rFIXFc components

Photo courtesy of Biogen

A recombinant factor IX Fc fusion protein (rFIXFc) has produced favorable results in children with severe hemophilia B, researchers have reported.

The team said rFIXFc was generally well-tolerated in the phase 3 Kids B-LONG study, and none of the patients on this trial developed inhibitors.

In addition, the annualized bleeding rate was low, and most patients were able to maintain once-weekly dosing.

“To date, Kids B-LONG is the largest study to evaluate the safety and efficacy of extended half-life factor IX therapy in children with hemophilia B, and the study’s results align with those in studies of [rFIXFc] in adults and adolescents,” said Roshni Kulkarni, MD, of Michigan State University in East Lansing.

Dr Kulkarni and her colleagues reported results of Kids B-LONG in The Lancet Haematology. The research was funded by Biogen and Sobi, the companies marketing rFIXFc (also known as eftrenonacog alfa) as Alprolix.

The study included 30 males under the age of 12 with previously treated, severe hemophilia B.

All patients initially received rFIXFc prophylaxis (50-60 IU/kg) once per week. Doses were adjusted as needed (≤100 IU/kg per infusion, up to 2 times per week).

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 patients received rFIXFc injections on at least 50 separate days.

None of the patients developed inhibitors to rFIXFc. There were no reports of anaphylaxis or serious hypersensitivity reactions, no vascular thrombotic events, and no deaths.

The most common adverse events were common cold (n=7, 23%) and fall (n=6, 20%). Four patients experienced serious adverse events while on study, all of which were considered unrelated to rFIXFc.

The median annualized bleeding rate was 2.0 overall, and there were no spontaneous joint bleeds.

Of all 30 patients treated, 10 (33%) experienced no bleeding episodes, and 19 (63%) reported no joint bleeding on-study.

Overall, 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

Following a switch to rFIXFc, 80% of children who completed the study (22/27) extended their dosing interval compared to previous treatment.

One patient had his dosing interval reduced to 5 days, but all other patients remained on once-weekly prophylactic dosing throughout the study.

rFIXFc components

Photo courtesy of Biogen

A recombinant factor IX Fc fusion protein (rFIXFc) has produced favorable results in children with severe hemophilia B, researchers have reported.

The team said rFIXFc was generally well-tolerated in the phase 3 Kids B-LONG study, and none of the patients on this trial developed inhibitors.

In addition, the annualized bleeding rate was low, and most patients were able to maintain once-weekly dosing.

“To date, Kids B-LONG is the largest study to evaluate the safety and efficacy of extended half-life factor IX therapy in children with hemophilia B, and the study’s results align with those in studies of [rFIXFc] in adults and adolescents,” said Roshni Kulkarni, MD, of Michigan State University in East Lansing.

Dr Kulkarni and her colleagues reported results of Kids B-LONG in The Lancet Haematology. The research was funded by Biogen and Sobi, the companies marketing rFIXFc (also known as eftrenonacog alfa) as Alprolix.

The study included 30 males under the age of 12 with previously treated, severe hemophilia B.

All patients initially received rFIXFc prophylaxis (50-60 IU/kg) once per week. Doses were adjusted as needed (≤100 IU/kg per infusion, up to 2 times per week).

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 patients received rFIXFc injections on at least 50 separate days.

None of the patients developed inhibitors to rFIXFc. There were no reports of anaphylaxis or serious hypersensitivity reactions, no vascular thrombotic events, and no deaths.

The most common adverse events were common cold (n=7, 23%) and fall (n=6, 20%). Four patients experienced serious adverse events while on study, all of which were considered unrelated to rFIXFc.

The median annualized bleeding rate was 2.0 overall, and there were no spontaneous joint bleeds.

Of all 30 patients treated, 10 (33%) experienced no bleeding episodes, and 19 (63%) reported no joint bleeding on-study.

Overall, 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

Following a switch to rFIXFc, 80% of children who completed the study (22/27) extended their dosing interval compared to previous treatment.

One patient had his dosing interval reduced to 5 days, but all other patients remained on once-weekly prophylactic dosing throughout the study.

rFIXFc components

Photo courtesy of Biogen

A recombinant factor IX Fc fusion protein (rFIXFc) has produced favorable results in children with severe hemophilia B, researchers have reported.

The team said rFIXFc was generally well-tolerated in the phase 3 Kids B-LONG study, and none of the patients on this trial developed inhibitors.

In addition, the annualized bleeding rate was low, and most patients were able to maintain once-weekly dosing.

“To date, Kids B-LONG is the largest study to evaluate the safety and efficacy of extended half-life factor IX therapy in children with hemophilia B, and the study’s results align with those in studies of [rFIXFc] in adults and adolescents,” said Roshni Kulkarni, MD, of Michigan State University in East Lansing.

Dr Kulkarni and her colleagues reported results of Kids B-LONG in The Lancet Haematology. The research was funded by Biogen and Sobi, the companies marketing rFIXFc (also known as eftrenonacog alfa) as Alprolix.

The study included 30 males under the age of 12 with previously treated, severe hemophilia B.

All patients initially received rFIXFc prophylaxis (50-60 IU/kg) once per week. Doses were adjusted as needed (≤100 IU/kg per infusion, up to 2 times per week).

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 patients received rFIXFc injections on at least 50 separate days.

None of the patients developed inhibitors to rFIXFc. There were no reports of anaphylaxis or serious hypersensitivity reactions, no vascular thrombotic events, and no deaths.

The most common adverse events were common cold (n=7, 23%) and fall (n=6, 20%). Four patients experienced serious adverse events while on study, all of which were considered unrelated to rFIXFc.

The median annualized bleeding rate was 2.0 overall, and there were no spontaneous joint bleeds.

Of all 30 patients treated, 10 (33%) experienced no bleeding episodes, and 19 (63%) reported no joint bleeding on-study.

Overall, 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

Following a switch to rFIXFc, 80% of children who completed the study (22/27) extended their dosing interval compared to previous treatment.

One patient had his dosing interval reduced to 5 days, but all other patients remained on once-weekly prophylactic dosing throughout the study.

“Nature’s condition, rightly interpreted, reveals a society’s culture and traditions as directly as does a novel or a newspaper or a code of laws.”

– Roderick F. Nash
 

Adverse effects of air pollution on human health have been known ever since the “Great London Smog” in 1952. Mankind is paying for rapid industrialization by adversely affecting the air that we breathe. The developed world has been able to improve the environmental standards by following stringent norms and practices regarding engines, fuels, and industrial safety. However, the same cannot be said about developing countries. Delhi, the capital of India, has seen high levels of air pollution for the last several decades.

The number of registered vehicles in Delhi has doubled over the last 10 years. This, along with rapidly increasing numbers of small scale industries and inconsistently regulated construction work, has led to ever-increasing levels of air pollution in Delhi. The city has witnessed smog for the last few years.

Common sources and pollutants with reference to Delhi

As in most cities around the world, rapid industrialization and increases in vehicles using fossil fuels are important contributors to ambient air pollution in Delhi. Additional sources of air pollution unique to Delhi include dust generation during building construction, ash generation from thermal power plants, crop residue burning in neighboring states, and burning of fossil fuels for domestic, as well as small scale, industrial use. Major pollutants include particulate matter (both PM2.5 and PM10), nitrogen oxides (NOx), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3).

Delhi is distinct in its geographic location adjoining the Great Indian Desert (Thar) in the west and cool hilly regions in the north and east. This accounts for great seasonal variations in temperature, humidity, and wind speed. Also, being a landlocked territory, there are no moderating effects of sea breeze available to other metropolitan cities (like Mumbai and Chennai).

Dust storms during the summer from the neighboring state of Rajasthan cause an increase in suspended particulate matter (SPM). All these contribute to seasonal and climatic variations in air quality. In addition, the use of fire crackers during the festival of Diwali leads to dangerous levels of air pollution also.
 

Adverse health effects as witnessed in clinics and community

Many adults, without any prior history of respiratory illness, attended our outpatient department (OPD) with breathlessness, chest congestion, and wheezing requiring inhaled bronchodilators. A significant proportion of patients with previously diagnosed respiratory diseases (including COPD, bronchial asthma, or interstitial lung disease) reported to OPDs or emergency services with worsening cough, wheezing, and breathlessness. A few patients coming from outside Delhi for routine follow-up had exacerbation of COPD after coming to Delhi (personal observations).

We have previously reported increases in asthma, COPD, and acute coronary events (by 21.30%, 24.90%, and 24.30%, respectively) due to higher than acceptable levels of air pollutants in Delhi (Pande JN, et al. Indian J Chest Dis Allied Sci. 2002;44[1]:13). Another concerning development has been the increase in the number of persons being diagnosed with bronchial asthma in middle age, probably related to worsening air quality. Persons at extremes of age (young children and elderly) are particularly affected.
 

Studies in Delhi assessing ambient air pollution–related morbidity and mortality

Studies have used risk of mortality/morbidity due to air pollution model (Ri–MAP) to assess health impact of various air pollutants in Delhi. According to their estimates, there were 18,229 excess deaths in Delhi in the year 2010, more than 50% of which were due to cardiovascular or respiratory causes. Also, 26,525 excess hospital admissions due to COPD exacerbation could be attributed to ambient air pollution (Nagpure A, et al. Atmospheric Pollution Res. 2014;5[3]:1309).

Interventions: Work in progress

The Central Pollution Control Board convened an Expert Committee (Dr. Khilnani as a member) for formulation and implementation of Air Quality Index (AQI) in major Indian cities (http://cpcb.nic.in/FINAL-REPORT_AQI_.pdf).

Currently reported AQI is calculated by using the following parameters: sulfur dioxide (SO₂), nitrogen dioxide (NO₂), particulate matter (PM10,PM2.5) averaged over 24 hours, along with ozone (O3) and carbon monoxide (CO), averaged over 1-8 hours. AQI is classified as good (0-50), satisfactory (51-100), moderate (101-200), poor (201-300), very poor (301-400), and severe (greater than 401).

AQI is reported daily in leading newspapers along with public and private news channels. Thanks to the mainstream and social media, smog has become a commonly understood word. Air pollution is a hot topic of discussion among people of all socioeconomic and demographic strata.

Children of almost all schools in Delhi pledged not to use firecrackers this Diwali. People are increasingly sharing taxis or carpooling. Utilization of public transport is gradually increasing.

The Delhi government ordered temporarily shutting off the only working thermal power plant in the megacity (source of 10%-15% of ambient air pollution). The government is also working on an action plan based on air quality, which includes both preventive and prohibitive measures.

Delhi Transport Corporation operates one of the world’s largest fleets of compressed natural gas–operated buses. Delhi Metro Corporation has been lauded by the United Nations for its efforts in reducing the carbon footprint and air pollution.

Yet, a lot needs to be done to improve the air quality in Delhi. Last mile connectivity remains a big hurdle; improving this will go a long way in promoting use of public transport. Implementation of methods to reduce particulate matter generation at construction sites, promoting use of vehicles using electricity or compressed natural gas, increasing parking charges for vehicles, banning the use of diesel-driven heavy vehicles in the city, road cleaning with vacuum cleaners to reduce PM 10 generation, increasing green areas, and promoting carpooling or taxi sharing are some other initiatives that need to be implemented on priority. Delhi and surrounding states need to strengthen awareness drives and norms to discourage crop residue burning on a priority basis.
 

Conclusion

Delhi’s poor air quality during this winter has indeed affected the respiratory health of the population. Healthy people, as well as those with preexisting respiratory diseases, are adversely affected. A series of actions at the personal and institutional level is required to control this menace.
 

Dr. Khilnani is Professor, and Dr. Tiwari is Research Officer, Department of Pulmonary Medicine & Sleep Disorders, All India Institute of Medical Sciences, New Delhi, India.

“Nature’s condition, rightly interpreted, reveals a society’s culture and traditions as directly as does a novel or a newspaper or a code of laws.”

– Roderick F. Nash
 

Adverse effects of air pollution on human health have been known ever since the “Great London Smog” in 1952. Mankind is paying for rapid industrialization by adversely affecting the air that we breathe. The developed world has been able to improve the environmental standards by following stringent norms and practices regarding engines, fuels, and industrial safety. However, the same cannot be said about developing countries. Delhi, the capital of India, has seen high levels of air pollution for the last several decades.

The number of registered vehicles in Delhi has doubled over the last 10 years. This, along with rapidly increasing numbers of small scale industries and inconsistently regulated construction work, has led to ever-increasing levels of air pollution in Delhi. The city has witnessed smog for the last few years.

Common sources and pollutants with reference to Delhi

As in most cities around the world, rapid industrialization and increases in vehicles using fossil fuels are important contributors to ambient air pollution in Delhi. Additional sources of air pollution unique to Delhi include dust generation during building construction, ash generation from thermal power plants, crop residue burning in neighboring states, and burning of fossil fuels for domestic, as well as small scale, industrial use. Major pollutants include particulate matter (both PM2.5 and PM10), nitrogen oxides (NOx), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3).

Delhi is distinct in its geographic location adjoining the Great Indian Desert (Thar) in the west and cool hilly regions in the north and east. This accounts for great seasonal variations in temperature, humidity, and wind speed. Also, being a landlocked territory, there are no moderating effects of sea breeze available to other metropolitan cities (like Mumbai and Chennai).

Dust storms during the summer from the neighboring state of Rajasthan cause an increase in suspended particulate matter (SPM). All these contribute to seasonal and climatic variations in air quality. In addition, the use of fire crackers during the festival of Diwali leads to dangerous levels of air pollution also.
 

Adverse health effects as witnessed in clinics and community

Many adults, without any prior history of respiratory illness, attended our outpatient department (OPD) with breathlessness, chest congestion, and wheezing requiring inhaled bronchodilators. A significant proportion of patients with previously diagnosed respiratory diseases (including COPD, bronchial asthma, or interstitial lung disease) reported to OPDs or emergency services with worsening cough, wheezing, and breathlessness. A few patients coming from outside Delhi for routine follow-up had exacerbation of COPD after coming to Delhi (personal observations).

We have previously reported increases in asthma, COPD, and acute coronary events (by 21.30%, 24.90%, and 24.30%, respectively) due to higher than acceptable levels of air pollutants in Delhi (Pande JN, et al. Indian J Chest Dis Allied Sci. 2002;44[1]:13). Another concerning development has been the increase in the number of persons being diagnosed with bronchial asthma in middle age, probably related to worsening air quality. Persons at extremes of age (young children and elderly) are particularly affected.
 

Studies in Delhi assessing ambient air pollution–related morbidity and mortality

Studies have used risk of mortality/morbidity due to air pollution model (Ri–MAP) to assess health impact of various air pollutants in Delhi. According to their estimates, there were 18,229 excess deaths in Delhi in the year 2010, more than 50% of which were due to cardiovascular or respiratory causes. Also, 26,525 excess hospital admissions due to COPD exacerbation could be attributed to ambient air pollution (Nagpure A, et al. Atmospheric Pollution Res. 2014;5[3]:1309).

Interventions: Work in progress

The Central Pollution Control Board convened an Expert Committee (Dr. Khilnani as a member) for formulation and implementation of Air Quality Index (AQI) in major Indian cities (http://cpcb.nic.in/FINAL-REPORT_AQI_.pdf).

