Illustrative case

A 6-year-old girl with a history of reactive airway disease comes to your office complaining of cough and wheezing. On exam, she has mild retractions, a respiratory rate of 35, and an oxygen saturation of 96% on room air. Her lung fields are diffusely wheezy. Her parents would like to keep her out of the hospital. How should you order her albuterol to decrease her wheezing and minimize adverse effects?

Asthma affects nearly 19 million adults and 7 million children in the United States.² Asthma exacerbations are the third most common reason for hospitalization in children.^2,3 Treatment usually requires multiple agents, including inhaled beta-agonists. These are most effective when delivered to the peripheral airways, which is a challenge during an asthma exacerbation because of airway swelling and rapid breathing. Two devices have been developed to effectively deliver medication to the peripheral airways: nebulizers and MDIs with a holding chamber (spacer).¹

Several studies have demonstrated that for mild to moderate asthma exacerbations, administering a beta-agonist via an MDI with a spacer is as effective as using a nebulizer.^4,5 Asthma treatment guidelines also state that spacers are either comparable to or preferred over nebulizers for beta-agonist administration in children and adults.^6,7 However, based on our experience, physicians still frequently order nebulizer treatments for patients with asthma exacerbations, despite several advantages of MDIs with spacers. Notably, they cost less and don’t require maintenance or a power source. Physicians administered nebulizer therapy at more than 3.6 million emergency department (ED) visits in 2006.⁸

In this latest Cochrane review, Cates et al¹ added 4 new studies to those included in their earlier Cochrane meta-analysis, and looked at what, if any, effect these studies had on our understanding of nebulizers vs MDIs with spacers.

STUDY SUMMARY: Outcomes with nebulizers are no better than those with spacers

This systematic review and meta-analysis pooled the results of RCTs comparing spacers to nebulizers for administering beta-agonists during acute, non-life-threatening asthma exacerbations.¹ The authors reviewed studies conducted in EDs, hospitals, and outpatient settings that included children and adults. The primary outcomes were hospital admission rates and duration of hospital stay. Secondary outcomes included time spent in the ED, change in pulse rate, and incidence of tremor.

The time children spent in the ED was cut by half an hour when MDIs with spacers were used.Cates et al¹ analyzed 39 trials that included 1897 children and 729 adults and were conducted primarily in an ED or outpatient setting. The 4 new studies added 295 children and 58 adults to the researchers’ earlier meta-analysis. Studies involving adults and children were pooled separately. Most patients received multiple treatments with beta-agonists titrated to the individual’s response.

No differences in hospitalizations. Rates of hospital admissions did not differ between patients receiving beta-agonists via a spacer compared to a nebulizer in both adults (relative risk [RR]=.94; 95% confidence interval [CI], .61-1.43) and children (RR=.71; 95% CI, .47-1.08). Duration of hospital stay did not differ between the 2 delivery methods in adults (mean difference [MD]=-.60 days; 95% CI, -3.23 to 2.03) and children (MD=.33 days; 95% CI, -.10 to .76).

For kids, spacers meant less time in the ED. Duration in the ED was approximately half an hour shorter for children using spacers (MD=-33.48 minutes; 95% CI, -43.3 to -23.6, P<.001). There was no difference in time spent in the ED observed in adults (MD=1.75 minutes; 95% CI, -23.45 to 26.95). The rate of tremor was lower in children using spacers (RR=.64; 95% CI, .44-.95, P=.027), and was similar in adults (RR=1.12; 95% CI, .66-1.9). The rise in pulse rate was lower in children using spacers (MD=-5.41% change from baseline; 95% CI, -8.34 to -2.48; P<.001), and was similar in adults (MD=-1.23%; 95% CI, -4.06 to 1.60).

WHAT'S NEW: Additional evidence that spacers are as effective as nebulizers

This meta-analysis, which included 4 new studies, should finally dispel the myth that nebulizers deliver beta-agonists more effectively than MDIs with spacers. Additionally, in children, spacers are associated with lower rates of side effects, including tremor and elevated pulse rate.

CAVEATS: Most studies involving children were open label

Although most of the adult trials in this meta-analysis involved a double-dummy design, which allows for effective participant blinding, most of the studies involving children were open label. This open-label design might have been a source of reporting bias for symptom-related outcomes, but should not have affected hospital admission rates or duration of hospital stay.

In the double-dummy studies, adults received both a nebulizer and a spacer, which likely explains the similar time spent in the ED by the treatment and control groups.

CHALLENGES TO IMPLEMENTATION: Old habits are hard to break

Doctors may think that patients view nebulizers as more potent or more effective than spacers and thus be more likely to order them. Some patients may prefer nebulizers because of convenience or other factors.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 6-year-old girl with a history of reactive airway disease comes to your office complaining of cough and wheezing. On exam, she has mild retractions, a respiratory rate of 35, and an oxygen saturation of 96% on room air. Her lung fields are diffusely wheezy. Her parents would like to keep her out of the hospital. How should you order her albuterol to decrease her wheezing and minimize adverse effects?

Asthma affects nearly 19 million adults and 7 million children in the United States.² Asthma exacerbations are the third most common reason for hospitalization in children.^2,3 Treatment usually requires multiple agents, including inhaled beta-agonists. These are most effective when delivered to the peripheral airways, which is a challenge during an asthma exacerbation because of airway swelling and rapid breathing. Two devices have been developed to effectively deliver medication to the peripheral airways: nebulizers and MDIs with a holding chamber (spacer).¹

Several studies have demonstrated that for mild to moderate asthma exacerbations, administering a beta-agonist via an MDI with a spacer is as effective as using a nebulizer.^4,5 Asthma treatment guidelines also state that spacers are either comparable to or preferred over nebulizers for beta-agonist administration in children and adults.^6,7 However, based on our experience, physicians still frequently order nebulizer treatments for patients with asthma exacerbations, despite several advantages of MDIs with spacers. Notably, they cost less and don’t require maintenance or a power source. Physicians administered nebulizer therapy at more than 3.6 million emergency department (ED) visits in 2006.⁸

In this latest Cochrane review, Cates et al¹ added 4 new studies to those included in their earlier Cochrane meta-analysis, and looked at what, if any, effect these studies had on our understanding of nebulizers vs MDIs with spacers.

STUDY SUMMARY: Outcomes with nebulizers are no better than those with spacers

This systematic review and meta-analysis pooled the results of RCTs comparing spacers to nebulizers for administering beta-agonists during acute, non-life-threatening asthma exacerbations.¹ The authors reviewed studies conducted in EDs, hospitals, and outpatient settings that included children and adults. The primary outcomes were hospital admission rates and duration of hospital stay. Secondary outcomes included time spent in the ED, change in pulse rate, and incidence of tremor.

The time children spent in the ED was cut by half an hour when MDIs with spacers were used.Cates et al¹ analyzed 39 trials that included 1897 children and 729 adults and were conducted primarily in an ED or outpatient setting. The 4 new studies added 295 children and 58 adults to the researchers’ earlier meta-analysis. Studies involving adults and children were pooled separately. Most patients received multiple treatments with beta-agonists titrated to the individual’s response.

No differences in hospitalizations. Rates of hospital admissions did not differ between patients receiving beta-agonists via a spacer compared to a nebulizer in both adults (relative risk [RR]=.94; 95% confidence interval [CI], .61-1.43) and children (RR=.71; 95% CI, .47-1.08). Duration of hospital stay did not differ between the 2 delivery methods in adults (mean difference [MD]=-.60 days; 95% CI, -3.23 to 2.03) and children (MD=.33 days; 95% CI, -.10 to .76).

For kids, spacers meant less time in the ED. Duration in the ED was approximately half an hour shorter for children using spacers (MD=-33.48 minutes; 95% CI, -43.3 to -23.6, P<.001). There was no difference in time spent in the ED observed in adults (MD=1.75 minutes; 95% CI, -23.45 to 26.95). The rate of tremor was lower in children using spacers (RR=.64; 95% CI, .44-.95, P=.027), and was similar in adults (RR=1.12; 95% CI, .66-1.9). The rise in pulse rate was lower in children using spacers (MD=-5.41% change from baseline; 95% CI, -8.34 to -2.48; P<.001), and was similar in adults (MD=-1.23%; 95% CI, -4.06 to 1.60).

WHAT'S NEW: Additional evidence that spacers are as effective as nebulizers

This meta-analysis, which included 4 new studies, should finally dispel the myth that nebulizers deliver beta-agonists more effectively than MDIs with spacers. Additionally, in children, spacers are associated with lower rates of side effects, including tremor and elevated pulse rate.

CAVEATS: Most studies involving children were open label

Although most of the adult trials in this meta-analysis involved a double-dummy design, which allows for effective participant blinding, most of the studies involving children were open label. This open-label design might have been a source of reporting bias for symptom-related outcomes, but should not have affected hospital admission rates or duration of hospital stay.

In the double-dummy studies, adults received both a nebulizer and a spacer, which likely explains the similar time spent in the ED by the treatment and control groups.

CHALLENGES TO IMPLEMENTATION: Old habits are hard to break

Doctors may think that patients view nebulizers as more potent or more effective than spacers and thus be more likely to order them. Some patients may prefer nebulizers because of convenience or other factors.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 6-year-old girl with a history of reactive airway disease comes to your office complaining of cough and wheezing. On exam, she has mild retractions, a respiratory rate of 35, and an oxygen saturation of 96% on room air. Her lung fields are diffusely wheezy. Her parents would like to keep her out of the hospital. How should you order her albuterol to decrease her wheezing and minimize adverse effects?

Asthma affects nearly 19 million adults and 7 million children in the United States.² Asthma exacerbations are the third most common reason for hospitalization in children.^2,3 Treatment usually requires multiple agents, including inhaled beta-agonists. These are most effective when delivered to the peripheral airways, which is a challenge during an asthma exacerbation because of airway swelling and rapid breathing. Two devices have been developed to effectively deliver medication to the peripheral airways: nebulizers and MDIs with a holding chamber (spacer).¹

Several studies have demonstrated that for mild to moderate asthma exacerbations, administering a beta-agonist via an MDI with a spacer is as effective as using a nebulizer.^4,5 Asthma treatment guidelines also state that spacers are either comparable to or preferred over nebulizers for beta-agonist administration in children and adults.^6,7 However, based on our experience, physicians still frequently order nebulizer treatments for patients with asthma exacerbations, despite several advantages of MDIs with spacers. Notably, they cost less and don’t require maintenance or a power source. Physicians administered nebulizer therapy at more than 3.6 million emergency department (ED) visits in 2006.⁸

In this latest Cochrane review, Cates et al¹ added 4 new studies to those included in their earlier Cochrane meta-analysis, and looked at what, if any, effect these studies had on our understanding of nebulizers vs MDIs with spacers.

STUDY SUMMARY: Outcomes with nebulizers are no better than those with spacers

This systematic review and meta-analysis pooled the results of RCTs comparing spacers to nebulizers for administering beta-agonists during acute, non-life-threatening asthma exacerbations.¹ The authors reviewed studies conducted in EDs, hospitals, and outpatient settings that included children and adults. The primary outcomes were hospital admission rates and duration of hospital stay. Secondary outcomes included time spent in the ED, change in pulse rate, and incidence of tremor.

The time children spent in the ED was cut by half an hour when MDIs with spacers were used.Cates et al¹ analyzed 39 trials that included 1897 children and 729 adults and were conducted primarily in an ED or outpatient setting. The 4 new studies added 295 children and 58 adults to the researchers’ earlier meta-analysis. Studies involving adults and children were pooled separately. Most patients received multiple treatments with beta-agonists titrated to the individual’s response.

