRIs is fairly consistent. Yet SSRI labels have not been updated with the abundance of new reproductive safety information that has become available.

Almost 10 years ago, paroxetine (Paxil) was switched from a category C to D, when first-trimester exposure was linked to an increased risk of birth defects, particularly heart defects. But it was not switched back to category C when data became available that did not support that level of concern. Because of some of its side effects, paroxetine may not be considered by many to be a first-line treatment for major depression, but it certainly would not be absolutely contraindicated during pregnancy as might be presumed by the assignment of a category D label.

Lithium and sodium valproate provide another example of the limitations of the old system, which will be addressed in the new system. While the teratogenicity of both agents has been well described, the absolute risk of malformations with fetal exposure to lithium is approximately 0.05%- 0.1%, but the risk of neural tube defects with sodium valproate is estimated at 8%. Complicating the issue further, in 2013, the FDA announced that sodium valproate had been changed from a category D to X for migraine prevention, but retained the category D classification for other indications.

Placing lithium in category D suggests a relative contraindication and yet discontinuing that medication during pregnancy can put the mother and her baby at risk, given the data supporting the rapid onset of relapse in women who stop mood stabilizers during pregnancy.

For women maintained on lithium for recurrent or brittle bipolar disorder, the drug would certainly not be contraindicated and may afford critical emotional well-being and protection from relapse during pregnancy; the clinical scenario of discontinuation of lithium proximate to or during pregnancy and subsequent relapse of underlying illness is a serious clinical matter frequently demanding urgent intervention.

Still another example of the incomplete informative value of the older system is found in the assignment of atypical antipsychotics into different risk categories. Lurasidone (Latuda), approved in 2010, is in category B, but other atypical antipsychotics are in category C. One might assume that this implies that there are more reproductive safety data available on lurasidone supporting safety, but in fact, reproductive safety data for this molecule are extremely limited, and the absence of adverse event information resulted in a category B. This is a great example of the clinical maxim that incomplete or sparse data is just that; it does not imply safety, it implies that we do not know a lot about the safety of a medication.

If the old system of pregnancy labeling was arbitrary, the PLLR will be more descriptive. Safety information during pregnancy and lactation in the drug label will appear in a section on pregnancy, reformatted to include a risk summary, clinical considerations, and data subsections, as well as a section on lactation, and a section on females and males of reproductive potential.

Ongoing revision of the label as information becomes outdated is a requirement, and manufacturers will be obligated to include information on whether there is a pregnancy registry for the given drug. The goal of the PLLR is thus to provide the patient and clinician with information which addresses both sides of the risk-benefit decision for a given medicine – risks of fetal drug exposure and the risk of untreated illness for the woman and baby, a factor that is not addressed at all with the current system.

Certainly, the new label system will be a charge to industry to establish, support, and encourage enrollment in well-designed pregnancy registries across therapeutic areas to provide ample amounts of good quality data that can then be used by patients along with their physicians to make the most appropriate clinical decisions.

Much of the currently available reproductive safety information on drugs is derived from spontaneous reports, where there has been inconsistent information and variable levels of scrutiny with respect to outcomes assessment, and from small, underpowered cohort studies or large administrative databases. Postmarketing surveillance efforts have been rather modest and have not been a priority for manufacturers in most cases. Hopefully, this will change as pregnancy registries become part of routine postmarketing surveillance.

The new system will not be a panacea, and I expect there will be growing pains, considering the huge challenge of reducing the available data of varying quality into distinct paragraphs. It may also be difficult to synthesize the volume of data and the nuanced differences between certain studies into a paragraph on risk assessment. The task will be simpler for some agents and more challenging for others where the data are less consistent. Questions also remain as to how data will be revised over time.

But despite these challenges, the new system represents a monumental change, and in my mind, will bring a focus to the importance of the issue of quantifying reproductive safety of medications used by women either planning to get pregnant or who are pregnant or breastfeeding, across therapeutic areas. Of particular importance, the new system will hopefully lead to more discussion between physician and patient about what is and is not known about the reproductive safety of a medication, versus a cursory reference to some previously assigned category label.

Our group has shown that when it comes to making decisions about using medication during pregnancy, even when given the same information, women will make different decisions. This is critical since people make personal decisions about the use of these medications in collaboration with their doctors on a case-by-case basis, based on personal preference, available information, and clinical conditions across a spectrum of severity.

As the FDA requirements shift from the arbitrary category label assignment to a more descriptive explanation of risk, based on available data, an important question will be what mechanism will be used by regulators collaborating with industry to update labels with the growing amounts of information on reproductive safety, particularly if there is a commitment from industry to enhance postmarketing surveillance with more pregnancy registries.

Better data can catalyze thoughtful discussions between doctor and patient regarding decisions to use or defer treatment with a given medicine. One might wonder if the new system will open a Pandora’s box. But I believe in this case, opening Pandora’s box would be welcome because it will hopefully lead to a more careful examination of the available information regarding reproductive safety and more informed decisions on the part of patients.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health. He has been a consultant to manufacturers of antidepressant medications and is the principal investigator of the National Pregnancy Registry for Atypical Antipsychotics, which receives support from the manufacturers of those drugs. To comment, e-mail him at [email protected]. Scan this QR code or go to obgynnews.com to view similar columns.