Currently reported AQI is calculated by using the following parameters: sulfur dioxide (SO₂), nitrogen dioxide (NO₂), particulate matter (PM10,PM2.5) averaged over 24 hours, along with ozone (O3) and carbon monoxide (CO), averaged over 1-8 hours. AQI is classified as good (0-50), satisfactory (51-100), moderate (101-200), poor (201-300), very poor (301-400), and severe (greater than 401).

AQI is reported daily in leading newspapers along with public and private news channels. Thanks to the mainstream and social media, smog has become a commonly understood word. Air pollution is a hot topic of discussion among people of all socioeconomic and demographic strata.

Children of almost all schools in Delhi pledged not to use firecrackers this Diwali. People are increasingly sharing taxis or carpooling. Utilization of public transport is gradually increasing.

The Delhi government ordered temporarily shutting off the only working thermal power plant in the megacity (source of 10%-15% of ambient air pollution). The government is also working on an action plan based on air quality, which includes both preventive and prohibitive measures.

Delhi Transport Corporation operates one of the world’s largest fleets of compressed natural gas–operated buses. Delhi Metro Corporation has been lauded by the United Nations for its efforts in reducing the carbon footprint and air pollution.

Yet, a lot needs to be done to improve the air quality in Delhi. Last mile connectivity remains a big hurdle; improving this will go a long way in promoting use of public transport. Implementation of methods to reduce particulate matter generation at construction sites, promoting use of vehicles using electricity or compressed natural gas, increasing parking charges for vehicles, banning the use of diesel-driven heavy vehicles in the city, road cleaning with vacuum cleaners to reduce PM 10 generation, increasing green areas, and promoting carpooling or taxi sharing are some other initiatives that need to be implemented on priority. Delhi and surrounding states need to strengthen awareness drives and norms to discourage crop residue burning on a priority basis.
 

Conclusion

Delhi’s poor air quality during this winter has indeed affected the respiratory health of the population. Healthy people, as well as those with preexisting respiratory diseases, are adversely affected. A series of actions at the personal and institutional level is required to control this menace.
 

Dr. Khilnani is Professor, and Dr. Tiwari is Research Officer, Department of Pulmonary Medicine & Sleep Disorders, All India Institute of Medical Sciences, New Delhi, India.

“Nature’s condition, rightly interpreted, reveals a society’s culture and traditions as directly as does a novel or a newspaper or a code of laws.”

– Roderick F. Nash
 

Adverse effects of air pollution on human health have been known ever since the “Great London Smog” in 1952. Mankind is paying for rapid industrialization by adversely affecting the air that we breathe. The developed world has been able to improve the environmental standards by following stringent norms and practices regarding engines, fuels, and industrial safety. However, the same cannot be said about developing countries. Delhi, the capital of India, has seen high levels of air pollution for the last several decades.

The number of registered vehicles in Delhi has doubled over the last 10 years. This, along with rapidly increasing numbers of small scale industries and inconsistently regulated construction work, has led to ever-increasing levels of air pollution in Delhi. The city has witnessed smog for the last few years.

Common sources and pollutants with reference to Delhi

As in most cities around the world, rapid industrialization and increases in vehicles using fossil fuels are important contributors to ambient air pollution in Delhi. Additional sources of air pollution unique to Delhi include dust generation during building construction, ash generation from thermal power plants, crop residue burning in neighboring states, and burning of fossil fuels for domestic, as well as small scale, industrial use. Major pollutants include particulate matter (both PM2.5 and PM10), nitrogen oxides (NOx), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3).

Delhi is distinct in its geographic location adjoining the Great Indian Desert (Thar) in the west and cool hilly regions in the north and east. This accounts for great seasonal variations in temperature, humidity, and wind speed. Also, being a landlocked territory, there are no moderating effects of sea breeze available to other metropolitan cities (like Mumbai and Chennai).

Dust storms during the summer from the neighboring state of Rajasthan cause an increase in suspended particulate matter (SPM). All these contribute to seasonal and climatic variations in air quality. In addition, the use of fire crackers during the festival of Diwali leads to dangerous levels of air pollution also.
 

Adverse health effects as witnessed in clinics and community

Many adults, without any prior history of respiratory illness, attended our outpatient department (OPD) with breathlessness, chest congestion, and wheezing requiring inhaled bronchodilators. A significant proportion of patients with previously diagnosed respiratory diseases (including COPD, bronchial asthma, or interstitial lung disease) reported to OPDs or emergency services with worsening cough, wheezing, and breathlessness. A few patients coming from outside Delhi for routine follow-up had exacerbation of COPD after coming to Delhi (personal observations).

We have previously reported increases in asthma, COPD, and acute coronary events (by 21.30%, 24.90%, and 24.30%, respectively) due to higher than acceptable levels of air pollutants in Delhi (Pande JN, et al. Indian J Chest Dis Allied Sci. 2002;44[1]:13). Another concerning development has been the increase in the number of persons being diagnosed with bronchial asthma in middle age, probably related to worsening air quality. Persons at extremes of age (young children and elderly) are particularly affected.
 

Studies in Delhi assessing ambient air pollution–related morbidity and mortality

Studies have used risk of mortality/morbidity due to air pollution model (Ri–MAP) to assess health impact of various air pollutants in Delhi. According to their estimates, there were 18,229 excess deaths in Delhi in the year 2010, more than 50% of which were due to cardiovascular or respiratory causes. Also, 26,525 excess hospital admissions due to COPD exacerbation could be attributed to ambient air pollution (Nagpure A, et al. Atmospheric Pollution Res. 2014;5[3]:1309).

Interventions: Work in progress

The Central Pollution Control Board convened an Expert Committee (Dr. Khilnani as a member) for formulation and implementation of Air Quality Index (AQI) in major Indian cities (http://cpcb.nic.in/FINAL-REPORT_AQI_.pdf).

Currently reported AQI is calculated by using the following parameters: sulfur dioxide (SO₂), nitrogen dioxide (NO₂), particulate matter (PM10,PM2.5) averaged over 24 hours, along with ozone (O3) and carbon monoxide (CO), averaged over 1-8 hours. AQI is classified as good (0-50), satisfactory (51-100), moderate (101-200), poor (201-300), very poor (301-400), and severe (greater than 401).

AQI is reported daily in leading newspapers along with public and private news channels. Thanks to the mainstream and social media, smog has become a commonly understood word. Air pollution is a hot topic of discussion among people of all socioeconomic and demographic strata.

Children of almost all schools in Delhi pledged not to use firecrackers this Diwali. People are increasingly sharing taxis or carpooling. Utilization of public transport is gradually increasing.

The Delhi government ordered temporarily shutting off the only working thermal power plant in the megacity (source of 10%-15% of ambient air pollution). The government is also working on an action plan based on air quality, which includes both preventive and prohibitive measures.

Delhi Transport Corporation operates one of the world’s largest fleets of compressed natural gas–operated buses. Delhi Metro Corporation has been lauded by the United Nations for its efforts in reducing the carbon footprint and air pollution.

Yet, a lot needs to be done to improve the air quality in Delhi. Last mile connectivity remains a big hurdle; improving this will go a long way in promoting use of public transport. Implementation of methods to reduce particulate matter generation at construction sites, promoting use of vehicles using electricity or compressed natural gas, increasing parking charges for vehicles, banning the use of diesel-driven heavy vehicles in the city, road cleaning with vacuum cleaners to reduce PM 10 generation, increasing green areas, and promoting carpooling or taxi sharing are some other initiatives that need to be implemented on priority. Delhi and surrounding states need to strengthen awareness drives and norms to discourage crop residue burning on a priority basis.
 

Conclusion

Delhi’s poor air quality during this winter has indeed affected the respiratory health of the population. Healthy people, as well as those with preexisting respiratory diseases, are adversely affected. A series of actions at the personal and institutional level is required to control this menace.
 

Dr. Khilnani is Professor, and Dr. Tiwari is Research Officer, Department of Pulmonary Medicine & Sleep Disorders, All India Institute of Medical Sciences, New Delhi, India.

Clinical Research

The unrecognized battlefield in our hospitals: Lessons from the US Navy SEALs

Burnout syndrome (BOS) is a psychological state resulting from prolonged exposure to job stressors. It is characterized by a vicious cycle of emotional exhaustion, detachment from others, and a feeling of decreased accomplishment. Severe BOS is seen in up to 45% of physicians and 33% of nurses who work in ICUs.¹

BOS has far-reaching consequences, being associated with an alarmingly high prevalence of posttraumatic stress disorder (PTSD) and substance abuse, almost equivalent to that experienced by veterans returning from war.² BOS also is associated with self-reported suboptimal patient care practices.³This crisis has long been underrecognized, but now that we have identified the problem, where does that leave us? There are currently no quality studies evaluating how to best treat and prevent BOS/PTSD in health-care professionals. Previous studies have focused on addressing organizational factors to alleviate job stressors, but the psychosocial characteristics of the individual have been largely ignored.

Our medical education has historically focused on an individual’s intelligence quotient (IQ), but developing an individual’s emotional quotient (EQ) is just as valuable. It has long been known that Navy SEALs have the lowest prevalence of PTSD among combat veterans due partially to their specific training in emotional resilience and adaptive psychosocial coping mechanisms.

For this reason, the research team at the University of Texas Health Science Center at San Antonio is collaborating with the US Navy SEAL team to design and validate a tool that teaches critical care staff resilience training similar to what their combat trainees undergo. The goal is to curb these alarming trends in BOS and create a paradigm shift in medical education within medical and nursing schools.

Bravein Amalakuhan, MD

Fellow-in-Training Member

References

1. Embriaco N, Azoulay E, Barrau K, et al. Am J Respir Crit Care Med. 2007;175(7):686.

2. Mealer ML, Shelton A, Berg B, et al. Am J Respir Crit Care Med. 2007;175(7):693.

3. Shanafelt TD, Bradley KA, Wipf JE, et al. Ann Intern Med. 2002;136(5):358.

Critical Care

End of the era for age of blood concerns?

Blood transfusions are common in critically ill patients, with two in five adults admitted to an ICU receiving a transfusion.^1,2 Recently, randomized trials have found that more restrictive thresholds for transfusions are associated with improved outcomes.^3,4 One theorized explanation for this somewhat counterintuitive association is that the prolonged storage time (i.e., the age of the blood being transfused) might affect outcomes.

There have been three recent publications that help to shed some more light on this. First, Lacroix et al.⁵ performed a multicenter randomized blinded trial in over 2,400 critically ill patients in 64 centers comparing new blood (mean storage (±SD) of 6.1±4.9 days) vs old blood with storage of 22.0±8.4 days (P less than .001). There was no statistically significant difference in 90-day mortality.⁵

The second study is a meta-analysis by Alexander et al.⁶ The investigators looked at 12 trials and 5,229 patients and compared “fresh blood” or blood stored for 3-10 days to “older blood” stored for longer durations. They found that there was no difference in mortality and no difference in adverse events, such as acute transfusion reactions, when comparing the two groups.

Lastly, Heddle et al.⁷ conducted a randomized trial that compared outcomes in 20,858 hospitalized patients transfused with fresh blood (mean storage time 13.0±7.6 days) to older blood (mean storage time 23.6±8.9 days). They found no differences in mortality when comparing those transfused with fresh vs. old blood (8.7% vs. 9.1%). In addition, there was no difference when examining the predetermined subgroups, including those undergoing cardiovascular surgery, those with cancer, and those admitted to the ICU.

So, is this the end of an era for health-care provider concern about how long blood can be stored to be safe for ICU patients? Possibly.

There may still be high-risk populations (such as patients receiving massive transfusions) for which age of the blood does matter. In addition, it is still unclear based on the present data as to whether blood stored between 35 and 42 days has any significant inherent risk.

However, these publications among others suggest that the age of transfused blood may not matter, even in critically ill patients. Therefore, the present storage practices of many blood banks around the United States and beyond are validated by the present publications regarding the scarce resource of blood.

Christopher L. Carroll, MD, MS, FCCP

Steering Committee Member

References

1. Corwin HL, Gettinger A, Pearl RG, et al. Crit Care Med. 2004;32(1):39.

2. Vincent JL, Baron JF, Reinhart K, et al.; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. JAMA. 2002;288(12):1499.

3. Holst LB, Haase N, Wetterslev J, et al.; TRISS Trial Group; Scandinavian Critical Care Trials Group. N Engl J Med. 2014;371(15):1381.

4. Lacroix J, Hebert PC, Hutchison JS, et al.; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network. N Engl J Med. 2007;356(16):1609.

5. Lacroix J, Hebert P, Fergusson DA, et al. N Engl J Med. 2015;372:1410.

6. Alexander PE, Barty R, Fei Y, et al. Blood. 2016;127(4):400.

7. Heddle NM, Cook RJ, Arnold DM, et al. N Engl J Med. 2016;375(2):1937.

Airways Disorders

Inhaled corticosteroids in COPD: When to hold and when to fold

The 2017 GOLD guidelines reiterated that inhaled corticosteroids (ICS) be reserved for COPD patients with continued symptoms and exacerbations, despite use of long-acting beta-agonists (LABAs) and long-acting muscarinic agents (LAMAs). ICS are appropriate in approximately 40% of patients; however, prescribing rates can exceed 80% (Yawn et al. 2016; Primary Care Respir J. 26:16068).

Recent literature has begun to define the appropriate use of ICS in COPD. ICS/LABA combinations improve outcomes in patients with moderate to very severe COPD with frequent exacerbations. However, ICS/LABA may not further diminish exacerbation risk compared with those treated with a LABA/LAMA combination (Wedzicha et al., N Engl J Med. 2016;374:2222).

While the addition of LAMA to an ICS/LABA combination (triple therapy) improved lung function and decreased exacerbation risk, the addition of ICS to LABA/LAMA combination did not decrease exacerbations (GOLD Guidelines 2017). It has been suggested that those with asthma-COPD overlap identified by sputum eosinophilia represent ideal candidates for ICS therapy (GINA Guideline 2016).

ICS use in COPD increases pneumonia risk. The risk was highest in the very group for which guidelines recommend its use – those with a FEV₁ less than 50% of predicted or with prior COPD exacerbation (Ernst et al. Eur Respir J. 2015;45:525).

ICS may be safely withdrawn in low-risk patients (FEV₁ less than 50% predicted and no exacerbations in the previous year [Yawn et al.]).

In a trial comparing patients with severe COPD (FEV₁ less than 50%) on continued LAMA/LABA/ICS triple therapy vs LAMA/LABA with ICS withdrawal, the risk of moderate or severe exacerbations at 52 weeks was not increased (Magnussen et al. N Engl J Med. 2014;371:1285).
 

Conclusions

Based on the 2017 GOLD guidelines:

• Monotherapy with ICS is not recommended in COPD.

• In patients with continued respiratory-related symptoms without exacerbations (GOLD group B), LAMA or LABA or LAMA/LABA combination is recommended. There is no recommendation for ICS in this group.

• In patients with frequent exacerbations (GOLD groups C and D), LAMA/LABA combinations are preferred to LABA/ICS because of superior effectiveness (especially in Group D) and the increased pneumonia risk with ICS. Escalation to triple therapy can be considered if there are continued exacerbations.