No differences in hospitalizations. Rates of hospital admissions did not differ between patients receiving beta-agonists via a spacer compared to a nebulizer in both adults (relative risk [RR]=.94; 95% confidence interval [CI], .61-1.43) and children (RR=.71; 95% CI, .47-1.08). Duration of hospital stay did not differ between the 2 delivery methods in adults (mean difference [MD]=-.60 days; 95% CI, -3.23 to 2.03) and children (MD=.33 days; 95% CI, -.10 to .76).

For kids, spacers meant less time in the ED. Duration in the ED was approximately half an hour shorter for children using spacers (MD=-33.48 minutes; 95% CI, -43.3 to -23.6, P<.001). There was no difference in time spent in the ED observed in adults (MD=1.75 minutes; 95% CI, -23.45 to 26.95). The rate of tremor was lower in children using spacers (RR=.64; 95% CI, .44-.95, P=.027), and was similar in adults (RR=1.12; 95% CI, .66-1.9). The rise in pulse rate was lower in children using spacers (MD=-5.41% change from baseline; 95% CI, -8.34 to -2.48; P<.001), and was similar in adults (MD=-1.23%; 95% CI, -4.06 to 1.60).

WHAT'S NEW: Additional evidence that spacers are as effective as nebulizers

This meta-analysis, which included 4 new studies, should finally dispel the myth that nebulizers deliver beta-agonists more effectively than MDIs with spacers. Additionally, in children, spacers are associated with lower rates of side effects, including tremor and elevated pulse rate.

CAVEATS: Most studies involving children were open label

Although most of the adult trials in this meta-analysis involved a double-dummy design, which allows for effective participant blinding, most of the studies involving children were open label. This open-label design might have been a source of reporting bias for symptom-related outcomes, but should not have affected hospital admission rates or duration of hospital stay.

In the double-dummy studies, adults received both a nebulizer and a spacer, which likely explains the similar time spent in the ED by the treatment and control groups.

CHALLENGES TO IMPLEMENTATION: Old habits are hard to break

Doctors may think that patients view nebulizers as more potent or more effective than spacers and thus be more likely to order them. Some patients may prefer nebulizers because of convenience or other factors.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

An elemental diet was more than 90% effective in inducing histologic remission in eosinophilic esophagitis patients, reported Dr. Ángel Arias and colleagues in the June issue of Gastroenterology.

The Six Food Elimination Diet was also highly efficacious, reinforcing the idea that dietary modification "should be considered as a first-line therapy in both children and adults affected by this disease," wrote the investigators (doi:10.1053/j.gastro.2014.02.006).

Dr. Arias of the Complejo Hospitalario La Mancha Centro, in Alcázar de San Juan, Spain, searched the MEDLINE, EMBASE, and SCOPUS databases for studies performed prior to June 2013 investigating the efficacy of dietary interventions in eosinophilic esophagitis (EoE).

Abstracts and other relevant material from conferences including Digestive Disease Week, the American College of Gastroenterology meeting, and European Gastroenterology Week were also included.

Overall, 33 studies were included, 23 of which were full articles with the remainder being abstracts; there were a total of 1,128 children and 189 adults included in the analysis.

Of the 13 studies that assessed the efficacy of exclusive feeding with an amino acid–based elemental diet (involving 411 children and 18 adults), 90.8% of patients achieved histologic remission of EoE, defined as fewer than 15 eosinophils per high-power field on esophageal biopsy (95% confidence interval, 84.7%-95.5%).

The next best diet, the Six Food Elimination Diet (SFED), offered a 72.1% efficacy rate (95% CI, 65.8%-78.1%) across 75 children and 122 adults and was "the only one assessed in more adults than children."

On the other hand, the strategy of eliminating foods that gave a positive result in skin allergy tests was assessed in 14 studies (594 children and 32 adults), and demonstrated an overall efficacy of just 45.5% (95% CI, 35.4%-55.7%).

Other less-studied diets included gluten-free and cow’s milk elimination diets, both of which seemed to result in histologic remission (58.7% and 68.2%, respectively).

However, "because studies assessing these dietary treatments are still scarce, making conclusions from them can be risky," wrote the authors.

"For example, although the overall efficacy of a gluten-free diet in achieving histologic remission of EoE was 58.7%, the remission rate ranged from 23.1% to 85.6%," they reported.

"Despite its obvious success, the multiple drawbacks of elemental diets, which include the need to avoid all table food, its unpleasant taste, and high cost, and the psychological effects produced by the social limitations that this diet entails, have probably contributed to the fact that this dietary intervention has been restricted almost exclusively to pediatric patients," commented Dr. Arias.

"In fact, no research on adults was available until 2013, with the reported remission rates being comparable with those documented in children."

On the other hand, the relatively high efficacy of the SFED diet, which avoids many of the disadvantages of the elemental diet, seems to make this the best choice for "children and motivated adult patients," added the researchers.

Future studies and meta-analyses should address whether diet adherence results in changes in esophageal fibrosis as well as quality of life issues brought on by diet adherence.

The authors disclosed no relevant financial conflicts.

[email protected]

An elemental diet was more than 90% effective in inducing histologic remission in eosinophilic esophagitis patients, reported Dr. Ángel Arias and colleagues in the June issue of Gastroenterology.

The Six Food Elimination Diet was also highly efficacious, reinforcing the idea that dietary modification "should be considered as a first-line therapy in both children and adults affected by this disease," wrote the investigators (doi:10.1053/j.gastro.2014.02.006).

Dr. Arias of the Complejo Hospitalario La Mancha Centro, in Alcázar de San Juan, Spain, searched the MEDLINE, EMBASE, and SCOPUS databases for studies performed prior to June 2013 investigating the efficacy of dietary interventions in eosinophilic esophagitis (EoE).

Abstracts and other relevant material from conferences including Digestive Disease Week, the American College of Gastroenterology meeting, and European Gastroenterology Week were also included.

Overall, 33 studies were included, 23 of which were full articles with the remainder being abstracts; there were a total of 1,128 children and 189 adults included in the analysis.

Of the 13 studies that assessed the efficacy of exclusive feeding with an amino acid–based elemental diet (involving 411 children and 18 adults), 90.8% of patients achieved histologic remission of EoE, defined as fewer than 15 eosinophils per high-power field on esophageal biopsy (95% confidence interval, 84.7%-95.5%).

The next best diet, the Six Food Elimination Diet (SFED), offered a 72.1% efficacy rate (95% CI, 65.8%-78.1%) across 75 children and 122 adults and was "the only one assessed in more adults than children."

On the other hand, the strategy of eliminating foods that gave a positive result in skin allergy tests was assessed in 14 studies (594 children and 32 adults), and demonstrated an overall efficacy of just 45.5% (95% CI, 35.4%-55.7%).

Other less-studied diets included gluten-free and cow’s milk elimination diets, both of which seemed to result in histologic remission (58.7% and 68.2%, respectively).

However, "because studies assessing these dietary treatments are still scarce, making conclusions from them can be risky," wrote the authors.

"For example, although the overall efficacy of a gluten-free diet in achieving histologic remission of EoE was 58.7%, the remission rate ranged from 23.1% to 85.6%," they reported.

"Despite its obvious success, the multiple drawbacks of elemental diets, which include the need to avoid all table food, its unpleasant taste, and high cost, and the psychological effects produced by the social limitations that this diet entails, have probably contributed to the fact that this dietary intervention has been restricted almost exclusively to pediatric patients," commented Dr. Arias.

"In fact, no research on adults was available until 2013, with the reported remission rates being comparable with those documented in children."

On the other hand, the relatively high efficacy of the SFED diet, which avoids many of the disadvantages of the elemental diet, seems to make this the best choice for "children and motivated adult patients," added the researchers.

Future studies and meta-analyses should address whether diet adherence results in changes in esophageal fibrosis as well as quality of life issues brought on by diet adherence.

The authors disclosed no relevant financial conflicts.

[email protected]

An elemental diet was more than 90% effective in inducing histologic remission in eosinophilic esophagitis patients, reported Dr. Ángel Arias and colleagues in the June issue of Gastroenterology.

The Six Food Elimination Diet was also highly efficacious, reinforcing the idea that dietary modification "should be considered as a first-line therapy in both children and adults affected by this disease," wrote the investigators (doi:10.1053/j.gastro.2014.02.006).

Dr. Arias of the Complejo Hospitalario La Mancha Centro, in Alcázar de San Juan, Spain, searched the MEDLINE, EMBASE, and SCOPUS databases for studies performed prior to June 2013 investigating the efficacy of dietary interventions in eosinophilic esophagitis (EoE).

Abstracts and other relevant material from conferences including Digestive Disease Week, the American College of Gastroenterology meeting, and European Gastroenterology Week were also included.

Overall, 33 studies were included, 23 of which were full articles with the remainder being abstracts; there were a total of 1,128 children and 189 adults included in the analysis.

Of the 13 studies that assessed the efficacy of exclusive feeding with an amino acid–based elemental diet (involving 411 children and 18 adults), 90.8% of patients achieved histologic remission of EoE, defined as fewer than 15 eosinophils per high-power field on esophageal biopsy (95% confidence interval, 84.7%-95.5%).

The next best diet, the Six Food Elimination Diet (SFED), offered a 72.1% efficacy rate (95% CI, 65.8%-78.1%) across 75 children and 122 adults and was "the only one assessed in more adults than children."

On the other hand, the strategy of eliminating foods that gave a positive result in skin allergy tests was assessed in 14 studies (594 children and 32 adults), and demonstrated an overall efficacy of just 45.5% (95% CI, 35.4%-55.7%).

Other less-studied diets included gluten-free and cow’s milk elimination diets, both of which seemed to result in histologic remission (58.7% and 68.2%, respectively).

However, "because studies assessing these dietary treatments are still scarce, making conclusions from them can be risky," wrote the authors.

"For example, although the overall efficacy of a gluten-free diet in achieving histologic remission of EoE was 58.7%, the remission rate ranged from 23.1% to 85.6%," they reported.

"Despite its obvious success, the multiple drawbacks of elemental diets, which include the need to avoid all table food, its unpleasant taste, and high cost, and the psychological effects produced by the social limitations that this diet entails, have probably contributed to the fact that this dietary intervention has been restricted almost exclusively to pediatric patients," commented Dr. Arias.

"In fact, no research on adults was available until 2013, with the reported remission rates being comparable with those documented in children."

On the other hand, the relatively high efficacy of the SFED diet, which avoids many of the disadvantages of the elemental diet, seems to make this the best choice for "children and motivated adult patients," added the researchers.

Future studies and meta-analyses should address whether diet adherence results in changes in esophageal fibrosis as well as quality of life issues brought on by diet adherence.

The authors disclosed no relevant financial conflicts.

[email protected]

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

A 32-year-old woman presents with a history of pelvic pain, dysmenorrhea, dyspareunia, dyschezia, and dysuria, with exacerbation of the symptoms during her menstrual cycles. Her menarche occurred at the age of 13 and her menses are regular. She has never undergone surgery and has no relevant pathologic processes. She also reports that for the past 18 months she has been unsuccessfully trying to conceive.

Two months ago, she went to the emergency department because of an acute episode of severe pelvic pain associated with abdominal cramps, vomiting, and dyschezia, occurring at the beginning of her menstrual cycle. At that time, her vital signs were within normal limits, but deep palpation of the right iliac fossa was painful. On that occasion, acute abdomen and bowel obstruction were excluded.

Now, vaginal examination reveals a bluish, painful, bulky induration in the posterior fornix. Digital rectal examination reveals a circular infiltrated area in the anterior rectal wall. Her cancer antigen 125 (CA 125) level is 230 U/mL (normal range 0–35 U/mL).