Allen Blaivas, DO, FCCP

Steering Committee Member

Home-Based Mechanical Ventilation and Neuromuscular Disease

Advances in neuromuscular disease

Spinal muscular atrophy (SMA) type 1 is the most deadly inherited disease among infants, with most infants dying by 1 to 2 years of age without supportive therapies, such as assisted ventilation. It is caused by homozygous deletions or mutations in the survival motor neuron 1 (SMN1) gene. Disease severity varies in part depending on the number of backup SMN2 gene copies that can produce some functional SMN protein (Arnold et al. Muscle Nerve. 2015;51[2]:157).

Recent developments of disease-modifying agents are giving hope to individuals with SMA and their families. Nusinersen (an antisense oligonucleotide) is an intrathecal medication that increases the production of functional SMN protein by increasing SMN2 exon 7 transcription (Chiriboga et al. Neurology. 2016;86[10]:890).

A recent open-label clinical trial by Finkel et al. (Lancet. 2017;388[10063]:3017) showed a “promising clinical response” that altered the natural history of disease progression. Most infants treated with multiple intrathecal doses of nusinersen had incremental improvement in their motor milestones and motor function (P = .008), as well as improved survival and/or avoidance of ventilation (P = .0014).

Moreover, the study found significant uptake of nusinersen by the motor neuron throughout the spinal cord and other neurons throughout the CNS. It appeared to be well tolerated. Disease-modifying medications may soon become “game changers” in many neuromuscular conditions.

However, a significant concern is the expected prohibitive cost both of a rare-disease-modifying therapy and of administrating intrathecal medications to fragile infants. As such, those obstacles will need to be overcome as neuromuscular clinics, hospitals, and payers start planning for the coming advances that our patients will be expecting.

Ahlam Mazi, MBBS

Fellow-in-Training Member

Interstitial and Diffuse Lung Disease

New advancements in predictive risk factors of IPF

In the last few years, many predictive risk factors were studied in clinical trials monitoring idiopathic pulmonary fibrosis (IPF), such as forced vital capacity and diffuse lung capacity for carbon monoxide (King TE Jr, et al. ASCEND Study Group. N Engl J Med. 2014;18;371­[12]:1172; Richeldi L, et al. INPULSIS Trial Investigators. N Engl J Med. 2015;20;373­[8]:782; Ley B, et al. Am J Respir Crit Care Med. 2016;15;194­[6]:711).

Recent data that have not yet been published by Carbone et al evaluate the prognostic value of the New York Heart Association index (NYHA) compared with high resolution CT scan, somatostatin receptor scintigraphy (octreoscan), and echocardiography in a study population of 128 patients suffering from IPF (61% male subjects), nonspecific interstitial pneumonia, and granulomatous lung diseases (alveolitis, sarcoidosis, granulomatosis with polyangiitis). All patients were confirmed histologically.

The NYHA came out as a reliable prognostic factor in each setting. In fact, the log-rank test showed significant differences among NYHA categories, as cases included with disease showed the worst survival rate while no death cases were observed when NYHA was negative.

Moreover, the prognostic value of NYHA was confirmed by multivariate analysis, where the survival rate results were significantly different among patients with level 7 after adjustment for other variables included in the model.

Furthermore, the prognostic value of the NYHA index was once again confirmed when the analysis was limited to cases with the histological pattern of IPF (usual interstitial pneumonia).

The authors, therefore, strongly recommend utilization of the NYHA index as a prognostic factor of IPF as well as granulomatous lung diseases.

Roberto Carbone, MD, FCCP

Steering Committee Member

Clinical Research

The unrecognized battlefield in our hospitals: Lessons from the US Navy SEALs

Burnout syndrome (BOS) is a psychological state resulting from prolonged exposure to job stressors. It is characterized by a vicious cycle of emotional exhaustion, detachment from others, and a feeling of decreased accomplishment. Severe BOS is seen in up to 45% of physicians and 33% of nurses who work in ICUs.¹

BOS has far-reaching consequences, being associated with an alarmingly high prevalence of posttraumatic stress disorder (PTSD) and substance abuse, almost equivalent to that experienced by veterans returning from war.² BOS also is associated with self-reported suboptimal patient care practices.³This crisis has long been underrecognized, but now that we have identified the problem, where does that leave us? There are currently no quality studies evaluating how to best treat and prevent BOS/PTSD in health-care professionals. Previous studies have focused on addressing organizational factors to alleviate job stressors, but the psychosocial characteristics of the individual have been largely ignored.

Our medical education has historically focused on an individual’s intelligence quotient (IQ), but developing an individual’s emotional quotient (EQ) is just as valuable. It has long been known that Navy SEALs have the lowest prevalence of PTSD among combat veterans due partially to their specific training in emotional resilience and adaptive psychosocial coping mechanisms.

For this reason, the research team at the University of Texas Health Science Center at San Antonio is collaborating with the US Navy SEAL team to design and validate a tool that teaches critical care staff resilience training similar to what their combat trainees undergo. The goal is to curb these alarming trends in BOS and create a paradigm shift in medical education within medical and nursing schools.

Bravein Amalakuhan, MD

Fellow-in-Training Member

References

1. Embriaco N, Azoulay E, Barrau K, et al. Am J Respir Crit Care Med. 2007;175(7):686.

2. Mealer ML, Shelton A, Berg B, et al. Am J Respir Crit Care Med. 2007;175(7):693.

3. Shanafelt TD, Bradley KA, Wipf JE, et al. Ann Intern Med. 2002;136(5):358.

Critical Care

End of the era for age of blood concerns?

Blood transfusions are common in critically ill patients, with two in five adults admitted to an ICU receiving a transfusion.^1,2 Recently, randomized trials have found that more restrictive thresholds for transfusions are associated with improved outcomes.^3,4 One theorized explanation for this somewhat counterintuitive association is that the prolonged storage time (i.e., the age of the blood being transfused) might affect outcomes.

There have been three recent publications that help to shed some more light on this. First, Lacroix et al.⁵ performed a multicenter randomized blinded trial in over 2,400 critically ill patients in 64 centers comparing new blood (mean storage (±SD) of 6.1±4.9 days) vs old blood with storage of 22.0±8.4 days (P less than .001). There was no statistically significant difference in 90-day mortality.⁵

The second study is a meta-analysis by Alexander et al.⁶ The investigators looked at 12 trials and 5,229 patients and compared “fresh blood” or blood stored for 3-10 days to “older blood” stored for longer durations. They found that there was no difference in mortality and no difference in adverse events, such as acute transfusion reactions, when comparing the two groups.

Lastly, Heddle et al.⁷ conducted a randomized trial that compared outcomes in 20,858 hospitalized patients transfused with fresh blood (mean storage time 13.0±7.6 days) to older blood (mean storage time 23.6±8.9 days). They found no differences in mortality when comparing those transfused with fresh vs. old blood (8.7% vs. 9.1%). In addition, there was no difference when examining the predetermined subgroups, including those undergoing cardiovascular surgery, those with cancer, and those admitted to the ICU.

So, is this the end of an era for health-care provider concern about how long blood can be stored to be safe for ICU patients? Possibly.

There may still be high-risk populations (such as patients receiving massive transfusions) for which age of the blood does matter. In addition, it is still unclear based on the present data as to whether blood stored between 35 and 42 days has any significant inherent risk.

However, these publications among others suggest that the age of transfused blood may not matter, even in critically ill patients. Therefore, the present storage practices of many blood banks around the United States and beyond are validated by the present publications regarding the scarce resource of blood.

Christopher L. Carroll, MD, MS, FCCP

Steering Committee Member

References

1. Corwin HL, Gettinger A, Pearl RG, et al. Crit Care Med. 2004;32(1):39.

2. Vincent JL, Baron JF, Reinhart K, et al.; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. JAMA. 2002;288(12):1499.

3. Holst LB, Haase N, Wetterslev J, et al.; TRISS Trial Group; Scandinavian Critical Care Trials Group. N Engl J Med. 2014;371(15):1381.

4. Lacroix J, Hebert PC, Hutchison JS, et al.; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network. N Engl J Med. 2007;356(16):1609.

5. Lacroix J, Hebert P, Fergusson DA, et al. N Engl J Med. 2015;372:1410.

6. Alexander PE, Barty R, Fei Y, et al. Blood. 2016;127(4):400.

7. Heddle NM, Cook RJ, Arnold DM, et al. N Engl J Med. 2016;375(2):1937.

Airways Disorders

Inhaled corticosteroids in COPD: When to hold and when to fold

The 2017 GOLD guidelines reiterated that inhaled corticosteroids (ICS) be reserved for COPD patients with continued symptoms and exacerbations, despite use of long-acting beta-agonists (LABAs) and long-acting muscarinic agents (LAMAs). ICS are appropriate in approximately 40% of patients; however, prescribing rates can exceed 80% (Yawn et al. 2016; Primary Care Respir J. 26:16068).

Recent literature has begun to define the appropriate use of ICS in COPD. ICS/LABA combinations improve outcomes in patients with moderate to very severe COPD with frequent exacerbations. However, ICS/LABA may not further diminish exacerbation risk compared with those treated with a LABA/LAMA combination (Wedzicha et al., N Engl J Med. 2016;374:2222).

While the addition of LAMA to an ICS/LABA combination (triple therapy) improved lung function and decreased exacerbation risk, the addition of ICS to LABA/LAMA combination did not decrease exacerbations (GOLD Guidelines 2017). It has been suggested that those with asthma-COPD overlap identified by sputum eosinophilia represent ideal candidates for ICS therapy (GINA Guideline 2016).

ICS use in COPD increases pneumonia risk. The risk was highest in the very group for which guidelines recommend its use – those with a FEV₁ less than 50% of predicted or with prior COPD exacerbation (Ernst et al. Eur Respir J. 2015;45:525).

ICS may be safely withdrawn in low-risk patients (FEV₁ less than 50% predicted and no exacerbations in the previous year [Yawn et al.]).

In a trial comparing patients with severe COPD (FEV₁ less than 50%) on continued LAMA/LABA/ICS triple therapy vs LAMA/LABA with ICS withdrawal, the risk of moderate or severe exacerbations at 52 weeks was not increased (Magnussen et al. N Engl J Med. 2014;371:1285).
 

Conclusions

Based on the 2017 GOLD guidelines:

• Monotherapy with ICS is not recommended in COPD.

• In patients with continued respiratory-related symptoms without exacerbations (GOLD group B), LAMA or LABA or LAMA/LABA combination is recommended. There is no recommendation for ICS in this group.

• In patients with frequent exacerbations (GOLD groups C and D), LAMA/LABA combinations are preferred to LABA/ICS because of superior effectiveness (especially in Group D) and the increased pneumonia risk with ICS. Escalation to triple therapy can be considered if there are continued exacerbations.

Allen Blaivas, DO, FCCP

Steering Committee Member

Home-Based Mechanical Ventilation and Neuromuscular Disease

Advances in neuromuscular disease

Spinal muscular atrophy (SMA) type 1 is the most deadly inherited disease among infants, with most infants dying by 1 to 2 years of age without supportive therapies, such as assisted ventilation. It is caused by homozygous deletions or mutations in the survival motor neuron 1 (SMN1) gene. Disease severity varies in part depending on the number of backup SMN2 gene copies that can produce some functional SMN protein (Arnold et al. Muscle Nerve. 2015;51[2]:157).

Recent developments of disease-modifying agents are giving hope to individuals with SMA and their families. Nusinersen (an antisense oligonucleotide) is an intrathecal medication that increases the production of functional SMN protein by increasing SMN2 exon 7 transcription (Chiriboga et al. Neurology. 2016;86[10]:890).

A recent open-label clinical trial by Finkel et al. (Lancet. 2017;388[10063]:3017) showed a “promising clinical response” that altered the natural history of disease progression. Most infants treated with multiple intrathecal doses of nusinersen had incremental improvement in their motor milestones and motor function (P = .008), as well as improved survival and/or avoidance of ventilation (P = .0014).

Moreover, the study found significant uptake of nusinersen by the motor neuron throughout the spinal cord and other neurons throughout the CNS. It appeared to be well tolerated. Disease-modifying medications may soon become “game changers” in many neuromuscular conditions.

However, a significant concern is the expected prohibitive cost both of a rare-disease-modifying therapy and of administrating intrathecal medications to fragile infants. As such, those obstacles will need to be overcome as neuromuscular clinics, hospitals, and payers start planning for the coming advances that our patients will be expecting.

Ahlam Mazi, MBBS

Fellow-in-Training Member

Interstitial and Diffuse Lung Disease

New advancements in predictive risk factors of IPF

In the last few years, many predictive risk factors were studied in clinical trials monitoring idiopathic pulmonary fibrosis (IPF), such as forced vital capacity and diffuse lung capacity for carbon monoxide (King TE Jr, et al. ASCEND Study Group. N Engl J Med. 2014;18;371­[12]:1172; Richeldi L, et al. INPULSIS Trial Investigators. N Engl J Med. 2015;20;373­[8]:782; Ley B, et al. Am J Respir Crit Care Med. 2016;15;194­[6]:711).

Recent data that have not yet been published by Carbone et al evaluate the prognostic value of the New York Heart Association index (NYHA) compared with high resolution CT scan, somatostatin receptor scintigraphy (octreoscan), and echocardiography in a study population of 128 patients suffering from IPF (61% male subjects), nonspecific interstitial pneumonia, and granulomatous lung diseases (alveolitis, sarcoidosis, granulomatosis with polyangiitis). All patients were confirmed histologically.

The NYHA came out as a reliable prognostic factor in each setting. In fact, the log-rank test showed significant differences among NYHA categories, as cases included with disease showed the worst survival rate while no death cases were observed when NYHA was negative.

Moreover, the prognostic value of NYHA was confirmed by multivariate analysis, where the survival rate results were significantly different among patients with level 7 after adjustment for other variables included in the model.

Furthermore, the prognostic value of the NYHA index was once again confirmed when the analysis was limited to cases with the histological pattern of IPF (usual interstitial pneumonia).

The authors, therefore, strongly recommend utilization of the NYHA index as a prognostic factor of IPF as well as granulomatous lung diseases.

Roberto Carbone, MD, FCCP

Steering Committee Member

Clinical Research

The unrecognized battlefield in our hospitals: Lessons from the US Navy SEALs

Burnout syndrome (BOS) is a psychological state resulting from prolonged exposure to job stressors. It is characterized by a vicious cycle of emotional exhaustion, detachment from others, and a feeling of decreased accomplishment. Severe BOS is seen in up to 45% of physicians and 33% of nurses who work in ICUs.¹

BOS has far-reaching consequences, being associated with an alarmingly high prevalence of posttraumatic stress disorder (PTSD) and substance abuse, almost equivalent to that experienced by veterans returning from war.² BOS also is associated with self-reported suboptimal patient care practices.³This crisis has long been underrecognized, but now that we have identified the problem, where does that leave us? There are currently no quality studies evaluating how to best treat and prevent BOS/PTSD in health-care professionals. Previous studies have focused on addressing organizational factors to alleviate job stressors, but the psychosocial characteristics of the individual have been largely ignored.

Our medical education has historically focused on an individual’s intelligence quotient (IQ), but developing an individual’s emotional quotient (EQ) is just as valuable. It has long been known that Navy SEALs have the lowest prevalence of PTSD among combat veterans due partially to their specific training in emotional resilience and adaptive psychosocial coping mechanisms.

For this reason, the research team at the University of Texas Health Science Center at San Antonio is collaborating with the US Navy SEAL team to design and validate a tool that teaches critical care staff resilience training similar to what their combat trainees undergo. The goal is to curb these alarming trends in BOS and create a paradigm shift in medical education within medical and nursing schools.

Bravein Amalakuhan, MD

Fellow-in-Training Member

References

1. Embriaco N, Azoulay E, Barrau K, et al. Am J Respir Crit Care Med. 2007;175(7):686.

2. Mealer ML, Shelton A, Berg B, et al. Am J Respir Crit Care Med. 2007;175(7):693.

3. Shanafelt TD, Bradley KA, Wipf JE, et al. Ann Intern Med. 2002;136(5):358.

Critical Care

End of the era for age of blood concerns?

Blood transfusions are common in critically ill patients, with two in five adults admitted to an ICU receiving a transfusion.^1,2 Recently, randomized trials have found that more restrictive thresholds for transfusions are associated with improved outcomes.^3,4 One theorized explanation for this somewhat counterintuitive association is that the prolonged storage time (i.e., the age of the blood being transfused) might affect outcomes.

There have been three recent publications that help to shed some more light on this. First, Lacroix et al.⁵ performed a multicenter randomized blinded trial in over 2,400 critically ill patients in 64 centers comparing new blood (mean storage (±SD) of 6.1±4.9 days) vs old blood with storage of 22.0±8.4 days (P less than .001). There was no statistically significant difference in 90-day mortality.⁵

The second study is a meta-analysis by Alexander et al.⁶ The investigators looked at 12 trials and 5,229 patients and compared “fresh blood” or blood stored for 3-10 days to “older blood” stored for longer durations. They found that there was no difference in mortality and no difference in adverse events, such as acute transfusion reactions, when comparing the two groups.

Lastly, Heddle et al.⁷ conducted a randomized trial that compared outcomes in 20,858 hospitalized patients transfused with fresh blood (mean storage time 13.0±7.6 days) to older blood (mean storage time 23.6±8.9 days). They found no differences in mortality when comparing those transfused with fresh vs. old blood (8.7% vs. 9.1%). In addition, there was no difference when examining the predetermined subgroups, including those undergoing cardiovascular surgery, those with cancer, and those admitted to the ICU.

So, is this the end of an era for health-care provider concern about how long blood can be stored to be safe for ICU patients? Possibly.

There may still be high-risk populations (such as patients receiving massive transfusions) for which age of the blood does matter. In addition, it is still unclear based on the present data as to whether blood stored between 35 and 42 days has any significant inherent risk.

However, these publications among others suggest that the age of transfused blood may not matter, even in critically ill patients. Therefore, the present storage practices of many blood banks around the United States and beyond are validated by the present publications regarding the scarce resource of blood.

Christopher L. Carroll, MD, MS, FCCP

Steering Committee Member

References

1. Corwin HL, Gettinger A, Pearl RG, et al. Crit Care Med. 2004;32(1):39.

2. Vincent JL, Baron JF, Reinhart K, et al.; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. JAMA. 2002;288(12):1499.

3. Holst LB, Haase N, Wetterslev J, et al.; TRISS Trial Group; Scandinavian Critical Care Trials Group. N Engl J Med. 2014;371(15):1381.

4. Lacroix J, Hebert PC, Hutchison JS, et al.; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network. N Engl J Med. 2007;356(16):1609.

5. Lacroix J, Hebert P, Fergusson DA, et al. N Engl J Med. 2015;372:1410.

6. Alexander PE, Barty R, Fei Y, et al. Blood. 2016;127(4):400.

7. Heddle NM, Cook RJ, Arnold DM, et al. N Engl J Med. 2016;375(2):1937.

Airways Disorders

Inhaled corticosteroids in COPD: When to hold and when to fold

The 2017 GOLD guidelines reiterated that inhaled corticosteroids (ICS) be reserved for COPD patients with continued symptoms and exacerbations, despite use of long-acting beta-agonists (LABAs) and long-acting muscarinic agents (LAMAs). ICS are appropriate in approximately 40% of patients; however, prescribing rates can exceed 80% (Yawn et al. 2016; Primary Care Respir J. 26:16068).

Recent literature has begun to define the appropriate use of ICS in COPD. ICS/LABA combinations improve outcomes in patients with moderate to very severe COPD with frequent exacerbations. However, ICS/LABA may not further diminish exacerbation risk compared with those treated with a LABA/LAMA combination (Wedzicha et al., N Engl J Med. 2016;374:2222).

While the addition of LAMA to an ICS/LABA combination (triple therapy) improved lung function and decreased exacerbation risk, the addition of ICS to LABA/LAMA combination did not decrease exacerbations (GOLD Guidelines 2017). It has been suggested that those with asthma-COPD overlap identified by sputum eosinophilia represent ideal candidates for ICS therapy (GINA Guideline 2016).

ICS use in COPD increases pneumonia risk. The risk was highest in the very group for which guidelines recommend its use – those with a FEV₁ less than 50% of predicted or with prior COPD exacerbation (Ernst et al. Eur Respir J. 2015;45:525).

ICS may be safely withdrawn in low-risk patients (FEV₁ less than 50% predicted and no exacerbations in the previous year [Yawn et al.]).

In a trial comparing patients with severe COPD (FEV₁ less than 50%) on continued LAMA/LABA/ICS triple therapy vs LAMA/LABA with ICS withdrawal, the risk of moderate or severe exacerbations at 52 weeks was not increased (Magnussen et al. N Engl J Med. 2014;371:1285).
 

Conclusions

Based on the 2017 GOLD guidelines:

• Monotherapy with ICS is not recommended in COPD.

• In patients with continued respiratory-related symptoms without exacerbations (GOLD group B), LAMA or LABA or LAMA/LABA combination is recommended. There is no recommendation for ICS in this group.

• In patients with frequent exacerbations (GOLD groups C and D), LAMA/LABA combinations are preferred to LABA/ICS because of superior effectiveness (especially in Group D) and the increased pneumonia risk with ICS. Escalation to triple therapy can be considered if there are continued exacerbations.

Allen Blaivas, DO, FCCP

Steering Committee Member

Home-Based Mechanical Ventilation and Neuromuscular Disease

Advances in neuromuscular disease

Spinal muscular atrophy (SMA) type 1 is the most deadly inherited disease among infants, with most infants dying by 1 to 2 years of age without supportive therapies, such as assisted ventilation. It is caused by homozygous deletions or mutations in the survival motor neuron 1 (SMN1) gene. Disease severity varies in part depending on the number of backup SMN2 gene copies that can produce some functional SMN protein (Arnold et al. Muscle Nerve. 2015;51[2]:157).

Recent developments of disease-modifying agents are giving hope to individuals with SMA and their families. Nusinersen (an antisense oligonucleotide) is an intrathecal medication that increases the production of functional SMN protein by increasing SMN2 exon 7 transcription (Chiriboga et al. Neurology. 2016;86[10]:890).

A recent open-label clinical trial by Finkel et al. (Lancet. 2017;388[10063]:3017) showed a “promising clinical response” that altered the natural history of disease progression. Most infants treated with multiple intrathecal doses of nusinersen had incremental improvement in their motor milestones and motor function (P = .008), as well as improved survival and/or avoidance of ventilation (P = .0014).

Moreover, the study found significant uptake of nusinersen by the motor neuron throughout the spinal cord and other neurons throughout the CNS. It appeared to be well tolerated. Disease-modifying medications may soon become “game changers” in many neuromuscular conditions.

However, a significant concern is the expected prohibitive cost both of a rare-disease-modifying therapy and of administrating intrathecal medications to fragile infants. As such, those obstacles will need to be overcome as neuromuscular clinics, hospitals, and payers start planning for the coming advances that our patients will be expecting.

Ahlam Mazi, MBBS

Fellow-in-Training Member

Interstitial and Diffuse Lung Disease

New advancements in predictive risk factors of IPF

In the last few years, many predictive risk factors were studied in clinical trials monitoring idiopathic pulmonary fibrosis (IPF), such as forced vital capacity and diffuse lung capacity for carbon monoxide (King TE Jr, et al. ASCEND Study Group. N Engl J Med. 2014;18;371­[12]:1172; Richeldi L, et al. INPULSIS Trial Investigators. N Engl J Med. 2015;20;373­[8]:782; Ley B, et al. Am J Respir Crit Care Med. 2016;15;194­[6]:711).

Recent data that have not yet been published by Carbone et al evaluate the prognostic value of the New York Heart Association index (NYHA) compared with high resolution CT scan, somatostatin receptor scintigraphy (octreoscan), and echocardiography in a study population of 128 patients suffering from IPF (61% male subjects), nonspecific interstitial pneumonia, and granulomatous lung diseases (alveolitis, sarcoidosis, granulomatosis with polyangiitis). All patients were confirmed histologically.

The NYHA came out as a reliable prognostic factor in each setting. In fact, the log-rank test showed significant differences among NYHA categories, as cases included with disease showed the worst survival rate while no death cases were observed when NYHA was negative.

Moreover, the prognostic value of NYHA was confirmed by multivariate analysis, where the survival rate results were significantly different among patients with level 7 after adjustment for other variables included in the model.

Furthermore, the prognostic value of the NYHA index was once again confirmed when the analysis was limited to cases with the histological pattern of IPF (usual interstitial pneumonia).

The authors, therefore, strongly recommend utilization of the NYHA index as a prognostic factor of IPF as well as granulomatous lung diseases.

Roberto Carbone, MD, FCCP

Steering Committee Member

The global burden of COPD is increasing and is one of the leading causes of disability worldwide. Attend COPD: Current Excellence and Future Development and join clinicians, experts, and specialists as they convene in Amsterdam to discuss best practices and future directions in diagnosis, treatment, and therapeutic innovations. Plan to discuss the latest cutting-edge findings in COPD with like-minded clinicians.

The conference, taking place at the NH Grand Hotel Krasnapolsky, in the center of Amsterdam, will include these session themes:

• History and burden of COPD.
• Polymorbidity in COPD.
• Infections and exacerbations in COPD.
• Current treatment of COPD.
• The future of COPD.

Don’t Miss These Speakers

• Dirkje Postma (Keynote speaker) – Professor of Pulmonary Medicine at the University of Groningen and the University Medical Center of Groningen. Professor Postma will give a keynote session “From Past to Present, Circle With COPD.”
• David M. Mannino (Conference chair) – Professor and Chair in the Department of Preventive Medicine and Environmental Health at the University of Kentucky (Lexington) College of Public Health. Dr. Mannino’s session topic is “The Natural History of COPD.”
• John Hurst, (Co-chair and speaker) – Senior Lecturer at University College, London, UK, Dr. Hurst’s session topic is “The Importance of Acute Exacerbations.”
• Alberto Papi (Co-chair and speaker) – Professor of Respiratory Medicine and Vice President of the School of Medicine at the University of Ferrara, Italy, and Director of the Respiratory Unit of the Department of Emergency Medicine, S. Anna University Hospital, Ferrara. Professor Papi’s talk will explore “The Role of Infections.”
• Peter J. Barnes (Conference speaker) – Margaret-Turner Warwick Professor of Medicine at the National Heart and Lung Institute, Head of Respiratory Medicine at Imperial College and Honorary Consultant Physician at Royal Brompton Hospital, London. Professor Barnes’ presentation will focus on “Future Novel Therapies.”
• Sally Singh (Conference speaker) - Professor of Pulmonary and Cardiac Rehabilitation at the University Hospitals of Leicester (one of the largest rehabilitation programs in the UK). Professor Singh’s session is on “Pulmonary Rehabilitation.”
• Nicholas Hopkinson (Conference speaker) – Dr. Hopkinson is a Reader in Respiratory Medicine & Honorary Consultant Physician at the National Heart and Lung Institute of Imperial College and the Royal Brompton Hospital. His session focuses on “Cigarette Smoking.”
• Joan Soriano (Conference speaker) - Since 2007, Dr. Soriano has been an Associate Editor of the European Respiratory Journal and since 2013 of the Lancet Respiratory Medicine. His session focuses on “Asthma-COPD Overlap.”

Learn more about what the conference has to offer and how to register at chestcopdconference.com.

The global burden of COPD is increasing and is one of the leading causes of disability worldwide. Attend COPD: Current Excellence and Future Development and join clinicians, experts, and specialists as they convene in Amsterdam to discuss best practices and future directions in diagnosis, treatment, and therapeutic innovations. Plan to discuss the latest cutting-edge findings in COPD with like-minded clinicians.

The conference, taking place at the NH Grand Hotel Krasnapolsky, in the center of Amsterdam, will include these session themes:

• History and burden of COPD.
• Polymorbidity in COPD.
• Infections and exacerbations in COPD.
• Current treatment of COPD.
• The future of COPD.

Don’t Miss These Speakers

• Dirkje Postma (Keynote speaker) – Professor of Pulmonary Medicine at the University of Groningen and the University Medical Center of Groningen. Professor Postma will give a keynote session “From Past to Present, Circle With COPD.”
• David M. Mannino (Conference chair) – Professor and Chair in the Department of Preventive Medicine and Environmental Health at the University of Kentucky (Lexington) College of Public Health. Dr. Mannino’s session topic is “The Natural History of COPD.”
• John Hurst, (Co-chair and speaker) – Senior Lecturer at University College, London, UK, Dr. Hurst’s session topic is “The Importance of Acute Exacerbations.”
• Alberto Papi (Co-chair and speaker) – Professor of Respiratory Medicine and Vice President of the School of Medicine at the University of Ferrara, Italy, and Director of the Respiratory Unit of the Department of Emergency Medicine, S. Anna University Hospital, Ferrara. Professor Papi’s talk will explore “The Role of Infections.”
• Peter J. Barnes (Conference speaker) – Margaret-Turner Warwick Professor of Medicine at the National Heart and Lung Institute, Head of Respiratory Medicine at Imperial College and Honorary Consultant Physician at Royal Brompton Hospital, London. Professor Barnes’ presentation will focus on “Future Novel Therapies.”
• Sally Singh (Conference speaker) - Professor of Pulmonary and Cardiac Rehabilitation at the University Hospitals of Leicester (one of the largest rehabilitation programs in the UK). Professor Singh’s session is on “Pulmonary Rehabilitation.”
• Nicholas Hopkinson (Conference speaker) – Dr. Hopkinson is a Reader in Respiratory Medicine & Honorary Consultant Physician at the National Heart and Lung Institute of Imperial College and the Royal Brompton Hospital. His session focuses on “Cigarette Smoking.”
• Joan Soriano (Conference speaker) - Since 2007, Dr. Soriano has been an Associate Editor of the European Respiratory Journal and since 2013 of the Lancet Respiratory Medicine. His session focuses on “Asthma-COPD Overlap.”

Learn more about what the conference has to offer and how to register at chestcopdconference.com.

The global burden of COPD is increasing and is one of the leading causes of disability worldwide. Attend COPD: Current Excellence and Future Development and join clinicians, experts, and specialists as they convene in Amsterdam to discuss best practices and future directions in diagnosis, treatment, and therapeutic innovations. Plan to discuss the latest cutting-edge findings in COPD with like-minded clinicians.