MENSES-RELATED SYMPTOMS AND THE DIAGNOSIS OF ENDOMETRIOSIS

The diagnosis of endometriosis should be considered in the patient described above. Many of her signs and symptoms can be associated with several diseases. However, the diagnostic hypothesis points strongly toward endometriosis, since her symptoms recur at the beginning of every menstrual cycle.¹

Endometriosis is the presence of endometrial tissue outside the uterine cavity. The affected organs usually include the ovaries, fallopian tubes,² peritoneal surface, vagina, cervix, abdominal wall,³ scar tissue, pouch of Douglas, urinary tract, and bowel. However, any organ can be involved.

So-called deeply infiltrating endometriosis is an endometriotic lesion penetrating into the retroperitoneal space (most often affecting the uterosacral ligaments and the rectovaginal septum) or the pelvic-organ wall to a depth of at least 5 mm and involving structures such as the rectum, vagina, ureters, and bladder.⁴ Its clinical presentation is highly variable, ranging from no symptoms to severe pain and dysfunction of pelvic organs.

Endometriosis can be diagnosed with certainty only when the endometriotic lesions are observed by laparoscopy or laparotomy and after the histologic examination of surgically resected lesions (Figure 1).¹ However, a presumptive diagnosis can be made on the basis of imaging findings, which can be useful in the differential diagnostic process (Table 1).

EXAMINATION AND BLOOD MARKERS PROVIDE LIMITED INFORMATION

Knowing the history of the patient, along with a physical examination that includes speculum and bimanual vaginal and rectal examination, can be helpful in the diagnostic process even if nothing abnormal is found.

Pelvic examination has a poor predictive value, as demonstrated in a study conducted by Nezhat et al⁵ in 91 patients with surgically confirmed endometriosis, 47% of whom had a normal bimanual examination.

CA 125 is the serologic marker most often used for diagnosing endometriosis. Levels are usually high in the sera of patients with endometriosis, especially in the advanced stages.⁶ However, levels increase both in the physiologic menstrual cycle and in epithelial ovarian cancers.⁷ Thus, the diagnostic value of CA 125 is limited in terms of both sensitivity and specificity.

INCLUDE IMAGING IN THE DIAGNOSTIC WORKUP

Surgical treatment is frequently offered to patients who have severe pelvic pain that does not respond to medical treatment, or in cases of infertility. Imaging investigations are mandatory both to ascertain the diagnosis and to assess involvement of internal organs before surgery. Moreover, imaging helps minimize the surgical risks.

The primary aim of the radiologic examination is to describe the precise location, the depth, and the number of pelvic endometriotic lesions. Furthermore, imaging is useful to check for endometriotic foci in pelvic organs such as the bowel, ureters, and bladder, which are often involved in the pathologic process.

Transvaginal ultrasonography and magnetic resonance imaging (MRI) can accurately delineate deeply infiltrating lesions of endometriosis that are not easily accessible laparoscopically.

Transvaginal ultrasonography

Transvaginal ultrasonography is the first-line imaging study when endometriosis is suspected: it is powerful, simple, widely available, and cost-effective. In particular, it is recommended for diagnosing endometriotic ovarian cysts (endometriomas)^8,9 and endometriosis of the bladder.¹⁰ However, its value for the assessment of superficial peritoneal lesions, ovarian foci, and deeply infiltrating endometriosis is questionable.

Although uncomfortable for the patient, transvaginal ultrasonography should be performed during menses, or when the pain reaches its highest level. In fact, during menstrual bleeding the endometrial implants grow and become easier to detect.

Mais et al⁸ reported that transvaginal ultrasonography has a sensitivity of 88% in differentiating endometriomas from other ovarian masses, and a specificity of 90% (Figure 2). Furthermore, its specificity is as high as that of MRI.^8,9

Endometriotic nodules detected in the uterosacral ligaments, rectovaginal septum, vagina, vesicouterine pouch, bladder (Figure 3), and ureters can be signs of deeply infiltrating endometriosis. Pelvic adhesions can be suspected when pelvic organs appear fixed to each other, when hyperechogenic plaques are found between the serosal surfaces of the different organs, and when the pouch of Douglas is partially or completely obliterated.

The accuracy of transvaginal ultrasonography strongly depends on the operator’s skill. Furthermore, lesions of the sigmoid colon are impossible to visualize by transvaginal ultrasonography; hence, further diagnostic procedures are required. Transvaginal ultrasonography is the most accurate technique in detecting endometriotic nodules of the bladder wall in patients with urinary symptoms.

Transvaginal ultrasonography combined with color Doppler can also demonstrate the flow of urine through the ureters to the bladder, thereby ascertaining the patency of the ureters and clarifying the anatomic relationship between the ureters and any endometriotic lesions in the detrusors.¹⁰ Hydronephrosis can arise from ureteral restriction caused by endometriotic nodules. Thus, transabdominal ultrasonography of the kidneys is always recommended when deeply infiltrating endometriosis is suspected.

Some centers use a bowel-preparation protocol consisting of a laxative taken 24 hours before the procedure, combined with a low-residue diet and an enema 1 hour before the examination to cleanse the rectosigmoid colon of fecal content and gas, which can interfere with the visual examination of the pelvic structures.¹¹

Transabdominal ultrasonography

Transabdominal ultrasonography can be used instead of transvaginal ultrasonography, eg, in young girls and women who have never been sexually active. When transabdominal ultrasonography is selected, the patient should have a full bladder to maximize the visualization of the pelvic structures. However, transvaginal ultrasonography is generally more sensitive than transabdominal in detecting adnexal masses and pelvic nodules.¹²

Magnetic resonance imaging

MRI has been recently introduced in the diagnosis of endometriosis. MRI is less operator-dependent than transvaginal ultrasonography and is more sensitive for detecting foci of deeply infiltrating endometriosis, because of its ability to completely survey the anterior and posterior compartments of the pelvis. However, its diagnostic value in cases of bladder endometriosis, superficial peritoneal lesions, and ovarian foci is still controversial.^13–16

On MRI, lesions of deeply infiltrating endometriosis mainly appear as areas or nodules with regular, irregular, indistinct, or stellate margins. A distortion of the normal pelvic anatomy or the detection of a loculated fluid collection can indirectly signal the presence of adhesions.

MRI has high specificity for the diagnosis of endometriomas as a result of its ability to detect aged hemorrhagic content (Figure 4).¹⁷ Despite the many studies that point to the limits of MRI in detecting small endometriotic lesions, recent studies demonstrated that MRI also has good sensitivity for small peritoneal implants and adhesions.^18,19 The injection of gadolinium contrast is still a debatable measure, because contrast-enhanced imaging cannot differentiate infiltrating lesions from other normal fibromuscular pelvic anatomic structures.^15,20

Bowel preparation can be done with an oral laxative the day before imaging, complemented by a low-residue diet. A single dose of a ready-to-use enema is given 30 minutes before the examination to cleanse the terminal section of the intestinal tract. To avoid motion artifacts caused by bowel peristalsis, images are obtained after intramuscular injections of a myorelaxant are given, if there is no contraindication. Bowel preparation is useful to eliminate fecal residue and gas, thereby allowing proper visualization of lesions of deeply infiltrating endometriosis, but it is not routinely prescribed in all centers.¹¹

In most cases, endometriotic lesions have an MRI signal intensity that comes very close to that of the surrounding fibromuscular structures. In this regard, vaginal and rectal distention and opacification using ultrasonographic gel clearly help to delineate the cervix, vaginal fornices, and vaginal wall, as well as the rectum and wall of the rectosigmoid junction (Figure  5).²⁰

PRESURGICAL IMAGING

Rectal endoscopic ultrasonography

Even though it should not be included in the routine diagnostic workup, rectal endoscopic ultrasonography, using a flexible echoendoscope, is suitable in certain presurgical cases. The aim of this imaging technique is to assess the depth of bowel wall infiltration thanks to the visualization of the different layers.²¹

Double-contrast barium enema and multislice computed tomography

Double-contrast barium enema is extensively used for the diagnosis of bowel endometriosis, once the decision to perform surgery has been made. It allows evaluation of the degree and length of the bowel occlusion at the level of the sigmoid or high rectosigmoid tract, but it does not permit differentiation of bowel endometriosis from other pathologies.

Multislice computed tomography offers the opportunity to evaluate the depth of the lesions with excellent precision. ²²

The most relevant disadvantage of both procedures is the exposure of women of reproductive age to ionizing radiation. In addition, multislice computed tomography requires the administration of an intravenous iodinated contrast medium and a retrograde colonic distention with about 2 L of water.

A 32-year-old woman presents with a history of pelvic pain, dysmenorrhea, dyspareunia, dyschezia, and dysuria, with exacerbation of the symptoms during her menstrual cycles. Her menarche occurred at the age of 13 and her menses are regular. She has never undergone surgery and has no relevant pathologic processes. She also reports that for the past 18 months she has been unsuccessfully trying to conceive.

Two months ago, she went to the emergency department because of an acute episode of severe pelvic pain associated with abdominal cramps, vomiting, and dyschezia, occurring at the beginning of her menstrual cycle. At that time, her vital signs were within normal limits, but deep palpation of the right iliac fossa was painful. On that occasion, acute abdomen and bowel obstruction were excluded.

Now, vaginal examination reveals a bluish, painful, bulky induration in the posterior fornix. Digital rectal examination reveals a circular infiltrated area in the anterior rectal wall. Her cancer antigen 125 (CA 125) level is 230 U/mL (normal range 0–35 U/mL).

MENSES-RELATED SYMPTOMS AND THE DIAGNOSIS OF ENDOMETRIOSIS

The diagnosis of endometriosis should be considered in the patient described above. Many of her signs and symptoms can be associated with several diseases. However, the diagnostic hypothesis points strongly toward endometriosis, since her symptoms recur at the beginning of every menstrual cycle.¹

Endometriosis is the presence of endometrial tissue outside the uterine cavity. The affected organs usually include the ovaries, fallopian tubes,² peritoneal surface, vagina, cervix, abdominal wall,³ scar tissue, pouch of Douglas, urinary tract, and bowel. However, any organ can be involved.

So-called deeply infiltrating endometriosis is an endometriotic lesion penetrating into the retroperitoneal space (most often affecting the uterosacral ligaments and the rectovaginal septum) or the pelvic-organ wall to a depth of at least 5 mm and involving structures such as the rectum, vagina, ureters, and bladder.⁴ Its clinical presentation is highly variable, ranging from no symptoms to severe pain and dysfunction of pelvic organs.

Endometriosis can be diagnosed with certainty only when the endometriotic lesions are observed by laparoscopy or laparotomy and after the histologic examination of surgically resected lesions (Figure 1).¹ However, a presumptive diagnosis can be made on the basis of imaging findings, which can be useful in the differential diagnostic process (Table 1).

EXAMINATION AND BLOOD MARKERS PROVIDE LIMITED INFORMATION

Knowing the history of the patient, along with a physical examination that includes speculum and bimanual vaginal and rectal examination, can be helpful in the diagnostic process even if nothing abnormal is found.

Pelvic examination has a poor predictive value, as demonstrated in a study conducted by Nezhat et al⁵ in 91 patients with surgically confirmed endometriosis, 47% of whom had a normal bimanual examination.

CA 125 is the serologic marker most often used for diagnosing endometriosis. Levels are usually high in the sera of patients with endometriosis, especially in the advanced stages.⁶ However, levels increase both in the physiologic menstrual cycle and in epithelial ovarian cancers.⁷ Thus, the diagnostic value of CA 125 is limited in terms of both sensitivity and specificity.

INCLUDE IMAGING IN THE DIAGNOSTIC WORKUP

Surgical treatment is frequently offered to patients who have severe pelvic pain that does not respond to medical treatment, or in cases of infertility. Imaging investigations are mandatory both to ascertain the diagnosis and to assess involvement of internal organs before surgery. Moreover, imaging helps minimize the surgical risks.

The primary aim of the radiologic examination is to describe the precise location, the depth, and the number of pelvic endometriotic lesions. Furthermore, imaging is useful to check for endometriotic foci in pelvic organs such as the bowel, ureters, and bladder, which are often involved in the pathologic process.

Transvaginal ultrasonography and magnetic resonance imaging (MRI) can accurately delineate deeply infiltrating lesions of endometriosis that are not easily accessible laparoscopically.

Transvaginal ultrasonography

Transvaginal ultrasonography is the first-line imaging study when endometriosis is suspected: it is powerful, simple, widely available, and cost-effective. In particular, it is recommended for diagnosing endometriotic ovarian cysts (endometriomas)^8,9 and endometriosis of the bladder.¹⁰ However, its value for the assessment of superficial peritoneal lesions, ovarian foci, and deeply infiltrating endometriosis is questionable.

Although uncomfortable for the patient, transvaginal ultrasonography should be performed during menses, or when the pain reaches its highest level. In fact, during menstrual bleeding the endometrial implants grow and become easier to detect.

Mais et al⁸ reported that transvaginal ultrasonography has a sensitivity of 88% in differentiating endometriomas from other ovarian masses, and a specificity of 90% (Figure 2). Furthermore, its specificity is as high as that of MRI.^8,9

Endometriotic nodules detected in the uterosacral ligaments, rectovaginal septum, vagina, vesicouterine pouch, bladder (Figure 3), and ureters can be signs of deeply infiltrating endometriosis. Pelvic adhesions can be suspected when pelvic organs appear fixed to each other, when hyperechogenic plaques are found between the serosal surfaces of the different organs, and when the pouch of Douglas is partially or completely obliterated.

The accuracy of transvaginal ultrasonography strongly depends on the operator’s skill. Furthermore, lesions of the sigmoid colon are impossible to visualize by transvaginal ultrasonography; hence, further diagnostic procedures are required. Transvaginal ultrasonography is the most accurate technique in detecting endometriotic nodules of the bladder wall in patients with urinary symptoms.

Transvaginal ultrasonography combined with color Doppler can also demonstrate the flow of urine through the ureters to the bladder, thereby ascertaining the patency of the ureters and clarifying the anatomic relationship between the ureters and any endometriotic lesions in the detrusors.¹⁰ Hydronephrosis can arise from ureteral restriction caused by endometriotic nodules. Thus, transabdominal ultrasonography of the kidneys is always recommended when deeply infiltrating endometriosis is suspected.

Some centers use a bowel-preparation protocol consisting of a laxative taken 24 hours before the procedure, combined with a low-residue diet and an enema 1 hour before the examination to cleanse the rectosigmoid colon of fecal content and gas, which can interfere with the visual examination of the pelvic structures.¹¹

Transabdominal ultrasonography

Transabdominal ultrasonography can be used instead of transvaginal ultrasonography, eg, in young girls and women who have never been sexually active. When transabdominal ultrasonography is selected, the patient should have a full bladder to maximize the visualization of the pelvic structures. However, transvaginal ultrasonography is generally more sensitive than transabdominal in detecting adnexal masses and pelvic nodules.¹²

Magnetic resonance imaging

MRI has been recently introduced in the diagnosis of endometriosis. MRI is less operator-dependent than transvaginal ultrasonography and is more sensitive for detecting foci of deeply infiltrating endometriosis, because of its ability to completely survey the anterior and posterior compartments of the pelvis. However, its diagnostic value in cases of bladder endometriosis, superficial peritoneal lesions, and ovarian foci is still controversial.^13–16

On MRI, lesions of deeply infiltrating endometriosis mainly appear as areas or nodules with regular, irregular, indistinct, or stellate margins. A distortion of the normal pelvic anatomy or the detection of a loculated fluid collection can indirectly signal the presence of adhesions.

MRI has high specificity for the diagnosis of endometriomas as a result of its ability to detect aged hemorrhagic content (Figure 4).¹⁷ Despite the many studies that point to the limits of MRI in detecting small endometriotic lesions, recent studies demonstrated that MRI also has good sensitivity for small peritoneal implants and adhesions.^18,19 The injection of gadolinium contrast is still a debatable measure, because contrast-enhanced imaging cannot differentiate infiltrating lesions from other normal fibromuscular pelvic anatomic structures.^15,20

Bowel preparation can be done with an oral laxative the day before imaging, complemented by a low-residue diet. A single dose of a ready-to-use enema is given 30 minutes before the examination to cleanse the terminal section of the intestinal tract. To avoid motion artifacts caused by bowel peristalsis, images are obtained after intramuscular injections of a myorelaxant are given, if there is no contraindication. Bowel preparation is useful to eliminate fecal residue and gas, thereby allowing proper visualization of lesions of deeply infiltrating endometriosis, but it is not routinely prescribed in all centers.¹¹

In most cases, endometriotic lesions have an MRI signal intensity that comes very close to that of the surrounding fibromuscular structures. In this regard, vaginal and rectal distention and opacification using ultrasonographic gel clearly help to delineate the cervix, vaginal fornices, and vaginal wall, as well as the rectum and wall of the rectosigmoid junction (Figure  5).²⁰

PRESURGICAL IMAGING

Rectal endoscopic ultrasonography

Even though it should not be included in the routine diagnostic workup, rectal endoscopic ultrasonography, using a flexible echoendoscope, is suitable in certain presurgical cases. The aim of this imaging technique is to assess the depth of bowel wall infiltration thanks to the visualization of the different layers.²¹

Double-contrast barium enema and multislice computed tomography

Double-contrast barium enema is extensively used for the diagnosis of bowel endometriosis, once the decision to perform surgery has been made. It allows evaluation of the degree and length of the bowel occlusion at the level of the sigmoid or high rectosigmoid tract, but it does not permit differentiation of bowel endometriosis from other pathologies.

Multislice computed tomography offers the opportunity to evaluate the depth of the lesions with excellent precision. ²²

The most relevant disadvantage of both procedures is the exposure of women of reproductive age to ionizing radiation. In addition, multislice computed tomography requires the administration of an intravenous iodinated contrast medium and a retrograde colonic distention with about 2 L of water.

A 32-year-old woman presents with a history of pelvic pain, dysmenorrhea, dyspareunia, dyschezia, and dysuria, with exacerbation of the symptoms during her menstrual cycles. Her menarche occurred at the age of 13 and her menses are regular. She has never undergone surgery and has no relevant pathologic processes. She also reports that for the past 18 months she has been unsuccessfully trying to conceive.

Two months ago, she went to the emergency department because of an acute episode of severe pelvic pain associated with abdominal cramps, vomiting, and dyschezia, occurring at the beginning of her menstrual cycle. At that time, her vital signs were within normal limits, but deep palpation of the right iliac fossa was painful. On that occasion, acute abdomen and bowel obstruction were excluded.

Now, vaginal examination reveals a bluish, painful, bulky induration in the posterior fornix. Digital rectal examination reveals a circular infiltrated area in the anterior rectal wall. Her cancer antigen 125 (CA 125) level is 230 U/mL (normal range 0–35 U/mL).

MENSES-RELATED SYMPTOMS AND THE DIAGNOSIS OF ENDOMETRIOSIS

The diagnosis of endometriosis should be considered in the patient described above. Many of her signs and symptoms can be associated with several diseases. However, the diagnostic hypothesis points strongly toward endometriosis, since her symptoms recur at the beginning of every menstrual cycle.¹

Endometriosis is the presence of endometrial tissue outside the uterine cavity. The affected organs usually include the ovaries, fallopian tubes,² peritoneal surface, vagina, cervix, abdominal wall,³ scar tissue, pouch of Douglas, urinary tract, and bowel. However, any organ can be involved.

So-called deeply infiltrating endometriosis is an endometriotic lesion penetrating into the retroperitoneal space (most often affecting the uterosacral ligaments and the rectovaginal septum) or the pelvic-organ wall to a depth of at least 5 mm and involving structures such as the rectum, vagina, ureters, and bladder.⁴ Its clinical presentation is highly variable, ranging from no symptoms to severe pain and dysfunction of pelvic organs.

Endometriosis can be diagnosed with certainty only when the endometriotic lesions are observed by laparoscopy or laparotomy and after the histologic examination of surgically resected lesions (Figure 1).¹ However, a presumptive diagnosis can be made on the basis of imaging findings, which can be useful in the differential diagnostic process (Table 1).

EXAMINATION AND BLOOD MARKERS PROVIDE LIMITED INFORMATION

Knowing the history of the patient, along with a physical examination that includes speculum and bimanual vaginal and rectal examination, can be helpful in the diagnostic process even if nothing abnormal is found.

Pelvic examination has a poor predictive value, as demonstrated in a study conducted by Nezhat et al⁵ in 91 patients with surgically confirmed endometriosis, 47% of whom had a normal bimanual examination.

CA 125 is the serologic marker most often used for diagnosing endometriosis. Levels are usually high in the sera of patients with endometriosis, especially in the advanced stages.⁶ However, levels increase both in the physiologic menstrual cycle and in epithelial ovarian cancers.⁷ Thus, the diagnostic value of CA 125 is limited in terms of both sensitivity and specificity.

INCLUDE IMAGING IN THE DIAGNOSTIC WORKUP

Surgical treatment is frequently offered to patients who have severe pelvic pain that does not respond to medical treatment, or in cases of infertility. Imaging investigations are mandatory both to ascertain the diagnosis and to assess involvement of internal organs before surgery. Moreover, imaging helps minimize the surgical risks.

The primary aim of the radiologic examination is to describe the precise location, the depth, and the number of pelvic endometriotic lesions. Furthermore, imaging is useful to check for endometriotic foci in pelvic organs such as the bowel, ureters, and bladder, which are often involved in the pathologic process.

Transvaginal ultrasonography and magnetic resonance imaging (MRI) can accurately delineate deeply infiltrating lesions of endometriosis that are not easily accessible laparoscopically.

Transvaginal ultrasonography

Transvaginal ultrasonography is the first-line imaging study when endometriosis is suspected: it is powerful, simple, widely available, and cost-effective. In particular, it is recommended for diagnosing endometriotic ovarian cysts (endometriomas)^8,9 and endometriosis of the bladder.¹⁰ However, its value for the assessment of superficial peritoneal lesions, ovarian foci, and deeply infiltrating endometriosis is questionable.

Although uncomfortable for the patient, transvaginal ultrasonography should be performed during menses, or when the pain reaches its highest level. In fact, during menstrual bleeding the endometrial implants grow and become easier to detect.

Mais et al⁸ reported that transvaginal ultrasonography has a sensitivity of 88% in differentiating endometriomas from other ovarian masses, and a specificity of 90% (Figure 2). Furthermore, its specificity is as high as that of MRI.^8,9

Endometriotic nodules detected in the uterosacral ligaments, rectovaginal septum, vagina, vesicouterine pouch, bladder (Figure 3), and ureters can be signs of deeply infiltrating endometriosis. Pelvic adhesions can be suspected when pelvic organs appear fixed to each other, when hyperechogenic plaques are found between the serosal surfaces of the different organs, and when the pouch of Douglas is partially or completely obliterated.

The accuracy of transvaginal ultrasonography strongly depends on the operator’s skill. Furthermore, lesions of the sigmoid colon are impossible to visualize by transvaginal ultrasonography; hence, further diagnostic procedures are required. Transvaginal ultrasonography is the most accurate technique in detecting endometriotic nodules of the bladder wall in patients with urinary symptoms.

Transvaginal ultrasonography combined with color Doppler can also demonstrate the flow of urine through the ureters to the bladder, thereby ascertaining the patency of the ureters and clarifying the anatomic relationship between the ureters and any endometriotic lesions in the detrusors.¹⁰ Hydronephrosis can arise from ureteral restriction caused by endometriotic nodules. Thus, transabdominal ultrasonography of the kidneys is always recommended when deeply infiltrating endometriosis is suspected.