The conference, taking place at the NH Grand Hotel Krasnapolsky, in the center of Amsterdam, will include these session themes:

• History and burden of COPD.
• Polymorbidity in COPD.
• Infections and exacerbations in COPD.
• Current treatment of COPD.
• The future of COPD.

Don’t Miss These Speakers

• Dirkje Postma (Keynote speaker) – Professor of Pulmonary Medicine at the University of Groningen and the University Medical Center of Groningen. Professor Postma will give a keynote session “From Past to Present, Circle With COPD.”
• David M. Mannino (Conference chair) – Professor and Chair in the Department of Preventive Medicine and Environmental Health at the University of Kentucky (Lexington) College of Public Health. Dr. Mannino’s session topic is “The Natural History of COPD.”
• John Hurst, (Co-chair and speaker) – Senior Lecturer at University College, London, UK, Dr. Hurst’s session topic is “The Importance of Acute Exacerbations.”
• Alberto Papi (Co-chair and speaker) – Professor of Respiratory Medicine and Vice President of the School of Medicine at the University of Ferrara, Italy, and Director of the Respiratory Unit of the Department of Emergency Medicine, S. Anna University Hospital, Ferrara. Professor Papi’s talk will explore “The Role of Infections.”
• Peter J. Barnes (Conference speaker) – Margaret-Turner Warwick Professor of Medicine at the National Heart and Lung Institute, Head of Respiratory Medicine at Imperial College and Honorary Consultant Physician at Royal Brompton Hospital, London. Professor Barnes’ presentation will focus on “Future Novel Therapies.”
• Sally Singh (Conference speaker) - Professor of Pulmonary and Cardiac Rehabilitation at the University Hospitals of Leicester (one of the largest rehabilitation programs in the UK). Professor Singh’s session is on “Pulmonary Rehabilitation.”
• Nicholas Hopkinson (Conference speaker) – Dr. Hopkinson is a Reader in Respiratory Medicine & Honorary Consultant Physician at the National Heart and Lung Institute of Imperial College and the Royal Brompton Hospital. His session focuses on “Cigarette Smoking.”
• Joan Soriano (Conference speaker) - Since 2007, Dr. Soriano has been an Associate Editor of the European Respiratory Journal and since 2013 of the Lancet Respiratory Medicine. His session focuses on “Asthma-COPD Overlap.”

Learn more about what the conference has to offer and how to register at chestcopdconference.com.

On Dec. 23, 2016, the Chinese National Health and Family Planning Commission officially endorsed Pulmonary and Critical Care Medicine (PCCM) as a pilot subspecialty within China. PCCM is one of three subspecialties (together with neurosurgery and cardiology) to pioneer fellowship training education in China. With the official endorsement of PCCM, local efforts will progress within China to administer programs and extend the standards of training throughout medical education in China. PCCM certification will now become a requirement for appointment of pulmonary department chairs and for promotion within the subspecialty.

Since 2012, CHEST has worked closely with partners, such as the Chinese Thoracic Society, the Chinese Association of Chest Physicians, and the Chinese Medical Doctor Association, on the development of China’s first fellowship program offering standardized training in PCCM for Chinese physicians. As a result of these collective efforts, PCCM has now officially earned endorsement as a medical subspecialty – the first of its kind in a country where medical training typically ends after a physician completes residency training. Only a decade ago, physicians in China went directly into practice following medical school. The development of a PCCM subspecialty in China – made possible through the engagement of CHEST’s expert faculty and administration – parallels what has occurred over the past 3 decades in the United States, during which the fields of pulmonary and critical care medicine evolved into the combined subspecialty of PCCM.

The China-CHEST PCCM Fellowship Program was officially launched in 2013 with 12 participating Chinese institutions starting their PCCM training programs. By the end of 2017, 30 programs with 300 fellows and 60 faculty will be participating at institutions throughout China, with the potential to impact the care of thousands of patients. The China-PCCM Fellowship Program proudly graduated its first class of fellows in September 2016.

China-CHEST leaders, including Renli Qiao, MD, PhD, FCCP; Chen Wang, MD, PhD, FCCP; and Jack Buckley, MD, MPH, FCCP; with Steve Welch, CHEST Executive Vice President, recently participated in local site visits to provide ongoing education and support to Chinese PCCM fellowship programs. They also participated in the November 2016 Mingdao Forum in Beijing to highlight the history and achievements of the China-CHEST PCCM program.

The vast reach and clinical exposure of this program highlights how an international professional medical association like CHEST, through innovative education and strategic collaborative partnerships, is able to impact medical training both within and beyond its specialty on a global scale.

Darcy Marciniuk, MD, FCCP
Chair, China–CHEST PCCM Steering Committee
Professor of Medicine, University of Saskatchewan,
Saskatoon, SK, Canada

Renli Qiao, MD, PhD, FCCP
Medical Director, China–CHEST PCCM Program
Professor of Clinical Medicine,
Keck School of Medicine of USC,
Los Angeles, California

Robb Rabito, CHCP
Director, Education Operations CHEST
Glenview, Illinois

On Dec. 23, 2016, the Chinese National Health and Family Planning Commission officially endorsed Pulmonary and Critical Care Medicine (PCCM) as a pilot subspecialty within China. PCCM is one of three subspecialties (together with neurosurgery and cardiology) to pioneer fellowship training education in China. With the official endorsement of PCCM, local efforts will progress within China to administer programs and extend the standards of training throughout medical education in China. PCCM certification will now become a requirement for appointment of pulmonary department chairs and for promotion within the subspecialty.

Since 2012, CHEST has worked closely with partners, such as the Chinese Thoracic Society, the Chinese Association of Chest Physicians, and the Chinese Medical Doctor Association, on the development of China’s first fellowship program offering standardized training in PCCM for Chinese physicians. As a result of these collective efforts, PCCM has now officially earned endorsement as a medical subspecialty – the first of its kind in a country where medical training typically ends after a physician completes residency training. Only a decade ago, physicians in China went directly into practice following medical school. The development of a PCCM subspecialty in China – made possible through the engagement of CHEST’s expert faculty and administration – parallels what has occurred over the past 3 decades in the United States, during which the fields of pulmonary and critical care medicine evolved into the combined subspecialty of PCCM.

The China-CHEST PCCM Fellowship Program was officially launched in 2013 with 12 participating Chinese institutions starting their PCCM training programs. By the end of 2017, 30 programs with 300 fellows and 60 faculty will be participating at institutions throughout China, with the potential to impact the care of thousands of patients. The China-PCCM Fellowship Program proudly graduated its first class of fellows in September 2016.

China-CHEST leaders, including Renli Qiao, MD, PhD, FCCP; Chen Wang, MD, PhD, FCCP; and Jack Buckley, MD, MPH, FCCP; with Steve Welch, CHEST Executive Vice President, recently participated in local site visits to provide ongoing education and support to Chinese PCCM fellowship programs. They also participated in the November 2016 Mingdao Forum in Beijing to highlight the history and achievements of the China-CHEST PCCM program.

The vast reach and clinical exposure of this program highlights how an international professional medical association like CHEST, through innovative education and strategic collaborative partnerships, is able to impact medical training both within and beyond its specialty on a global scale.

Darcy Marciniuk, MD, FCCP
Chair, China–CHEST PCCM Steering Committee
Professor of Medicine, University of Saskatchewan,
Saskatoon, SK, Canada

Renli Qiao, MD, PhD, FCCP
Medical Director, China–CHEST PCCM Program
Professor of Clinical Medicine,
Keck School of Medicine of USC,
Los Angeles, California

Robb Rabito, CHCP
Director, Education Operations CHEST
Glenview, Illinois

On Dec. 23, 2016, the Chinese National Health and Family Planning Commission officially endorsed Pulmonary and Critical Care Medicine (PCCM) as a pilot subspecialty within China. PCCM is one of three subspecialties (together with neurosurgery and cardiology) to pioneer fellowship training education in China. With the official endorsement of PCCM, local efforts will progress within China to administer programs and extend the standards of training throughout medical education in China. PCCM certification will now become a requirement for appointment of pulmonary department chairs and for promotion within the subspecialty.

Since 2012, CHEST has worked closely with partners, such as the Chinese Thoracic Society, the Chinese Association of Chest Physicians, and the Chinese Medical Doctor Association, on the development of China’s first fellowship program offering standardized training in PCCM for Chinese physicians. As a result of these collective efforts, PCCM has now officially earned endorsement as a medical subspecialty – the first of its kind in a country where medical training typically ends after a physician completes residency training. Only a decade ago, physicians in China went directly into practice following medical school. The development of a PCCM subspecialty in China – made possible through the engagement of CHEST’s expert faculty and administration – parallels what has occurred over the past 3 decades in the United States, during which the fields of pulmonary and critical care medicine evolved into the combined subspecialty of PCCM.

The China-CHEST PCCM Fellowship Program was officially launched in 2013 with 12 participating Chinese institutions starting their PCCM training programs. By the end of 2017, 30 programs with 300 fellows and 60 faculty will be participating at institutions throughout China, with the potential to impact the care of thousands of patients. The China-PCCM Fellowship Program proudly graduated its first class of fellows in September 2016.

China-CHEST leaders, including Renli Qiao, MD, PhD, FCCP; Chen Wang, MD, PhD, FCCP; and Jack Buckley, MD, MPH, FCCP; with Steve Welch, CHEST Executive Vice President, recently participated in local site visits to provide ongoing education and support to Chinese PCCM fellowship programs. They also participated in the November 2016 Mingdao Forum in Beijing to highlight the history and achievements of the China-CHEST PCCM program.

The vast reach and clinical exposure of this program highlights how an international professional medical association like CHEST, through innovative education and strategic collaborative partnerships, is able to impact medical training both within and beyond its specialty on a global scale.

Darcy Marciniuk, MD, FCCP
Chair, China–CHEST PCCM Steering Committee
Professor of Medicine, University of Saskatchewan,
Saskatoon, SK, Canada

Renli Qiao, MD, PhD, FCCP
Medical Director, China–CHEST PCCM Program
Professor of Clinical Medicine,
Keck School of Medicine of USC,
Los Angeles, California

Robb Rabito, CHCP
Director, Education Operations CHEST
Glenview, Illinois

Overutilization of tests, treatments, and procedures is an important example of low-value care that adds to the high cost of health care and provides little to no benefit for patients. To combat this problem, the American Board of Internal Medicine Foundation developed the Choosing Wisely Campaign, tasking professional societies to develop lists of the top five medical services that patients should question.

The Critical Care Societies Collaborative (CCSC), which comprises the four major U.S. professional and scientific societies – the American Association of Critical-Care Nurses, the American College of Chest Physicians, the American Thoracic Society, and the Society of Critical Care Medicine – participated by creating a task force that addressed this task to focus on critical care delivery.

Five CCSC recommendations were formulated:

1. Don’t order diagnostic tests at regular intervals (such as every day), but rather in response to specific clinical questions.

2. Don’t transfuse red blood cells in hemodynamically stable, nonbleeding patients with a hemoglobin concentration greater than 7 mg/dL.

3. Don’t use parenteral nutrition in adequately nourished critically ill patients within the first 7 days of an ICU stay.

4. Don’t deeply sedate mechanically ventilated patients without a specific indication and without daily attempts to lighten sedation.

5. Don’t continue life support for patients at high risk for death or severely impaired functional recovery without offering patients and their families the alternative of care focused entirely on comfort.

The CCSC is tracking use/implementation of the Choosing Wisely recommendations among its four member organizations. Please complete this short survey at https://redcap.rush.edu/redcap/surveys/?s. Please click submit when finished.

Overutilization of tests, treatments, and procedures is an important example of low-value care that adds to the high cost of health care and provides little to no benefit for patients. To combat this problem, the American Board of Internal Medicine Foundation developed the Choosing Wisely Campaign, tasking professional societies to develop lists of the top five medical services that patients should question.

The Critical Care Societies Collaborative (CCSC), which comprises the four major U.S. professional and scientific societies – the American Association of Critical-Care Nurses, the American College of Chest Physicians, the American Thoracic Society, and the Society of Critical Care Medicine – participated by creating a task force that addressed this task to focus on critical care delivery.

Five CCSC recommendations were formulated:

1. Don’t order diagnostic tests at regular intervals (such as every day), but rather in response to specific clinical questions.

2. Don’t transfuse red blood cells in hemodynamically stable, nonbleeding patients with a hemoglobin concentration greater than 7 mg/dL.

3. Don’t use parenteral nutrition in adequately nourished critically ill patients within the first 7 days of an ICU stay.

4. Don’t deeply sedate mechanically ventilated patients without a specific indication and without daily attempts to lighten sedation.

5. Don’t continue life support for patients at high risk for death or severely impaired functional recovery without offering patients and their families the alternative of care focused entirely on comfort.

The CCSC is tracking use/implementation of the Choosing Wisely recommendations among its four member organizations. Please complete this short survey at https://redcap.rush.edu/redcap/surveys/?s. Please click submit when finished.

Overutilization of tests, treatments, and procedures is an important example of low-value care that adds to the high cost of health care and provides little to no benefit for patients. To combat this problem, the American Board of Internal Medicine Foundation developed the Choosing Wisely Campaign, tasking professional societies to develop lists of the top five medical services that patients should question.

The Critical Care Societies Collaborative (CCSC), which comprises the four major U.S. professional and scientific societies – the American Association of Critical-Care Nurses, the American College of Chest Physicians, the American Thoracic Society, and the Society of Critical Care Medicine – participated by creating a task force that addressed this task to focus on critical care delivery.

Five CCSC recommendations were formulated:

1. Don’t order diagnostic tests at regular intervals (such as every day), but rather in response to specific clinical questions.

2. Don’t transfuse red blood cells in hemodynamically stable, nonbleeding patients with a hemoglobin concentration greater than 7 mg/dL.

3. Don’t use parenteral nutrition in adequately nourished critically ill patients within the first 7 days of an ICU stay.

4. Don’t deeply sedate mechanically ventilated patients without a specific indication and without daily attempts to lighten sedation.

5. Don’t continue life support for patients at high risk for death or severely impaired functional recovery without offering patients and their families the alternative of care focused entirely on comfort.

The CCSC is tracking use/implementation of the Choosing Wisely recommendations among its four member organizations. Please complete this short survey at https://redcap.rush.edu/redcap/surveys/?s. Please click submit when finished.

Every year, the CHEST Foundation awards more than a half-million dollars in grants to the next generation of lung health champions. February 2017 marks the start of the foundation’s next grant cycle, and we are excited to announce a new clinical research grant in Cystic Fibrosis, among many other disease-state topics. In 2016, the foundation awarded 11 CHEST members for their innovative and inspiring research proposals and community service programs.

“I am very proud to have been awarded a CHEST Foundation grant and pleased that clinical research and real-world evidence are a priority to the foundation,” stated Alice Turner, MBChB, PhD. Dr. Turner was awarded the 2016 CHEST Foundation and the Alpha-1 Foundation Clinical Research Grant in Alpha-1 Antitrypsin Deficiency. “This award means that my patients can now see publicly the efforts that are being made to reduce inequities in care and ensure that the best treatments are made available in the UK.”

Every year, the CHEST Foundation awards more than a half-million dollars in grants to the next generation of lung health champions. February 2017 marks the start of the foundation’s next grant cycle, and we are excited to announce a new clinical research grant in Cystic Fibrosis, among many other disease-state topics. In 2016, the foundation awarded 11 CHEST members for their innovative and inspiring research proposals and community service programs.

“I am very proud to have been awarded a CHEST Foundation grant and pleased that clinical research and real-world evidence are a priority to the foundation,” stated Alice Turner, MBChB, PhD. Dr. Turner was awarded the 2016 CHEST Foundation and the Alpha-1 Foundation Clinical Research Grant in Alpha-1 Antitrypsin Deficiency. “This award means that my patients can now see publicly the efforts that are being made to reduce inequities in care and ensure that the best treatments are made available in the UK.”

Every year, the CHEST Foundation awards more than a half-million dollars in grants to the next generation of lung health champions. February 2017 marks the start of the foundation’s next grant cycle, and we are excited to announce a new clinical research grant in Cystic Fibrosis, among many other disease-state topics. In 2016, the foundation awarded 11 CHEST members for their innovative and inspiring research proposals and community service programs.

“I am very proud to have been awarded a CHEST Foundation grant and pleased that clinical research and real-world evidence are a priority to the foundation,” stated Alice Turner, MBChB, PhD. Dr. Turner was awarded the 2016 CHEST Foundation and the Alpha-1 Foundation Clinical Research Grant in Alpha-1 Antitrypsin Deficiency. “This award means that my patients can now see publicly the efforts that are being made to reduce inequities in care and ensure that the best treatments are made available in the UK.”

Editorial

GOLD 2017: A New Report
By Dr. P. J. Barnes

Original Research

Long-term Outcomes of Patients With Ground-Glass Opacities Detected Using CT Scanning. By Dr. S. Sawada, et al.

ICU Telemedicine Program Financial Outcomes. By Dr. C. M. Lilly et al.

Accuracy of Lung Ultrasonography in the Diagnosis of Pneumonia in Adults: Systematic Review and Meta-Analysis. By Dr. A. M. Llamas-Álvarez, et al.

Evidence-based Medicine

Cough in the Athlete: CHEST Guideline and Expert Panel Report. By Dr. L-P Boulet, et al, on behalf of the CHEST Expert Cough Panel.

Editorial

GOLD 2017: A New Report
By Dr. P. J. Barnes

Original Research

Long-term Outcomes of Patients With Ground-Glass Opacities Detected Using CT Scanning. By Dr. S. Sawada, et al.

ICU Telemedicine Program Financial Outcomes. By Dr. C. M. Lilly et al.

Accuracy of Lung Ultrasonography in the Diagnosis of Pneumonia in Adults: Systematic Review and Meta-Analysis. By Dr. A. M. Llamas-Álvarez, et al.

Evidence-based Medicine

Cough in the Athlete: CHEST Guideline and Expert Panel Report. By Dr. L-P Boulet, et al, on behalf of the CHEST Expert Cough Panel.

Editorial

GOLD 2017: A New Report
By Dr. P. J. Barnes

Original Research

Long-term Outcomes of Patients With Ground-Glass Opacities Detected Using CT Scanning. By Dr. S. Sawada, et al.

ICU Telemedicine Program Financial Outcomes. By Dr. C. M. Lilly et al.

Accuracy of Lung Ultrasonography in the Diagnosis of Pneumonia in Adults: Systematic Review and Meta-Analysis. By Dr. A. M. Llamas-Álvarez, et al.

Evidence-based Medicine

Cough in the Athlete: CHEST Guideline and Expert Panel Report. By Dr. L-P Boulet, et al, on behalf of the CHEST Expert Cough Panel.

Clayton T. Cowl, MD, FCCP, is the CHEST President-Designate and sits as a member of the Board of Regents. Dr. Cowl’s presidential term will be 2018-2019. He currently is the Chair of the Division of Preventive, Occupational, and Aerospace Medicine with a joint appointment in the Division of Pulmonary and Critical Care Medicine at Mayo Clinic in Rochester, Minnesota.

Dr. Cowl is triple board-certified in Pulmonary and Critical Care Medicine, Occupational Medicine, and Internal Medicine, with an interest in airway disorders, occupational-related respiratory health, toxicology, altitude physiology, and transportation medicine.

His research focus has included projects in altitude physiology at Mayo Clinic’s altitude chamber and testing for the emergency oxygen passenger mask in the Boeing 787 airliner. He has also published in the areas of occupational asthma and toxic inhalations.

Clayton T. Cowl, MD, FCCP, is the CHEST President-Designate and sits as a member of the Board of Regents. Dr. Cowl’s presidential term will be 2018-2019. He currently is the Chair of the Division of Preventive, Occupational, and Aerospace Medicine with a joint appointment in the Division of Pulmonary and Critical Care Medicine at Mayo Clinic in Rochester, Minnesota.

Dr. Cowl is triple board-certified in Pulmonary and Critical Care Medicine, Occupational Medicine, and Internal Medicine, with an interest in airway disorders, occupational-related respiratory health, toxicology, altitude physiology, and transportation medicine.

His research focus has included projects in altitude physiology at Mayo Clinic’s altitude chamber and testing for the emergency oxygen passenger mask in the Boeing 787 airliner. He has also published in the areas of occupational asthma and toxic inhalations.

Clayton T. Cowl, MD, FCCP, is the CHEST President-Designate and sits as a member of the Board of Regents. Dr. Cowl’s presidential term will be 2018-2019. He currently is the Chair of the Division of Preventive, Occupational, and Aerospace Medicine with a joint appointment in the Division of Pulmonary and Critical Care Medicine at Mayo Clinic in Rochester, Minnesota.

Dr. Cowl is triple board-certified in Pulmonary and Critical Care Medicine, Occupational Medicine, and Internal Medicine, with an interest in airway disorders, occupational-related respiratory health, toxicology, altitude physiology, and transportation medicine.

His research focus has included projects in altitude physiology at Mayo Clinic’s altitude chamber and testing for the emergency oxygen passenger mask in the Boeing 787 airliner. He has also published in the areas of occupational asthma and toxic inhalations.

Civil rights for the lesbian, gay, bisexual, and transgender population have advanced markedly in the past decade, and the medical community has gradually begun to address more of their health concerns. More recently, media attention to transgender individuals has encouraged many more to openly seek care.^1,2

It is estimated that anywhere from 0.3% to 5% of the US population identifies as transgender.^1-3 While awareness of this population has slowly increased, there is a paucity of research on the hormone treatment that is often essential to patients’ well-being. Studies of surgical options for transgender patients have been minimal, as well.

Primary care providers are uniquely positioned to coordinate medical services and ensure continuity of care for transgender patients as they strive to become their authentic selves. Our goal in writing this article is to equip you with the tools to provide this patient population with sensitive, high-quality care (see Table 1).^4-7 Our focus is on the diagnosis of gender dysphoria (GD) and its medical and hormonal management—the realm of primary care providers. We briefly discuss surgical management of GD, as well.

UNDERSTANDING AND DIAGNOSING GENDER DYSPHORIA

Two classification systems are used for diagnoses related to GD: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Ed (DSM-5)⁸ and the International Classification of Diseases, 10th Rev (ICD-10).⁹

ICD-10 criteria use the term gender identity disorder; DSM-5 refers to gender dysphoria instead. It is important to emphasize that these classification systems represent an attempt to categorize a group of signs and symptoms that lead to distress for the patient and are not meant to suggest that being transgender is pathological. In fact, in DSM-5—released in 2013—the American Psychiatric Association revised the terminology to emphasize that such individuals are not “disordered” by the nature of their identity, but rather by the distress that being transgender causes.⁸

For a diagnosis of GD in children, DSM-5 criteria include characteristics perceived to be incongruent between the child’s sex at birth and the self-identified gender based on preferred activities or dislike of his or her own sexual anatomy. The child must meet six or more of the following for at least six months

• A repeatedly stated desire to be, or insistence that he or she is, of the other gender
• In boys, a preference for cross-dressing or simulating female attire; in girls, insistence on wearing only stereotypical masculine clothing
• Strong and persistent preferences for cross-gender roles in make-believe play or fantasy
• A strong rejection of toys/games typically associated with the child’s sex
• Intense desire to participate in stereotypical games and pastimes of the other gender
• Strong preference for playmates of the other gender
• A strong dislike of one’s sexual anatomy
• A strong desire for the primary (eg, penis or vagina) or secondary (eg, menstruation) sex characteristics of the other gender.⁸

Adolescents and adults must meet two or more of the following for at least six months

• A noticeable incongruence between the gender that the patient sees themselves as and their sex characteristics
• An intense need to do away with (or prevent) his or her primary or secondary sex features
• An intense desire to have the primary and/or secondary sex features of the other gender
• A deep desire to transform into another gender
• A profound need for society to treat them as someone of the other gender
• A powerful assurance of having the characteristic feelings and responses of the other gender.⁸

For children as well as adolescents and adults, the condition should cause the patient significant distress or significantly affect him or her socially, at work or school, and in other important areas of life.⁸

Is the patient a candidate for hormone therapy?

Two primary sources—Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7, issued by the World Professional Association for Transgender Health (WPATH)¹⁰ and Endocrine Treatment of Transsexual Persons¹¹ by the Endocrine Society—offer clinical practice guidance based on evidence and expert opinion.

WPATH recommends that a mental health professional (MHP) experienced in transgender care diagnose GD to ensure that it is not mistaken for a psychiatric condition manifesting as altered gender identity. However, if no one with such experience is available or accessible in the region, it is reasonable for a primary care provider to make the diagnosis and consider initiating hormone therapy without a mental health referral,¹² as the expected benefits outweigh the risks of nontreatment.¹³

Whether or not an MHP confirms a diagnosis of GD, it is still up to the treating provider to confirm the patient’s eligibility and readiness for hormone therapy: He or she should meet DSM-5 or ICD-10 criteria for GD, have no psychiatric comorbidity (eg, schizophrenia, body dysmorphic disorder, or uncontrolled bipolar disorder) likely to interfere with treatment, understand the expected outcomes and the social benefits and risks, and have indicated a willingness to take the hormones responsibly.

Historically, patients were required to have a documented real-life experience, defined as having fully adopted the new gender role in everyday life for at least three months.^10,11 This model has fallen out of favor, however, as it is unsupported by evidence and may place transgender individuals at physical and emotional risk. Instead, readiness is confirmed by obtaining informed consent.¹²

Puberty may be suppressed with a gonadotropin-releasing hormone (GnRH) agonist in adolescents who have a GD diagnosis and are at Tanner stage 2 to 3 of puberty until age 16. At that point, hormone therapy consistent with their gender identification may be initiated (see “How to Help Transgender Teens”).¹¹

Beginning the transition

The transitioning process is a complex and individualized journey that can include inward or outward change, or both.

For patients interested in medical interventions, possible therapies include cross-sex hormone administration and gender-affirming surgery. Both are aimed at making the physical and the psychologic more congruent. Hormone treatment (see Table 2) is often essential to reduce the distress of individuals with GD and to help them feel comfortable in their own body.^10,11,21 Psychologic conditions, such as depression, tend to improve as the transitioning process gets underway.²²

FEMALE-TO-MALE TRANSITION

CASE 1 Jennie R, a 55-year-old postmenopausal patient, comes to your office for an annual exam. Although you’ve been her primary care provider for several years, she confides for the first time that she has never been comfortable as a woman. “I’ve always felt that my body didn’t belong to me,” the patient admits, and goes on to say that for the past several years she has been living as a man. Jennie R says she is ready to start hormone therapy to assist with the gender transition and asks about the process, the benefits and risks, and how quickly she can expect to achieve the desired results.

If Jennie R were your patient, how would you respond?

Masculinizing hormone treatment

As you would explain to a patient like Jennie R, the goal of hormone therapy is to suppress the effects of the sex assigned at birth and replace them with those of the desired gender. In the case of a female transitioning to a male (known as a transman), masculinizing hormones would promote growth of facial and body hair, cessation of menses, increased muscle mass, deepening of the voice, and clitoral enlargement.^11,23,24

Physical changes induced by masculinizing hormone therapy have an expected onset of one to six months and achieve maximum effect in approximately two to five years.^10,11 Although there have been no controlled clinical trials evaluating the safety or efficacy of any transitional hormone regimen, WPATH and the Center of Excellence for Transgender Health at the University of California, San Francisco, suggest initiating intramuscular or transdermal testosterone at increasing doses until normal physiologic male testosterone levels between 350 and 700 ng/dL are achieved, or until cessation of menses.^13,25-28 The dose at which either, or both, occur should be continued as long-term maintenance therapy. Medroxyprogesterone can be added, if necessary for menstrual cessation, and a GnRH agonist or endometrial ablation can be used for refractory uterine bleeding.^29,30

Testosterone is not a contraceptive. It is important to emphasize to transmen like Jennie that they remain at risk for pregnancy if they are having sex with fertile males. Caution patients not to assume that the possibility of pregnancy ends when menses stop.

Treat minor adverse effects. Adverse effects of masculinizing hormones include vaginal atrophy, fat redistribution and weight gain, polycythemia, acne, scalp hair loss, sleep apnea, elevated liver enzymes, hyperlipidemia, cardiovascular disease, diabetes, and bone density loss. Increased risk for cancer of the female organs has not been proven.^10,11 It is reasonable to treat minor adverse effects after reviewing the risks/benefits of doing so, as discontinuing hormone therapy could be detrimental to the well-being of transitioning patients.¹¹

There are absolute contraindications to masculinizing hormone therapy, however, including pregnancy, unstable coronary artery disease, and untreated polycythemia with a hematocrit > 55%.¹⁰

Monitoring is essential. Patients receiving masculinizing hormone therapy should be monitored every three months during the first year and once or twice a year there­after, with a focused history (including mood symptoms), physical exam (including weight and blood pressure), and labs (including complete blood count, liver function, renal function, and lipids) at each visit.^11,23 Some clinicians also check estradiol levels until they fall below 50 pg/mL,^23,27 while others take the cessation of uterine bleeding for > 6 months as an indicator of estrogen ­suppression.

Preventive health measures continue. Routine screening should continue, based on the patient’s assigned sex at birth. Thus, a transman who has not had a hysterectomy still needs Pap smears, mammograms if the patient has not had a double mastectomy, and bone mineral density (BMD) testing to screen for osteoporosis.^31,32 Some experts recommend starting to test BMD at age 50 for patients receiving masculinizing hormones, given the unknown effect of testosterone on bone density.^11,31,32

CASE 1 The first question for a transgender patient is about his or her current gender identity, but Jennie R has already reported living as a man. So you start by asking “What name do you prefer to use?” and “Do you prefer to be referred to with male or female pronouns?”

The patient tells you that he sees himself as a man, he wants to be called Jeff, and he prefers male pronouns. You explain that you believe he has gender dysphoria and would benefit from hormone therapy, but it is important to confirm this diagnosis with an MHP. You explain that testosterone can be prescribed for masculinizing effects, and describe the expected effects—more facial and body hair, a deeper voice, and greater muscle mass, among others—and review the likely time frame.

You also discuss the risks of masculinizing hormones (hyperlipidemia, cardiovascular disease, diabetes, and loss of bone density) that will need to be monitored. Before he leaves, you give him the name of an MHP who is experienced in transgender care and tell him to make a follow-up appointment with you after he has seen her. At the conclusion of the visit, you make a note of the patient’s name and gender identity in the chart and inform the staff of the changes.