Some centers use a bowel-preparation protocol consisting of a laxative taken 24 hours before the procedure, combined with a low-residue diet and an enema 1 hour before the examination to cleanse the rectosigmoid colon of fecal content and gas, which can interfere with the visual examination of the pelvic structures.¹¹

Transabdominal ultrasonography

Transabdominal ultrasonography can be used instead of transvaginal ultrasonography, eg, in young girls and women who have never been sexually active. When transabdominal ultrasonography is selected, the patient should have a full bladder to maximize the visualization of the pelvic structures. However, transvaginal ultrasonography is generally more sensitive than transabdominal in detecting adnexal masses and pelvic nodules.¹²

Magnetic resonance imaging

MRI has been recently introduced in the diagnosis of endometriosis. MRI is less operator-dependent than transvaginal ultrasonography and is more sensitive for detecting foci of deeply infiltrating endometriosis, because of its ability to completely survey the anterior and posterior compartments of the pelvis. However, its diagnostic value in cases of bladder endometriosis, superficial peritoneal lesions, and ovarian foci is still controversial.^13–16

On MRI, lesions of deeply infiltrating endometriosis mainly appear as areas or nodules with regular, irregular, indistinct, or stellate margins. A distortion of the normal pelvic anatomy or the detection of a loculated fluid collection can indirectly signal the presence of adhesions.

MRI has high specificity for the diagnosis of endometriomas as a result of its ability to detect aged hemorrhagic content (Figure 4).¹⁷ Despite the many studies that point to the limits of MRI in detecting small endometriotic lesions, recent studies demonstrated that MRI also has good sensitivity for small peritoneal implants and adhesions.^18,19 The injection of gadolinium contrast is still a debatable measure, because contrast-enhanced imaging cannot differentiate infiltrating lesions from other normal fibromuscular pelvic anatomic structures.^15,20

Bowel preparation can be done with an oral laxative the day before imaging, complemented by a low-residue diet. A single dose of a ready-to-use enema is given 30 minutes before the examination to cleanse the terminal section of the intestinal tract. To avoid motion artifacts caused by bowel peristalsis, images are obtained after intramuscular injections of a myorelaxant are given, if there is no contraindication. Bowel preparation is useful to eliminate fecal residue and gas, thereby allowing proper visualization of lesions of deeply infiltrating endometriosis, but it is not routinely prescribed in all centers.¹¹

In most cases, endometriotic lesions have an MRI signal intensity that comes very close to that of the surrounding fibromuscular structures. In this regard, vaginal and rectal distention and opacification using ultrasonographic gel clearly help to delineate the cervix, vaginal fornices, and vaginal wall, as well as the rectum and wall of the rectosigmoid junction (Figure  5).²⁰

PRESURGICAL IMAGING

Rectal endoscopic ultrasonography

Even though it should not be included in the routine diagnostic workup, rectal endoscopic ultrasonography, using a flexible echoendoscope, is suitable in certain presurgical cases. The aim of this imaging technique is to assess the depth of bowel wall infiltration thanks to the visualization of the different layers.²¹

Double-contrast barium enema and multislice computed tomography

Double-contrast barium enema is extensively used for the diagnosis of bowel endometriosis, once the decision to perform surgery has been made. It allows evaluation of the degree and length of the bowel occlusion at the level of the sigmoid or high rectosigmoid tract, but it does not permit differentiation of bowel endometriosis from other pathologies.

Multislice computed tomography offers the opportunity to evaluate the depth of the lesions with excellent precision. ²²

The most relevant disadvantage of both procedures is the exposure of women of reproductive age to ionizing radiation. In addition, multislice computed tomography requires the administration of an intravenous iodinated contrast medium and a retrograde colonic distention with about 2 L of water.

Managing a patient with chronic alcohol abuse who is beginning to withdraw is a situation in which to expect the unexpected.

A 61-year-old man with a 40-year history of alcohol abuse was admitted to the hospital after presenting with a 6-month history of weakness and increasing frequency of falls, as well as a 2-day history of myalgias and fatigue. He had anorexia and chronic diarrhea, and he reported an unintentional 100-lb weight loss over the past year. He consumed at least three to five alcoholic drinks daily, including a daily “eye-opener,” and his diet was essentially devoid of meat, bread, fruits, and vegetables. His last drink had been on the morning of admission.

On physical examination, his vital signs were notable for marked orthostatic hypotension. He had angular cheilitis, an erythematous, scaly facial rash, and poorly healing severe sunburn on the dorsal surface of the left forearm, acquired 1 month earlier after minimal sun exposure while driving his car (Figure 1).

The neurologic examination noted decreased sensation in a stocking distribution, reduced proprioception in both great toes, and an intention tremor. His upper extremities were slightly hyperreflexic, he had down-going toes, he did not have clonus, and his gait was wide-based.

Laboratory results were notable for mild anemia, with an elevated mean corpuscular volume of 109.2 fL and a normal thyrotropin level. Urinalysis and urine culture were normal. Stool testing for Clostridium difficile toxin was negative. Computed tomography of the head was unremarkable.

He was placed on the Clinical Institute Withdrawal Assessment for Alcohol revised protocol,1 and he was started on careful fluid, electrolyte, and nutritional management, including intravenous supplementation with thiamine 100 mg daily, folic acid 1 mg twice daily, and an oral multivitamin. Despite these interventions, he became delirious and developed horizontal nystagmus, visual hallucinations, dizziness, and increasing weakness. Benzodiazepine toxicity, which may cause similar findings, was thought unlikely, as he had received only a maximum of 4 mg of lorazepam in any single 24-hour period. His ongoing confusion, orthostatic hypotension, ataxia, and nystagmus raised concern for Wernicke encephalopathy. Thiamine was increased to 500 mg intravenously three times daily for 2 days, followed by 500 mg daily for 2 days, as recommended for acute Wernicke encephalopathy by the Royal College of Physicians.2

Although his ocular findings resolved and his blood pressure improved with high-dose thiamine, he remained confused. Other causes of delirium were considered, including other micronutrient deficiencies. He was evaluated for magnesium deficiency, as magnesium is a necessary cofactor in thiamine metabolism,³ but his level was within normal limits. The constellation of symptoms, including persistent delirium, diarrhea, and skin findings, appeared to be consistent with pellagra, and niacin deficiency became a concern.

PELLAGRA AND ALCOHOL ABUSE

Niacin is a water-soluble vitamin converted to two important coenzymes involved in carbohydrate metabolism and fatty-acid synthesis.⁴ Body stores are minimal, although the liver can convert tryptophan to niacin.⁴

In the United States, pellagra has become rare since niacin enrichment of bread and flour began in the 1940s. However, the risk is increased in those with chronic alcohol dependency, metabolic disease such as carcinoid syndrome, and malabsorptive states such as Crohn disease.⁵ Alcohol abuse is commonly associated with micronutrient deficiencies. Even in alcoholics with sufficient food intake, their ability to absorb niacin may be impaired both directly and indirectly because of the toxic effects of alcohol on the gastrointestinal tract.⁵

The three D’s of niacin deficiency

The clinical picture of pellagra includes the three “D’s” of niacin deficiency—diarrhea, dementia, and dermatitis—representing the organ systems most commonly affected (ie, the gastrointestinal tract, nervous system, and skin). Gastrointestinal signs and symptoms may include anorexia, diarrhea, stomatitis, and abdominal discomfort.⁴ Neurologic signs and symptoms are the most frequent clinical manifestations of pellagra but are often overlooked in alcoholics with altered mental status.^5,6 Early neurologic findings may include apathy, depression, paresthesias, dizziness, and falling.^4,5 Later findings may include hallucinations, seizures, and psychosis.^4,5 If severe enough, this may progress to coma and to a fourth “D”—death—if left untreated.

Skin findings, if present, are typically the most characteristic of pellagra.^5,6 They include a photosensitive eruption that most commonly appears on the face, arms, and the “V” of the neck (“Casal’s necklace”).^3,6 Erythema develops on areas of sun-exposed skin and may be painful or pruritic.⁶ It may take up to four times as long to resolve as a normal sunburn.⁶ On repeated exposure, the skin becomes thickened, hyperkeratotic, and hyperpigmented.⁶

DIAGNOSIS AND TREATMENT OF PELLAGRA

Suspicion of pellagra should be high in any patient with chronic alcohol abuse with changes in mental status.⁵ Pellagra is typically diagnosed clinically. Although testing of serum levels of niacin or urine levels of niacin metabolites can be performed,^4,5 these tests are not commonly used, as they are neither widely available nor reliable.^3,4 Because there is little downside to giving niacin, treatment should be started if there is clinical suspicion of pellagra.^3,4 The diagnosis is confirmed by clinical improvement after niacin replacement begins.⁴

Pellagra is easy and inexpensive to treat once the diagnosis has been established. Supplementation can be given orally at 50 mg to 100 mg three times daily, with a maximum of 500 mg daily for 3 to 4 weeks.^3,5 The multivitamin our patient initially received provided only 30 mg of niacin, which was insufficient to treat his deficiency.

Other micronutrient deficiencies are also common in pellagra, such as the suspected thiamine deficiency in this patient. Although rare in adults, pyridoxine deficiency should be considered because pyridoxine plays an important role in niacin metabolism, and in patients such as this, the signs and symptoms of pellagra will not resolve with niacin administration alone.^3,4

Neurologic symptoms can begin to resolve as soon as 24 to 48 hours after replacement therapy is started, although skin symptoms take longer to respond.⁶

OUR PATIENT’S MANAGEMENT AND LESSONS LEARNED

Our patient was treated with extended-release niacin 500 mg daily. He was significantly less confused within 24 hours, and 2 days later he was no longer delirious. His diarrhea resolved, but his peripheral neuropathy improved only modestly, and we believe that this was the result of his long history of alcohol abuse.

Although there are guidelines to help with the management of patients undergoing alcohol withdrawal, our experience with this patient illustrates that important clinical conditions, including micronutrient deficiencies, can easily be overlooked or misattributed, with potentially dangerous consequences. It is crucial to be mindful of these considerations.

Managing a patient with chronic alcohol abuse who is beginning to withdraw is a situation in which to expect the unexpected.

A 61-year-old man with a 40-year history of alcohol abuse was admitted to the hospital after presenting with a 6-month history of weakness and increasing frequency of falls, as well as a 2-day history of myalgias and fatigue. He had anorexia and chronic diarrhea, and he reported an unintentional 100-lb weight loss over the past year. He consumed at least three to five alcoholic drinks daily, including a daily “eye-opener,” and his diet was essentially devoid of meat, bread, fruits, and vegetables. His last drink had been on the morning of admission.

On physical examination, his vital signs were notable for marked orthostatic hypotension. He had angular cheilitis, an erythematous, scaly facial rash, and poorly healing severe sunburn on the dorsal surface of the left forearm, acquired 1 month earlier after minimal sun exposure while driving his car (Figure 1).

The neurologic examination noted decreased sensation in a stocking distribution, reduced proprioception in both great toes, and an intention tremor. His upper extremities were slightly hyperreflexic, he had down-going toes, he did not have clonus, and his gait was wide-based.

Laboratory results were notable for mild anemia, with an elevated mean corpuscular volume of 109.2 fL and a normal thyrotropin level. Urinalysis and urine culture were normal. Stool testing for Clostridium difficile toxin was negative. Computed tomography of the head was unremarkable.

He was placed on the Clinical Institute Withdrawal Assessment for Alcohol revised protocol,1 and he was started on careful fluid, electrolyte, and nutritional management, including intravenous supplementation with thiamine 100 mg daily, folic acid 1 mg twice daily, and an oral multivitamin. Despite these interventions, he became delirious and developed horizontal nystagmus, visual hallucinations, dizziness, and increasing weakness. Benzodiazepine toxicity, which may cause similar findings, was thought unlikely, as he had received only a maximum of 4 mg of lorazepam in any single 24-hour period. His ongoing confusion, orthostatic hypotension, ataxia, and nystagmus raised concern for Wernicke encephalopathy. Thiamine was increased to 500 mg intravenously three times daily for 2 days, followed by 500 mg daily for 2 days, as recommended for acute Wernicke encephalopathy by the Royal College of Physicians.2

Although his ocular findings resolved and his blood pressure improved with high-dose thiamine, he remained confused. Other causes of delirium were considered, including other micronutrient deficiencies. He was evaluated for magnesium deficiency, as magnesium is a necessary cofactor in thiamine metabolism,³ but his level was within normal limits. The constellation of symptoms, including persistent delirium, diarrhea, and skin findings, appeared to be consistent with pellagra, and niacin deficiency became a concern.

PELLAGRA AND ALCOHOL ABUSE

Niacin is a water-soluble vitamin converted to two important coenzymes involved in carbohydrate metabolism and fatty-acid synthesis.⁴ Body stores are minimal, although the liver can convert tryptophan to niacin.⁴

In the United States, pellagra has become rare since niacin enrichment of bread and flour began in the 1940s. However, the risk is increased in those with chronic alcohol dependency, metabolic disease such as carcinoid syndrome, and malabsorptive states such as Crohn disease.⁵ Alcohol abuse is commonly associated with micronutrient deficiencies. Even in alcoholics with sufficient food intake, their ability to absorb niacin may be impaired both directly and indirectly because of the toxic effects of alcohol on the gastrointestinal tract.⁵

The three D’s of niacin deficiency

The clinical picture of pellagra includes the three “D’s” of niacin deficiency—diarrhea, dementia, and dermatitis—representing the organ systems most commonly affected (ie, the gastrointestinal tract, nervous system, and skin). Gastrointestinal signs and symptoms may include anorexia, diarrhea, stomatitis, and abdominal discomfort.⁴ Neurologic signs and symptoms are the most frequent clinical manifestations of pellagra but are often overlooked in alcoholics with altered mental status.^5,6 Early neurologic findings may include apathy, depression, paresthesias, dizziness, and falling.^4,5 Later findings may include hallucinations, seizures, and psychosis.^4,5 If severe enough, this may progress to coma and to a fourth “D”—death—if left untreated.

Skin findings, if present, are typically the most characteristic of pellagra.^5,6 They include a photosensitive eruption that most commonly appears on the face, arms, and the “V” of the neck (“Casal’s necklace”).^3,6 Erythema develops on areas of sun-exposed skin and may be painful or pruritic.⁶ It may take up to four times as long to resolve as a normal sunburn.⁶ On repeated exposure, the skin becomes thickened, hyperkeratotic, and hyperpigmented.⁶

DIAGNOSIS AND TREATMENT OF PELLAGRA

Suspicion of pellagra should be high in any patient with chronic alcohol abuse with changes in mental status.⁵ Pellagra is typically diagnosed clinically. Although testing of serum levels of niacin or urine levels of niacin metabolites can be performed,^4,5 these tests are not commonly used, as they are neither widely available nor reliable.^3,4 Because there is little downside to giving niacin, treatment should be started if there is clinical suspicion of pellagra.^3,4 The diagnosis is confirmed by clinical improvement after niacin replacement begins.⁴

Pellagra is easy and inexpensive to treat once the diagnosis has been established. Supplementation can be given orally at 50 mg to 100 mg three times daily, with a maximum of 500 mg daily for 3 to 4 weeks.^3,5 The multivitamin our patient initially received provided only 30 mg of niacin, which was insufficient to treat his deficiency.

Other micronutrient deficiencies are also common in pellagra, such as the suspected thiamine deficiency in this patient. Although rare in adults, pyridoxine deficiency should be considered because pyridoxine plays an important role in niacin metabolism, and in patients such as this, the signs and symptoms of pellagra will not resolve with niacin administration alone.^3,4

Neurologic symptoms can begin to resolve as soon as 24 to 48 hours after replacement therapy is started, although skin symptoms take longer to respond.⁶

OUR PATIENT’S MANAGEMENT AND LESSONS LEARNED

Our patient was treated with extended-release niacin 500 mg daily. He was significantly less confused within 24 hours, and 2 days later he was no longer delirious. His diarrhea resolved, but his peripheral neuropathy improved only modestly, and we believe that this was the result of his long history of alcohol abuse.

Although there are guidelines to help with the management of patients undergoing alcohol withdrawal, our experience with this patient illustrates that important clinical conditions, including micronutrient deficiencies, can easily be overlooked or misattributed, with potentially dangerous consequences. It is crucial to be mindful of these considerations.

Managing a patient with chronic alcohol abuse who is beginning to withdraw is a situation in which to expect the unexpected.

A 61-year-old man with a 40-year history of alcohol abuse was admitted to the hospital after presenting with a 6-month history of weakness and increasing frequency of falls, as well as a 2-day history of myalgias and fatigue. He had anorexia and chronic diarrhea, and he reported an unintentional 100-lb weight loss over the past year. He consumed at least three to five alcoholic drinks daily, including a daily “eye-opener,” and his diet was essentially devoid of meat, bread, fruits, and vegetables. His last drink had been on the morning of admission.

On physical examination, his vital signs were notable for marked orthostatic hypotension. He had angular cheilitis, an erythematous, scaly facial rash, and poorly healing severe sunburn on the dorsal surface of the left forearm, acquired 1 month earlier after minimal sun exposure while driving his car (Figure 1).

The neurologic examination noted decreased sensation in a stocking distribution, reduced proprioception in both great toes, and an intention tremor. His upper extremities were slightly hyperreflexic, he had down-going toes, he did not have clonus, and his gait was wide-based.

Laboratory results were notable for mild anemia, with an elevated mean corpuscular volume of 109.2 fL and a normal thyrotropin level. Urinalysis and urine culture were normal. Stool testing for Clostridium difficile toxin was negative. Computed tomography of the head was unremarkable.

He was placed on the Clinical Institute Withdrawal Assessment for Alcohol revised protocol,1 and he was started on careful fluid, electrolyte, and nutritional management, including intravenous supplementation with thiamine 100 mg daily, folic acid 1 mg twice daily, and an oral multivitamin. Despite these interventions, he became delirious and developed horizontal nystagmus, visual hallucinations, dizziness, and increasing weakness. Benzodiazepine toxicity, which may cause similar findings, was thought unlikely, as he had received only a maximum of 4 mg of lorazepam in any single 24-hour period. His ongoing confusion, orthostatic hypotension, ataxia, and nystagmus raised concern for Wernicke encephalopathy. Thiamine was increased to 500 mg intravenously three times daily for 2 days, followed by 500 mg daily for 2 days, as recommended for acute Wernicke encephalopathy by the Royal College of Physicians.2

Although his ocular findings resolved and his blood pressure improved with high-dose thiamine, he remained confused. Other causes of delirium were considered, including other micronutrient deficiencies. He was evaluated for magnesium deficiency, as magnesium is a necessary cofactor in thiamine metabolism,³ but his level was within normal limits. The constellation of symptoms, including persistent delirium, diarrhea, and skin findings, appeared to be consistent with pellagra, and niacin deficiency became a concern.

PELLAGRA AND ALCOHOL ABUSE

Niacin is a water-soluble vitamin converted to two important coenzymes involved in carbohydrate metabolism and fatty-acid synthesis.⁴ Body stores are minimal, although the liver can convert tryptophan to niacin.⁴

In the United States, pellagra has become rare since niacin enrichment of bread and flour began in the 1940s. However, the risk is increased in those with chronic alcohol dependency, metabolic disease such as carcinoid syndrome, and malabsorptive states such as Crohn disease.⁵ Alcohol abuse is commonly associated with micronutrient deficiencies. Even in alcoholics with sufficient food intake, their ability to absorb niacin may be impaired both directly and indirectly because of the toxic effects of alcohol on the gastrointestinal tract.⁵

The three D’s of niacin deficiency

The clinical picture of pellagra includes the three “D’s” of niacin deficiency—diarrhea, dementia, and dermatitis—representing the organ systems most commonly affected (ie, the gastrointestinal tract, nervous system, and skin). Gastrointestinal signs and symptoms may include anorexia, diarrhea, stomatitis, and abdominal discomfort.⁴ Neurologic signs and symptoms are the most frequent clinical manifestations of pellagra but are often overlooked in alcoholics with altered mental status.^5,6 Early neurologic findings may include apathy, depression, paresthesias, dizziness, and falling.^4,5 Later findings may include hallucinations, seizures, and psychosis.^4,5 If severe enough, this may progress to coma and to a fourth “D”—death—if left untreated.

Skin findings, if present, are typically the most characteristic of pellagra.^5,6 They include a photosensitive eruption that most commonly appears on the face, arms, and the “V” of the neck (“Casal’s necklace”).^3,6 Erythema develops on areas of sun-exposed skin and may be painful or pruritic.⁶ It may take up to four times as long to resolve as a normal sunburn.⁶ On repeated exposure, the skin becomes thickened, hyperkeratotic, and hyperpigmented.⁶

DIAGNOSIS AND TREATMENT OF PELLAGRA

Suspicion of pellagra should be high in any patient with chronic alcohol abuse with changes in mental status.⁵ Pellagra is typically diagnosed clinically. Although testing of serum levels of niacin or urine levels of niacin metabolites can be performed,^4,5 these tests are not commonly used, as they are neither widely available nor reliable.^3,4 Because there is little downside to giving niacin, treatment should be started if there is clinical suspicion of pellagra.^3,4 The diagnosis is confirmed by clinical improvement after niacin replacement begins.⁴

Pellagra is easy and inexpensive to treat once the diagnosis has been established. Supplementation can be given orally at 50 mg to 100 mg three times daily, with a maximum of 500 mg daily for 3 to 4 weeks.^3,5 The multivitamin our patient initially received provided only 30 mg of niacin, which was insufficient to treat his deficiency.

Other micronutrient deficiencies are also common in pellagra, such as the suspected thiamine deficiency in this patient. Although rare in adults, pyridoxine deficiency should be considered because pyridoxine plays an important role in niacin metabolism, and in patients such as this, the signs and symptoms of pellagra will not resolve with niacin administration alone.^3,4

Neurologic symptoms can begin to resolve as soon as 24 to 48 hours after replacement therapy is started, although skin symptoms take longer to respond.⁶

OUR PATIENT’S MANAGEMENT AND LESSONS LEARNED

Our patient was treated with extended-release niacin 500 mg daily. He was significantly less confused within 24 hours, and 2 days later he was no longer delirious. His diarrhea resolved, but his peripheral neuropathy improved only modestly, and we believe that this was the result of his long history of alcohol abuse.

Although there are guidelines to help with the management of patients undergoing alcohol withdrawal, our experience with this patient illustrates that important clinical conditions, including micronutrient deficiencies, can easily be overlooked or misattributed, with potentially dangerous consequences. It is crucial to be mindful of these considerations.

The Advisory Committee on Immunization Practices (ACIP) currently recommends that people who have not completed the three-dose vaccination series against hepatitis B virus (HBV) should receive the missed doses: ie, the three-dose regimen does not need to be restarted.¹ However, evidence suggests that a two-dose regimen may provide adequate seroprotection for healthy young adults.

As the three-dose regimen has been shown to protect 90% to 100% of adults,² it has gained widespread acceptance and is now standard clinical practice.² However, deviating from the three-dose regimen may not leave healthy young adults vulnerable to HBV infection.