MALE-TO-FEMALE TRANSITION

CASE 2 Before heading into your office to talk to a new patient named Carl S, you glance at his chart and see that he is a healthy 21-year-old who has come in for a routine physical. When you enter the room, you find Carl wearing a dress, heels, and make-up. After confirming that you have the right patient, you ask, “What is your current gender identity?” “Female,” says Carl, who indicates that she now goes by Carol. The patient has no medical problems, surgical history, or significant family history but reports that she has been taking spironolactone and estrogen for the past three years. Carol also says she has a new female partner and is having unprotected sexual activity.

Feminizing hormone treatment

The desired effects of feminizing hormones include voice change, decreased hair growth, breast growth, body fat redistribution, decreased muscle mass, skin softening, decreased oiliness of skin and hair, and a decrease in spontaneous erections, testicular volume, and sperm production.^10,11 The onset of feminizing effects ranges from one month to one year and the expected maximum effect occurs anywhere between three months and five years.^10,11 Regimens usually include anti-androgen agents and estrogen.^13,26-28

The medications that have been most studied with anti-androgenic effects include spironolactone and 5-α reductase inhibitors (5-ARIs) such as finasteride. Spironolactone inhibits testosterone secretion and inhibits androgen binding to androgen receptors; 5-ARIs block the conversion of testosterone to 5-α-dihydrotestosterone, the more active form.

Estrogen can be administered via oral, sublingual, transdermal, or intramuscular route, but parenteral formulations are preferred to avoid first-pass metabolism. The serum estradiol target is similar to the mean daily level of premenopausal women (< 200 pg/mL) and the level of testosterone should be in the normal female range (< 55 ng/dL).^13,26-28

The selection of medications should be individualized for each patient. Comorbidities must be considered, as well as the risk for adverse effects, which include venous thromboembolism, elevated liver enzymes, breast cancer, cardiovascular disease, diabetes, hyperprolactinemia, weight gain, gallstones, cerebrovascular disease, and severe migraine headaches.^10,11 Estrogen therapy is not reported to induce hypertrophy or premalignant changes in the prostate.³³ As is the case for masculinizing hormones, feminizing hormone therapy should be continued indefinitely for long-term effects.

Frequent monitoring is recommended. Patients taking feminizing hormones (transwomen) should be seen every two to three months in the first year and monitored once or twice a year thereafter. Serum testosterone and estradiol levels should initially be monitored every three months; serum electrolytes, specifically potassium, should be monitored every two to three months in the first year until stable.

CASE 2 You recommend that Carol S be screened annually for sexually transmitted diseases, as you would for any 21-year-old patient. You point out, too, that while estrogen and androgen-suppressing therapy decrease sperm production, there is a possibility that the patient could impregnate a female partner and recommend that contraception be used if the couple is not trying to conceive.

You also discuss the risks and benefits of hormone therapy and reasonable expectations of continued treatment. You ask Carol to schedule a follow-up visit in six months, as her hormone regimen is stable. Finally, if the patient remains on hormone therapy, you mention that the only screening unique to men transitioning to women is for breast cancer, which should begin at age 40 to 50 (as it should for all women).

Gender-affirming surgical options

Surgical management of transgender patients is not within the scope of family medicine. But it is essential to know what procedures are available, as you may have occasion to advocate for patients during the surgical referral process and possibly to provide postoperative care.

For transmen, surgical options include chest reconstruction, hysterectomy/oophorectomy, metoidioplasty (using the clitoris to surgically approximate a penis), phalloplasty, scrotoplasty, urethroplasty, and vaginectomy.^10,34 The surgeries available for transwomen are orchiectomy, vaginoplasty, penectomy, breast augmentation, thyroid chondroplasty and voice surgery, and facial feminization.^10,34 Keep in mind that not all transgender individuals desire surgery as part of the transitioning process.
 

The authors would like to acknowledge the assistance of Michelle Forcier, MD, MPH, and Karen S. Bernstein, MD, MPH, in the preparation of this manuscript.

Civil rights for the lesbian, gay, bisexual, and transgender population have advanced markedly in the past decade, and the medical community has gradually begun to address more of their health concerns. More recently, media attention to transgender individuals has encouraged many more to openly seek care.^1,2

It is estimated that anywhere from 0.3% to 5% of the US population identifies as transgender.^1-3 While awareness of this population has slowly increased, there is a paucity of research on the hormone treatment that is often essential to patients’ well-being. Studies of surgical options for transgender patients have been minimal, as well.

Primary care providers are uniquely positioned to coordinate medical services and ensure continuity of care for transgender patients as they strive to become their authentic selves. Our goal in writing this article is to equip you with the tools to provide this patient population with sensitive, high-quality care (see Table 1).^4-7 Our focus is on the diagnosis of gender dysphoria (GD) and its medical and hormonal management—the realm of primary care providers. We briefly discuss surgical management of GD, as well.

UNDERSTANDING AND DIAGNOSING GENDER DYSPHORIA

Two classification systems are used for diagnoses related to GD: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Ed (DSM-5)⁸ and the International Classification of Diseases, 10th Rev (ICD-10).⁹

ICD-10 criteria use the term gender identity disorder; DSM-5 refers to gender dysphoria instead. It is important to emphasize that these classification systems represent an attempt to categorize a group of signs and symptoms that lead to distress for the patient and are not meant to suggest that being transgender is pathological. In fact, in DSM-5—released in 2013—the American Psychiatric Association revised the terminology to emphasize that such individuals are not “disordered” by the nature of their identity, but rather by the distress that being transgender causes.⁸

For a diagnosis of GD in children, DSM-5 criteria include characteristics perceived to be incongruent between the child’s sex at birth and the self-identified gender based on preferred activities or dislike of his or her own sexual anatomy. The child must meet six or more of the following for at least six months

• A repeatedly stated desire to be, or insistence that he or she is, of the other gender
• In boys, a preference for cross-dressing or simulating female attire; in girls, insistence on wearing only stereotypical masculine clothing
• Strong and persistent preferences for cross-gender roles in make-believe play or fantasy
• A strong rejection of toys/games typically associated with the child’s sex
• Intense desire to participate in stereotypical games and pastimes of the other gender
• Strong preference for playmates of the other gender
• A strong dislike of one’s sexual anatomy
• A strong desire for the primary (eg, penis or vagina) or secondary (eg, menstruation) sex characteristics of the other gender.⁸

Adolescents and adults must meet two or more of the following for at least six months

• A noticeable incongruence between the gender that the patient sees themselves as and their sex characteristics
• An intense need to do away with (or prevent) his or her primary or secondary sex features
• An intense desire to have the primary and/or secondary sex features of the other gender
• A deep desire to transform into another gender
• A profound need for society to treat them as someone of the other gender
• A powerful assurance of having the characteristic feelings and responses of the other gender.⁸

For children as well as adolescents and adults, the condition should cause the patient significant distress or significantly affect him or her socially, at work or school, and in other important areas of life.⁸

Is the patient a candidate for hormone therapy?

Two primary sources—Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7, issued by the World Professional Association for Transgender Health (WPATH)¹⁰ and Endocrine Treatment of Transsexual Persons¹¹ by the Endocrine Society—offer clinical practice guidance based on evidence and expert opinion.

WPATH recommends that a mental health professional (MHP) experienced in transgender care diagnose GD to ensure that it is not mistaken for a psychiatric condition manifesting as altered gender identity. However, if no one with such experience is available or accessible in the region, it is reasonable for a primary care provider to make the diagnosis and consider initiating hormone therapy without a mental health referral,¹² as the expected benefits outweigh the risks of nontreatment.¹³

Whether or not an MHP confirms a diagnosis of GD, it is still up to the treating provider to confirm the patient’s eligibility and readiness for hormone therapy: He or she should meet DSM-5 or ICD-10 criteria for GD, have no psychiatric comorbidity (eg, schizophrenia, body dysmorphic disorder, or uncontrolled bipolar disorder) likely to interfere with treatment, understand the expected outcomes and the social benefits and risks, and have indicated a willingness to take the hormones responsibly.

Historically, patients were required to have a documented real-life experience, defined as having fully adopted the new gender role in everyday life for at least three months.^10,11 This model has fallen out of favor, however, as it is unsupported by evidence and may place transgender individuals at physical and emotional risk. Instead, readiness is confirmed by obtaining informed consent.¹²

Puberty may be suppressed with a gonadotropin-releasing hormone (GnRH) agonist in adolescents who have a GD diagnosis and are at Tanner stage 2 to 3 of puberty until age 16. At that point, hormone therapy consistent with their gender identification may be initiated (see “How to Help Transgender Teens”).¹¹

Beginning the transition

The transitioning process is a complex and individualized journey that can include inward or outward change, or both.

For patients interested in medical interventions, possible therapies include cross-sex hormone administration and gender-affirming surgery. Both are aimed at making the physical and the psychologic more congruent. Hormone treatment (see Table 2) is often essential to reduce the distress of individuals with GD and to help them feel comfortable in their own body.^10,11,21 Psychologic conditions, such as depression, tend to improve as the transitioning process gets underway.²²

FEMALE-TO-MALE TRANSITION

CASE 1 Jennie R, a 55-year-old postmenopausal patient, comes to your office for an annual exam. Although you’ve been her primary care provider for several years, she confides for the first time that she has never been comfortable as a woman. “I’ve always felt that my body didn’t belong to me,” the patient admits, and goes on to say that for the past several years she has been living as a man. Jennie R says she is ready to start hormone therapy to assist with the gender transition and asks about the process, the benefits and risks, and how quickly she can expect to achieve the desired results.

If Jennie R were your patient, how would you respond?

Masculinizing hormone treatment

As you would explain to a patient like Jennie R, the goal of hormone therapy is to suppress the effects of the sex assigned at birth and replace them with those of the desired gender. In the case of a female transitioning to a male (known as a transman), masculinizing hormones would promote growth of facial and body hair, cessation of menses, increased muscle mass, deepening of the voice, and clitoral enlargement.^11,23,24

Physical changes induced by masculinizing hormone therapy have an expected onset of one to six months and achieve maximum effect in approximately two to five years.^10,11 Although there have been no controlled clinical trials evaluating the safety or efficacy of any transitional hormone regimen, WPATH and the Center of Excellence for Transgender Health at the University of California, San Francisco, suggest initiating intramuscular or transdermal testosterone at increasing doses until normal physiologic male testosterone levels between 350 and 700 ng/dL are achieved, or until cessation of menses.^13,25-28 The dose at which either, or both, occur should be continued as long-term maintenance therapy. Medroxyprogesterone can be added, if necessary for menstrual cessation, and a GnRH agonist or endometrial ablation can be used for refractory uterine bleeding.^29,30

Testosterone is not a contraceptive. It is important to emphasize to transmen like Jennie that they remain at risk for pregnancy if they are having sex with fertile males. Caution patients not to assume that the possibility of pregnancy ends when menses stop.

Treat minor adverse effects. Adverse effects of masculinizing hormones include vaginal atrophy, fat redistribution and weight gain, polycythemia, acne, scalp hair loss, sleep apnea, elevated liver enzymes, hyperlipidemia, cardiovascular disease, diabetes, and bone density loss. Increased risk for cancer of the female organs has not been proven.^10,11 It is reasonable to treat minor adverse effects after reviewing the risks/benefits of doing so, as discontinuing hormone therapy could be detrimental to the well-being of transitioning patients.¹¹

There are absolute contraindications to masculinizing hormone therapy, however, including pregnancy, unstable coronary artery disease, and untreated polycythemia with a hematocrit > 55%.¹⁰

Monitoring is essential. Patients receiving masculinizing hormone therapy should be monitored every three months during the first year and once or twice a year there­after, with a focused history (including mood symptoms), physical exam (including weight and blood pressure), and labs (including complete blood count, liver function, renal function, and lipids) at each visit.^11,23 Some clinicians also check estradiol levels until they fall below 50 pg/mL,^23,27 while others take the cessation of uterine bleeding for > 6 months as an indicator of estrogen ­suppression.

Preventive health measures continue. Routine screening should continue, based on the patient’s assigned sex at birth. Thus, a transman who has not had a hysterectomy still needs Pap smears, mammograms if the patient has not had a double mastectomy, and bone mineral density (BMD) testing to screen for osteoporosis.^31,32 Some experts recommend starting to test BMD at age 50 for patients receiving masculinizing hormones, given the unknown effect of testosterone on bone density.^11,31,32

CASE 1 The first question for a transgender patient is about his or her current gender identity, but Jennie R has already reported living as a man. So you start by asking “What name do you prefer to use?” and “Do you prefer to be referred to with male or female pronouns?”

The patient tells you that he sees himself as a man, he wants to be called Jeff, and he prefers male pronouns. You explain that you believe he has gender dysphoria and would benefit from hormone therapy, but it is important to confirm this diagnosis with an MHP. You explain that testosterone can be prescribed for masculinizing effects, and describe the expected effects—more facial and body hair, a deeper voice, and greater muscle mass, among others—and review the likely time frame.

You also discuss the risks of masculinizing hormones (hyperlipidemia, cardiovascular disease, diabetes, and loss of bone density) that will need to be monitored. Before he leaves, you give him the name of an MHP who is experienced in transgender care and tell him to make a follow-up appointment with you after he has seen her. At the conclusion of the visit, you make a note of the patient’s name and gender identity in the chart and inform the staff of the changes.

MALE-TO-FEMALE TRANSITION

CASE 2 Before heading into your office to talk to a new patient named Carl S, you glance at his chart and see that he is a healthy 21-year-old who has come in for a routine physical. When you enter the room, you find Carl wearing a dress, heels, and make-up. After confirming that you have the right patient, you ask, “What is your current gender identity?” “Female,” says Carl, who indicates that she now goes by Carol. The patient has no medical problems, surgical history, or significant family history but reports that she has been taking spironolactone and estrogen for the past three years. Carol also says she has a new female partner and is having unprotected sexual activity.

Feminizing hormone treatment

The desired effects of feminizing hormones include voice change, decreased hair growth, breast growth, body fat redistribution, decreased muscle mass, skin softening, decreased oiliness of skin and hair, and a decrease in spontaneous erections, testicular volume, and sperm production.^10,11 The onset of feminizing effects ranges from one month to one year and the expected maximum effect occurs anywhere between three months and five years.^10,11 Regimens usually include anti-androgen agents and estrogen.^13,26-28

The medications that have been most studied with anti-androgenic effects include spironolactone and 5-α reductase inhibitors (5-ARIs) such as finasteride. Spironolactone inhibits testosterone secretion and inhibits androgen binding to androgen receptors; 5-ARIs block the conversion of testosterone to 5-α-dihydrotestosterone, the more active form.

Estrogen can be administered via oral, sublingual, transdermal, or intramuscular route, but parenteral formulations are preferred to avoid first-pass metabolism. The serum estradiol target is similar to the mean daily level of premenopausal women (< 200 pg/mL) and the level of testosterone should be in the normal female range (< 55 ng/dL).^13,26-28

The selection of medications should be individualized for each patient. Comorbidities must be considered, as well as the risk for adverse effects, which include venous thromboembolism, elevated liver enzymes, breast cancer, cardiovascular disease, diabetes, hyperprolactinemia, weight gain, gallstones, cerebrovascular disease, and severe migraine headaches.^10,11 Estrogen therapy is not reported to induce hypertrophy or premalignant changes in the prostate.³³ As is the case for masculinizing hormones, feminizing hormone therapy should be continued indefinitely for long-term effects.

Frequent monitoring is recommended. Patients taking feminizing hormones (transwomen) should be seen every two to three months in the first year and monitored once or twice a year thereafter. Serum testosterone and estradiol levels should initially be monitored every three months; serum electrolytes, specifically potassium, should be monitored every two to three months in the first year until stable.

CASE 2 You recommend that Carol S be screened annually for sexually transmitted diseases, as you would for any 21-year-old patient. You point out, too, that while estrogen and androgen-suppressing therapy decrease sperm production, there is a possibility that the patient could impregnate a female partner and recommend that contraception be used if the couple is not trying to conceive.

You also discuss the risks and benefits of hormone therapy and reasonable expectations of continued treatment. You ask Carol to schedule a follow-up visit in six months, as her hormone regimen is stable. Finally, if the patient remains on hormone therapy, you mention that the only screening unique to men transitioning to women is for breast cancer, which should begin at age 40 to 50 (as it should for all women).

Gender-affirming surgical options

Surgical management of transgender patients is not within the scope of family medicine. But it is essential to know what procedures are available, as you may have occasion to advocate for patients during the surgical referral process and possibly to provide postoperative care.

For transmen, surgical options include chest reconstruction, hysterectomy/oophorectomy, metoidioplasty (using the clitoris to surgically approximate a penis), phalloplasty, scrotoplasty, urethroplasty, and vaginectomy.^10,34 The surgeries available for transwomen are orchiectomy, vaginoplasty, penectomy, breast augmentation, thyroid chondroplasty and voice surgery, and facial feminization.^10,34 Keep in mind that not all transgender individuals desire surgery as part of the transitioning process.
 

The authors would like to acknowledge the assistance of Michelle Forcier, MD, MPH, and Karen S. Bernstein, MD, MPH, in the preparation of this manuscript.

Civil rights for the lesbian, gay, bisexual, and transgender population have advanced markedly in the past decade, and the medical community has gradually begun to address more of their health concerns. More recently, media attention to transgender individuals has encouraged many more to openly seek care.^1,2

It is estimated that anywhere from 0.3% to 5% of the US population identifies as transgender.^1-3 While awareness of this population has slowly increased, there is a paucity of research on the hormone treatment that is often essential to patients’ well-being. Studies of surgical options for transgender patients have been minimal, as well.

Primary care providers are uniquely positioned to coordinate medical services and ensure continuity of care for transgender patients as they strive to become their authentic selves. Our goal in writing this article is to equip you with the tools to provide this patient population with sensitive, high-quality care (see Table 1).^4-7 Our focus is on the diagnosis of gender dysphoria (GD) and its medical and hormonal management—the realm of primary care providers. We briefly discuss surgical management of GD, as well.

UNDERSTANDING AND DIAGNOSING GENDER DYSPHORIA

Two classification systems are used for diagnoses related to GD: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Ed (DSM-5)⁸ and the International Classification of Diseases, 10th Rev (ICD-10).⁹

ICD-10 criteria use the term gender identity disorder; DSM-5 refers to gender dysphoria instead. It is important to emphasize that these classification systems represent an attempt to categorize a group of signs and symptoms that lead to distress for the patient and are not meant to suggest that being transgender is pathological. In fact, in DSM-5—released in 2013—the American Psychiatric Association revised the terminology to emphasize that such individuals are not “disordered” by the nature of their identity, but rather by the distress that being transgender causes.⁸

For a diagnosis of GD in children, DSM-5 criteria include characteristics perceived to be incongruent between the child’s sex at birth and the self-identified gender based on preferred activities or dislike of his or her own sexual anatomy. The child must meet six or more of the following for at least six months

• A repeatedly stated desire to be, or insistence that he or she is, of the other gender
• In boys, a preference for cross-dressing or simulating female attire; in girls, insistence on wearing only stereotypical masculine clothing
• Strong and persistent preferences for cross-gender roles in make-believe play or fantasy
• A strong rejection of toys/games typically associated with the child’s sex
• Intense desire to participate in stereotypical games and pastimes of the other gender
• Strong preference for playmates of the other gender
• A strong dislike of one’s sexual anatomy
• A strong desire for the primary (eg, penis or vagina) or secondary (eg, menstruation) sex characteristics of the other gender.⁸

Adolescents and adults must meet two or more of the following for at least six months

• A noticeable incongruence between the gender that the patient sees themselves as and their sex characteristics
• An intense need to do away with (or prevent) his or her primary or secondary sex features
• An intense desire to have the primary and/or secondary sex features of the other gender
• A deep desire to transform into another gender
• A profound need for society to treat them as someone of the other gender
• A powerful assurance of having the characteristic feelings and responses of the other gender.⁸

For children as well as adolescents and adults, the condition should cause the patient significant distress or significantly affect him or her socially, at work or school, and in other important areas of life.⁸

Is the patient a candidate for hormone therapy?

Two primary sources—Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7, issued by the World Professional Association for Transgender Health (WPATH)¹⁰ and Endocrine Treatment of Transsexual Persons¹¹ by the Endocrine Society—offer clinical practice guidance based on evidence and expert opinion.

WPATH recommends that a mental health professional (MHP) experienced in transgender care diagnose GD to ensure that it is not mistaken for a psychiatric condition manifesting as altered gender identity. However, if no one with such experience is available or accessible in the region, it is reasonable for a primary care provider to make the diagnosis and consider initiating hormone therapy without a mental health referral,¹² as the expected benefits outweigh the risks of nontreatment.¹³

Whether or not an MHP confirms a diagnosis of GD, it is still up to the treating provider to confirm the patient’s eligibility and readiness for hormone therapy: He or she should meet DSM-5 or ICD-10 criteria for GD, have no psychiatric comorbidity (eg, schizophrenia, body dysmorphic disorder, or uncontrolled bipolar disorder) likely to interfere with treatment, understand the expected outcomes and the social benefits and risks, and have indicated a willingness to take the hormones responsibly.

Historically, patients were required to have a documented real-life experience, defined as having fully adopted the new gender role in everyday life for at least three months.^10,11 This model has fallen out of favor, however, as it is unsupported by evidence and may place transgender individuals at physical and emotional risk. Instead, readiness is confirmed by obtaining informed consent.¹²

Puberty may be suppressed with a gonadotropin-releasing hormone (GnRH) agonist in adolescents who have a GD diagnosis and are at Tanner stage 2 to 3 of puberty until age 16. At that point, hormone therapy consistent with their gender identification may be initiated (see “How to Help Transgender Teens”).¹¹

Beginning the transition

The transitioning process is a complex and individualized journey that can include inward or outward change, or both.

For patients interested in medical interventions, possible therapies include cross-sex hormone administration and gender-affirming surgery. Both are aimed at making the physical and the psychologic more congruent. Hormone treatment (see Table 2) is often essential to reduce the distress of individuals with GD and to help them feel comfortable in their own body.^10,11,21 Psychologic conditions, such as depression, tend to improve as the transitioning process gets underway.²²

FEMALE-TO-MALE TRANSITION

CASE 1 Jennie R, a 55-year-old postmenopausal patient, comes to your office for an annual exam. Although you’ve been her primary care provider for several years, she confides for the first time that she has never been comfortable as a woman. “I’ve always felt that my body didn’t belong to me,” the patient admits, and goes on to say that for the past several years she has been living as a man. Jennie R says she is ready to start hormone therapy to assist with the gender transition and asks about the process, the benefits and risks, and how quickly she can expect to achieve the desired results.

If Jennie R were your patient, how would you respond?

Masculinizing hormone treatment

As you would explain to a patient like Jennie R, the goal of hormone therapy is to suppress the effects of the sex assigned at birth and replace them with those of the desired gender. In the case of a female transitioning to a male (known as a transman), masculinizing hormones would promote growth of facial and body hair, cessation of menses, increased muscle mass, deepening of the voice, and clitoral enlargement.^11,23,24

Physical changes induced by masculinizing hormone therapy have an expected onset of one to six months and achieve maximum effect in approximately two to five years.^10,11 Although there have been no controlled clinical trials evaluating the safety or efficacy of any transitional hormone regimen, WPATH and the Center of Excellence for Transgender Health at the University of California, San Francisco, suggest initiating intramuscular or transdermal testosterone at increasing doses until normal physiologic male testosterone levels between 350 and 700 ng/dL are achieved, or until cessation of menses.^13,25-28 The dose at which either, or both, occur should be continued as long-term maintenance therapy. Medroxyprogesterone can be added, if necessary for menstrual cessation, and a GnRH agonist or endometrial ablation can be used for refractory uterine bleeding.^29,30

Testosterone is not a contraceptive. It is important to emphasize to transmen like Jennie that they remain at risk for pregnancy if they are having sex with fertile males. Caution patients not to assume that the possibility of pregnancy ends when menses stop.

Treat minor adverse effects. Adverse effects of masculinizing hormones include vaginal atrophy, fat redistribution and weight gain, polycythemia, acne, scalp hair loss, sleep apnea, elevated liver enzymes, hyperlipidemia, cardiovascular disease, diabetes, and bone density loss. Increased risk for cancer of the female organs has not been proven.^10,11 It is reasonable to treat minor adverse effects after reviewing the risks/benefits of doing so, as discontinuing hormone therapy could be detrimental to the well-being of transitioning patients.¹¹

There are absolute contraindications to masculinizing hormone therapy, however, including pregnancy, unstable coronary artery disease, and untreated polycythemia with a hematocrit > 55%.¹⁰

Monitoring is essential. Patients receiving masculinizing hormone therapy should be monitored every three months during the first year and once or twice a year there­after, with a focused history (including mood symptoms), physical exam (including weight and blood pressure), and labs (including complete blood count, liver function, renal function, and lipids) at each visit.^11,23 Some clinicians also check estradiol levels until they fall below 50 pg/mL,^23,27 while others take the cessation of uterine bleeding for > 6 months as an indicator of estrogen ­suppression.

Preventive health measures continue. Routine screening should continue, based on the patient’s assigned sex at birth. Thus, a transman who has not had a hysterectomy still needs Pap smears, mammograms if the patient has not had a double mastectomy, and bone mineral density (BMD) testing to screen for osteoporosis.^31,32 Some experts recommend starting to test BMD at age 50 for patients receiving masculinizing hormones, given the unknown effect of testosterone on bone density.^11,31,32

CASE 1 The first question for a transgender patient is about his or her current gender identity, but Jennie R has already reported living as a man. So you start by asking “What name do you prefer to use?” and “Do you prefer to be referred to with male or female pronouns?”

The patient tells you that he sees himself as a man, he wants to be called Jeff, and he prefers male pronouns. You explain that you believe he has gender dysphoria and would benefit from hormone therapy, but it is important to confirm this diagnosis with an MHP. You explain that testosterone can be prescribed for masculinizing effects, and describe the expected effects—more facial and body hair, a deeper voice, and greater muscle mass, among others—and review the likely time frame.

You also discuss the risks of masculinizing hormones (hyperlipidemia, cardiovascular disease, diabetes, and loss of bone density) that will need to be monitored. Before he leaves, you give him the name of an MHP who is experienced in transgender care and tell him to make a follow-up appointment with you after he has seen her. At the conclusion of the visit, you make a note of the patient’s name and gender identity in the chart and inform the staff of the changes.

MALE-TO-FEMALE TRANSITION

CASE 2 Before heading into your office to talk to a new patient named Carl S, you glance at his chart and see that he is a healthy 21-year-old who has come in for a routine physical. When you enter the room, you find Carl wearing a dress, heels, and make-up. After confirming that you have the right patient, you ask, “What is your current gender identity?” “Female,” says Carl, who indicates that she now goes by Carol. The patient has no medical problems, surgical history, or significant family history but reports that she has been taking spironolactone and estrogen for the past three years. Carol also says she has a new female partner and is having unprotected sexual activity.

Feminizing hormone treatment

The desired effects of feminizing hormones include voice change, decreased hair growth, breast growth, body fat redistribution, decreased muscle mass, skin softening, decreased oiliness of skin and hair, and a decrease in spontaneous erections, testicular volume, and sperm production.^10,11 The onset of feminizing effects ranges from one month to one year and the expected maximum effect occurs anywhere between three months and five years.^10,11 Regimens usually include anti-androgen agents and estrogen.^13,26-28

The medications that have been most studied with anti-androgenic effects include spironolactone and 5-α reductase inhibitors (5-ARIs) such as finasteride. Spironolactone inhibits testosterone secretion and inhibits androgen binding to androgen receptors; 5-ARIs block the conversion of testosterone to 5-α-dihydrotestosterone, the more active form.

Estrogen can be administered via oral, sublingual, transdermal, or intramuscular route, but parenteral formulations are preferred to avoid first-pass metabolism. The serum estradiol target is similar to the mean daily level of premenopausal women (< 200 pg/mL) and the level of testosterone should be in the normal female range (< 55 ng/dL).^13,26-28

The selection of medications should be individualized for each patient. Comorbidities must be considered, as well as the risk for adverse effects, which include venous thromboembolism, elevated liver enzymes, breast cancer, cardiovascular disease, diabetes, hyperprolactinemia, weight gain, gallstones, cerebrovascular disease, and severe migraine headaches.^10,11 Estrogen therapy is not reported to induce hypertrophy or premalignant changes in the prostate.³³ As is the case for masculinizing hormones, feminizing hormone therapy should be continued indefinitely for long-term effects.

Frequent monitoring is recommended. Patients taking feminizing hormones (transwomen) should be seen every two to three months in the first year and monitored once or twice a year thereafter. Serum testosterone and estradiol levels should initially be monitored every three months; serum electrolytes, specifically potassium, should be monitored every two to three months in the first year until stable.

CASE 2 You recommend that Carol S be screened annually for sexually transmitted diseases, as you would for any 21-year-old patient. You point out, too, that while estrogen and androgen-suppressing therapy decrease sperm production, there is a possibility that the patient could impregnate a female partner and recommend that contraception be used if the couple is not trying to conceive.

You also discuss the risks and benefits of hormone therapy and reasonable expectations of continued treatment. You ask Carol to schedule a follow-up visit in six months, as her hormone regimen is stable. Finally, if the patient remains on hormone therapy, you mention that the only screening unique to men transitioning to women is for breast cancer, which should begin at age 40 to 50 (as it should for all women).

Gender-affirming surgical options

Surgical management of transgender patients is not within the scope of family medicine. But it is essential to know what procedures are available, as you may have occasion to advocate for patients during the surgical referral process and possibly to provide postoperative care.

For transmen, surgical options include chest reconstruction, hysterectomy/oophorectomy, metoidioplasty (using the clitoris to surgically approximate a penis), phalloplasty, scrotoplasty, urethroplasty, and vaginectomy.^10,34 The surgeries available for transwomen are orchiectomy, vaginoplasty, penectomy, breast augmentation, thyroid chondroplasty and voice surgery, and facial feminization.^10,34 Keep in mind that not all transgender individuals desire surgery as part of the transitioning process.
 

The authors would like to acknowledge the assistance of Michelle Forcier, MD, MPH, and Karen S. Bernstein, MD, MPH, in the preparation of this manuscript.