RECOMMENDED DOSES AND SCHEDULES

Widespread use of the three-dose regimen for HBV stemmed from the first clinical evaluation of the recombinant vaccine, in which three 10-μg doses were given at 0, 1, and 6 months to healthy, low-risk adult volunteers.³ This regimen was shown to provide seroprotection in over 95% of adolescents and 90% of healthy adults.²

Currently, three HBV vaccines for adults are approved in the United States: Recombivax HB, Engerix-B, and Twinrix (Table 1). While Recombivax has a seroprotection rate of 89% in healthy adults over age 40, it has higher seroprotection rates in younger people: eg, two doses of Recombivax given 4 to 6 months apart provide seroprotection to 99% of children aged 11 to 15.⁴ On the other hand, patients on hemodialysis require three 40-μg doses of Recombivax or four 40-μg doses of Engerix-B.

Evidence for a two-dose regimen

Since the development of the recombinant HBV vaccine used today, studies have shown that a two-dose regimen offers seroprotection comparable with, if not better than, the three-dose regimen in adolescents and healthy young adults. Marsano et al⁵ found that with a two-dose regimen, 96% to 99% of young adults attained seroprotection, with immune memory persisting for up to 2 years.⁵ Moreover, Cassidy et al⁶ randomized adolescents to a two-dose or a three-dose regimen and found the two regimens to be equally effective in conferring immunogenicity and immunologic memory.⁶

Other studies in adolescents have confirmed these findings and offered new evidence in support of the two-dose regimen.^7,8 For example, studies found that the two-dose regimen conferred seroprotection at even lower doses than previously studied, and that it conferred immune memory lasting at least 5 years.^6,7

However, because these studies were conducted in adolescents and healthy young adults, the findings may not hold true for other populations. Studies suggest that the three-dose regimen is best for those over age 40. Moreover, it is advisable to adhere to a three-dose regimen when treating people at high risk of contracting HBV, such as health care workers; people with chronic liver disease, diabetes mellitus, or end-stage renal disease on hemodialysis; people who have multiple sex partners; and men who have sex with men.

The impact of long intervals between doses

Although the aforementioned studies focused on a two-dose regimen with a 6-month interval, longer intervals between doses do not impair seroprotection and in some cases may even prove beneficial. Heron et al⁹ demonstrated that a two-dose regimen with a 12-month interval induces seroprotection as effectively as a standard three-dose or two-dose regimen with a 6-month interval.⁹ Moreover, studies of the impact of deviating from a three-dose regimen found that intervals of longer than 1 year did not impede seroprotection. Not only may seroprotection be attained with intervals of 5 to 10 years before the final dose, but final antibody levels tend to increase with increasing time between doses.¹⁰

Nevertheless, even though an extended interval between doses may prove beneficial after the final dose is received, delaying doses may leave patients unprotected. Indeed, alternative three-dose and even four-dose schedules with shorter intervals between doses exist for certain high-risk populations, such as those recently exposed to HBV and travelers to areas of high prevalence. Therefore, intentionally extending intervals between doses may be inappropriate.

SEROPROTECTION AND PROTECTION AGAINST INFECTION

Legitimate concerns exist about the final antibody level attained with a two-dose regimen, which is typically lower than that attained with a three-dose regimen. As HBV antibody levels decline with time, lower final antibody levels theoretically increase the risk of losing seroprotection. Study of vaccine efficacy has defined seroprotection as antibody levels greater than or equal to 10 mIU/mL.¹¹ Yet evidence suggests that even when antibody levels drop below this level, the risk of symptomatic HBV infection does not increase. Evidence also suggests that immune memory outlasts the presence of seroprotective antibody levels, indicating that true protection against significant infection does not necessarily correlate with, and may even exceed, seroprotection.² This may relate to HBV’s long incubation period, which allows memory cells time to generate an effective immune response.¹⁰ For example, Floreani et al¹² showed that even though 15% of adults lost seroprotective antibody levels 10 years after vaccination, none demonstrated hepatitis B antigen reactivity or seroconversion.

POSTVACCINATION TESTING AND ADDITIONAL DOSES

At times, it may be wise to measure antibody levels after the final dose to confirm seroprotection. Seroprotection should be documented when knowledge of the patient’s immune status will affect subsequent management. As recommended by the US Centers for Disease Control and Prevention, health care workers, hemodialysis patients, immunocompromised patients, and sexual partners of patients with chronic HBV infection should undergo antibody testing 1 to 2 months after the completion of a three-dose vaccination regimen. Hemodialysis patients require annual confirmation of seroprotection and should receive booster doses of HBV vaccine if necessary.

Postvaccination testing (quantitative HBV surface antibody testing) costs about the same as a single dose of HBV vaccine. Therefore, if postvaccination testing is considered because of missed vaccine doses, it may be more cost-efficient to simply administer the missed dose.

The Advisory Committee on Immunization Practices (ACIP) currently recommends that people who have not completed the three-dose vaccination series against hepatitis B virus (HBV) should receive the missed doses: ie, the three-dose regimen does not need to be restarted.¹ However, evidence suggests that a two-dose regimen may provide adequate seroprotection for healthy young adults.

As the three-dose regimen has been shown to protect 90% to 100% of adults,² it has gained widespread acceptance and is now standard clinical practice.² However, deviating from the three-dose regimen may not leave healthy young adults vulnerable to HBV infection.

RECOMMENDED DOSES AND SCHEDULES

Widespread use of the three-dose regimen for HBV stemmed from the first clinical evaluation of the recombinant vaccine, in which three 10-μg doses were given at 0, 1, and 6 months to healthy, low-risk adult volunteers.³ This regimen was shown to provide seroprotection in over 95% of adolescents and 90% of healthy adults.²

Currently, three HBV vaccines for adults are approved in the United States: Recombivax HB, Engerix-B, and Twinrix (Table 1). While Recombivax has a seroprotection rate of 89% in healthy adults over age 40, it has higher seroprotection rates in younger people: eg, two doses of Recombivax given 4 to 6 months apart provide seroprotection to 99% of children aged 11 to 15.⁴ On the other hand, patients on hemodialysis require three 40-μg doses of Recombivax or four 40-μg doses of Engerix-B.

Evidence for a two-dose regimen

Since the development of the recombinant HBV vaccine used today, studies have shown that a two-dose regimen offers seroprotection comparable with, if not better than, the three-dose regimen in adolescents and healthy young adults. Marsano et al⁵ found that with a two-dose regimen, 96% to 99% of young adults attained seroprotection, with immune memory persisting for up to 2 years.⁵ Moreover, Cassidy et al⁶ randomized adolescents to a two-dose or a three-dose regimen and found the two regimens to be equally effective in conferring immunogenicity and immunologic memory.⁶

Other studies in adolescents have confirmed these findings and offered new evidence in support of the two-dose regimen.^7,8 For example, studies found that the two-dose regimen conferred seroprotection at even lower doses than previously studied, and that it conferred immune memory lasting at least 5 years.^6,7

However, because these studies were conducted in adolescents and healthy young adults, the findings may not hold true for other populations. Studies suggest that the three-dose regimen is best for those over age 40. Moreover, it is advisable to adhere to a three-dose regimen when treating people at high risk of contracting HBV, such as health care workers; people with chronic liver disease, diabetes mellitus, or end-stage renal disease on hemodialysis; people who have multiple sex partners; and men who have sex with men.

The impact of long intervals between doses

Although the aforementioned studies focused on a two-dose regimen with a 6-month interval, longer intervals between doses do not impair seroprotection and in some cases may even prove beneficial. Heron et al⁹ demonstrated that a two-dose regimen with a 12-month interval induces seroprotection as effectively as a standard three-dose or two-dose regimen with a 6-month interval.⁹ Moreover, studies of the impact of deviating from a three-dose regimen found that intervals of longer than 1 year did not impede seroprotection. Not only may seroprotection be attained with intervals of 5 to 10 years before the final dose, but final antibody levels tend to increase with increasing time between doses.¹⁰

Nevertheless, even though an extended interval between doses may prove beneficial after the final dose is received, delaying doses may leave patients unprotected. Indeed, alternative three-dose and even four-dose schedules with shorter intervals between doses exist for certain high-risk populations, such as those recently exposed to HBV and travelers to areas of high prevalence. Therefore, intentionally extending intervals between doses may be inappropriate.

SEROPROTECTION AND PROTECTION AGAINST INFECTION

Legitimate concerns exist about the final antibody level attained with a two-dose regimen, which is typically lower than that attained with a three-dose regimen. As HBV antibody levels decline with time, lower final antibody levels theoretically increase the risk of losing seroprotection. Study of vaccine efficacy has defined seroprotection as antibody levels greater than or equal to 10 mIU/mL.¹¹ Yet evidence suggests that even when antibody levels drop below this level, the risk of symptomatic HBV infection does not increase. Evidence also suggests that immune memory outlasts the presence of seroprotective antibody levels, indicating that true protection against significant infection does not necessarily correlate with, and may even exceed, seroprotection.² This may relate to HBV’s long incubation period, which allows memory cells time to generate an effective immune response.¹⁰ For example, Floreani et al¹² showed that even though 15% of adults lost seroprotective antibody levels 10 years after vaccination, none demonstrated hepatitis B antigen reactivity or seroconversion.

POSTVACCINATION TESTING AND ADDITIONAL DOSES

At times, it may be wise to measure antibody levels after the final dose to confirm seroprotection. Seroprotection should be documented when knowledge of the patient’s immune status will affect subsequent management. As recommended by the US Centers for Disease Control and Prevention, health care workers, hemodialysis patients, immunocompromised patients, and sexual partners of patients with chronic HBV infection should undergo antibody testing 1 to 2 months after the completion of a three-dose vaccination regimen. Hemodialysis patients require annual confirmation of seroprotection and should receive booster doses of HBV vaccine if necessary.

Postvaccination testing (quantitative HBV surface antibody testing) costs about the same as a single dose of HBV vaccine. Therefore, if postvaccination testing is considered because of missed vaccine doses, it may be more cost-efficient to simply administer the missed dose.

The Advisory Committee on Immunization Practices (ACIP) currently recommends that people who have not completed the three-dose vaccination series against hepatitis B virus (HBV) should receive the missed doses: ie, the three-dose regimen does not need to be restarted.¹ However, evidence suggests that a two-dose regimen may provide adequate seroprotection for healthy young adults.

As the three-dose regimen has been shown to protect 90% to 100% of adults,² it has gained widespread acceptance and is now standard clinical practice.² However, deviating from the three-dose regimen may not leave healthy young adults vulnerable to HBV infection.

RECOMMENDED DOSES AND SCHEDULES

Widespread use of the three-dose regimen for HBV stemmed from the first clinical evaluation of the recombinant vaccine, in which three 10-μg doses were given at 0, 1, and 6 months to healthy, low-risk adult volunteers.³ This regimen was shown to provide seroprotection in over 95% of adolescents and 90% of healthy adults.²

Currently, three HBV vaccines for adults are approved in the United States: Recombivax HB, Engerix-B, and Twinrix (Table 1). While Recombivax has a seroprotection rate of 89% in healthy adults over age 40, it has higher seroprotection rates in younger people: eg, two doses of Recombivax given 4 to 6 months apart provide seroprotection to 99% of children aged 11 to 15.⁴ On the other hand, patients on hemodialysis require three 40-μg doses of Recombivax or four 40-μg doses of Engerix-B.

Evidence for a two-dose regimen

Since the development of the recombinant HBV vaccine used today, studies have shown that a two-dose regimen offers seroprotection comparable with, if not better than, the three-dose regimen in adolescents and healthy young adults. Marsano et al⁵ found that with a two-dose regimen, 96% to 99% of young adults attained seroprotection, with immune memory persisting for up to 2 years.⁵ Moreover, Cassidy et al⁶ randomized adolescents to a two-dose or a three-dose regimen and found the two regimens to be equally effective in conferring immunogenicity and immunologic memory.⁶

Other studies in adolescents have confirmed these findings and offered new evidence in support of the two-dose regimen.^7,8 For example, studies found that the two-dose regimen conferred seroprotection at even lower doses than previously studied, and that it conferred immune memory lasting at least 5 years.^6,7

However, because these studies were conducted in adolescents and healthy young adults, the findings may not hold true for other populations. Studies suggest that the three-dose regimen is best for those over age 40. Moreover, it is advisable to adhere to a three-dose regimen when treating people at high risk of contracting HBV, such as health care workers; people with chronic liver disease, diabetes mellitus, or end-stage renal disease on hemodialysis; people who have multiple sex partners; and men who have sex with men.

The impact of long intervals between doses

Although the aforementioned studies focused on a two-dose regimen with a 6-month interval, longer intervals between doses do not impair seroprotection and in some cases may even prove beneficial. Heron et al⁹ demonstrated that a two-dose regimen with a 12-month interval induces seroprotection as effectively as a standard three-dose or two-dose regimen with a 6-month interval.⁹ Moreover, studies of the impact of deviating from a three-dose regimen found that intervals of longer than 1 year did not impede seroprotection. Not only may seroprotection be attained with intervals of 5 to 10 years before the final dose, but final antibody levels tend to increase with increasing time between doses.¹⁰

Nevertheless, even though an extended interval between doses may prove beneficial after the final dose is received, delaying doses may leave patients unprotected. Indeed, alternative three-dose and even four-dose schedules with shorter intervals between doses exist for certain high-risk populations, such as those recently exposed to HBV and travelers to areas of high prevalence. Therefore, intentionally extending intervals between doses may be inappropriate.

SEROPROTECTION AND PROTECTION AGAINST INFECTION

Legitimate concerns exist about the final antibody level attained with a two-dose regimen, which is typically lower than that attained with a three-dose regimen. As HBV antibody levels decline with time, lower final antibody levels theoretically increase the risk of losing seroprotection. Study of vaccine efficacy has defined seroprotection as antibody levels greater than or equal to 10 mIU/mL.¹¹ Yet evidence suggests that even when antibody levels drop below this level, the risk of symptomatic HBV infection does not increase. Evidence also suggests that immune memory outlasts the presence of seroprotective antibody levels, indicating that true protection against significant infection does not necessarily correlate with, and may even exceed, seroprotection.² This may relate to HBV’s long incubation period, which allows memory cells time to generate an effective immune response.¹⁰ For example, Floreani et al¹² showed that even though 15% of adults lost seroprotective antibody levels 10 years after vaccination, none demonstrated hepatitis B antigen reactivity or seroconversion.

POSTVACCINATION TESTING AND ADDITIONAL DOSES

At times, it may be wise to measure antibody levels after the final dose to confirm seroprotection. Seroprotection should be documented when knowledge of the patient’s immune status will affect subsequent management. As recommended by the US Centers for Disease Control and Prevention, health care workers, hemodialysis patients, immunocompromised patients, and sexual partners of patients with chronic HBV infection should undergo antibody testing 1 to 2 months after the completion of a three-dose vaccination regimen. Hemodialysis patients require annual confirmation of seroprotection and should receive booster doses of HBV vaccine if necessary.

Postvaccination testing (quantitative HBV surface antibody testing) costs about the same as a single dose of HBV vaccine. Therefore, if postvaccination testing is considered because of missed vaccine doses, it may be more cost-efficient to simply administer the missed dose.

Some common diseases outside of my specialty areas of interest have, over time, blended into the background of daily practice. When patients have clearly inadequately controlled disease I refer them back to their internist or relevant subspecialist. Otherwise I find myself accepting the clinical status quo, providing stopgap care when necessary, utilizing my present knowledge of the disease process. But if I am not aware of any paradigm shifts in management, I tend to just peruse the published studies of new drug therapies as they appear in major journals, and not necessarily incorporate new therapies into my practice.

Chronic obstructive pulmonary disease (COPD) is one of those diseases, and the update by Hatipoğlu and Aboussouan in this issue of the Journal provided the opportunity to review some important things I have missed and to take note of the therapeutic principles that haven’t changed that much.

The incidence of COPD seems to be increasing. Cigarette smoking remains the major reversible cause, but one-fourth of current COPD patients have never smoked.

Patients who have early COPD may not be asked about or may not volunteer complaints specific to COPD. Lung examinations are insensitive, and chest radiography, if done, rarely identifies patients with early disease, so it is no surprise that COPD is underdiagnosed. While for many patients it is unclear whether the natural progression of lung damage can be dramatically altered by early diagnosis, other than by stopping smoking, that may not be the case for subsets of patients such as those with alpha-1 antitrypsin deficiency. But COPD generally has to be suspected in order to prompt appropriate screening for it.

COPD is still diagnosed by spirometry, with findings demonstrating incompletely reversible airway obstruction. The forced expiratory volume in 1 second (FEV₁), a spirometric measure required to make the diagnosis, has been a useful surrogate marker of drug efficacy, but it is far from the ideal measure of disease progression and risk of death. Patients who have frequent exacerbations requiring hospitalization tend to have a tumultuous clinical course. The best predictor of future exacerbations is the patient’s history of exacerbations. Reducing the exacerbation rate improves the quality of life but may not translate to a benefit in terms of the mortality risk.

A lower risk of death is most consistently attained by helping patients stop smoking and, if they have sustained hypoxemia, giving them supplemental oxygen. The former intervention is the population game-changer—yet the US Centers for Disease Control and Prevention reports that 18% of American adults still smoke cigarettes, a number that dropped only slightly between 2005 and 2012. Americans with less education and less income more frequently smoke cigarettes, and it is estimated that one in 13 Americans currently 17 years or younger will die prematurely from the effects of cigarette smoking.

As for newer therapies, many that are applicable to most patients with COPD represent a fine-tuning of drug therapies we have been using for decades. Thus, it is not surprising that no dramatic increase in survival rates has been achieved. The advantage of several of the newer therapies in terms of FEV₁ or exacerbation rate is statistically significant but relatively modest in terms of clinical impact. Their clinical promise (including specific antibiotics in low doses), revealed in recent studies, may be dependent upon using them in the most appropriate patients. Reducing the exacerbation rate is a significant advantage, but I would also like to know which drugs or drug combinations are most likely to permit major reductions in patients’ corticosteroid requirements. Hopefully, these data will come from real-world comparative efficacy studies.

Reading the article by Hatipoğlu and Aboussouan, I was reminded that utilizing our pulmonary colleagues’ expertise is of particular value in individualizing therapy for our patients with COPD—using newer drugs and combinations when most appropriate, not just because they are readily available. As physicians who are not pulmonary specialists, we need to be vigilant in recognizing the treatable comorbidities that contribute to dyspnea and poor outcome in patients with COPD, such as obstructive sleep apnea, congestive heart failure, obesity, and thromboembolism.

But to make the largest impact on the mortality rate, we need to continue to engage in and expand the ongoing war against cigarette use.

Some common diseases outside of my specialty areas of interest have, over time, blended into the background of daily practice. When patients have clearly inadequately controlled disease I refer them back to their internist or relevant subspecialist. Otherwise I find myself accepting the clinical status quo, providing stopgap care when necessary, utilizing my present knowledge of the disease process. But if I am not aware of any paradigm shifts in management, I tend to just peruse the published studies of new drug therapies as they appear in major journals, and not necessarily incorporate new therapies into my practice.

Chronic obstructive pulmonary disease (COPD) is one of those diseases, and the update by Hatipoğlu and Aboussouan in this issue of the Journal provided the opportunity to review some important things I have missed and to take note of the therapeutic principles that haven’t changed that much.

The incidence of COPD seems to be increasing. Cigarette smoking remains the major reversible cause, but one-fourth of current COPD patients have never smoked.

Patients who have early COPD may not be asked about or may not volunteer complaints specific to COPD. Lung examinations are insensitive, and chest radiography, if done, rarely identifies patients with early disease, so it is no surprise that COPD is underdiagnosed. While for many patients it is unclear whether the natural progression of lung damage can be dramatically altered by early diagnosis, other than by stopping smoking, that may not be the case for subsets of patients such as those with alpha-1 antitrypsin deficiency. But COPD generally has to be suspected in order to prompt appropriate screening for it.

COPD is still diagnosed by spirometry, with findings demonstrating incompletely reversible airway obstruction. The forced expiratory volume in 1 second (FEV₁), a spirometric measure required to make the diagnosis, has been a useful surrogate marker of drug efficacy, but it is far from the ideal measure of disease progression and risk of death. Patients who have frequent exacerbations requiring hospitalization tend to have a tumultuous clinical course. The best predictor of future exacerbations is the patient’s history of exacerbations. Reducing the exacerbation rate improves the quality of life but may not translate to a benefit in terms of the mortality risk.

A lower risk of death is most consistently attained by helping patients stop smoking and, if they have sustained hypoxemia, giving them supplemental oxygen. The former intervention is the population game-changer—yet the US Centers for Disease Control and Prevention reports that 18% of American adults still smoke cigarettes, a number that dropped only slightly between 2005 and 2012. Americans with less education and less income more frequently smoke cigarettes, and it is estimated that one in 13 Americans currently 17 years or younger will die prematurely from the effects of cigarette smoking.

As for newer therapies, many that are applicable to most patients with COPD represent a fine-tuning of drug therapies we have been using for decades. Thus, it is not surprising that no dramatic increase in survival rates has been achieved. The advantage of several of the newer therapies in terms of FEV₁ or exacerbation rate is statistically significant but relatively modest in terms of clinical impact. Their clinical promise (including specific antibiotics in low doses), revealed in recent studies, may be dependent upon using them in the most appropriate patients. Reducing the exacerbation rate is a significant advantage, but I would also like to know which drugs or drug combinations are most likely to permit major reductions in patients’ corticosteroid requirements. Hopefully, these data will come from real-world comparative efficacy studies.

Reading the article by Hatipoğlu and Aboussouan, I was reminded that utilizing our pulmonary colleagues’ expertise is of particular value in individualizing therapy for our patients with COPD—using newer drugs and combinations when most appropriate, not just because they are readily available. As physicians who are not pulmonary specialists, we need to be vigilant in recognizing the treatable comorbidities that contribute to dyspnea and poor outcome in patients with COPD, such as obstructive sleep apnea, congestive heart failure, obesity, and thromboembolism.

But to make the largest impact on the mortality rate, we need to continue to engage in and expand the ongoing war against cigarette use.

Some common diseases outside of my specialty areas of interest have, over time, blended into the background of daily practice. When patients have clearly inadequately controlled disease I refer them back to their internist or relevant subspecialist. Otherwise I find myself accepting the clinical status quo, providing stopgap care when necessary, utilizing my present knowledge of the disease process. But if I am not aware of any paradigm shifts in management, I tend to just peruse the published studies of new drug therapies as they appear in major journals, and not necessarily incorporate new therapies into my practice.

Chronic obstructive pulmonary disease (COPD) is one of those diseases, and the update by Hatipoğlu and Aboussouan in this issue of the Journal provided the opportunity to review some important things I have missed and to take note of the therapeutic principles that haven’t changed that much.

The incidence of COPD seems to be increasing. Cigarette smoking remains the major reversible cause, but one-fourth of current COPD patients have never smoked.

Patients who have early COPD may not be asked about or may not volunteer complaints specific to COPD. Lung examinations are insensitive, and chest radiography, if done, rarely identifies patients with early disease, so it is no surprise that COPD is underdiagnosed. While for many patients it is unclear whether the natural progression of lung damage can be dramatically altered by early diagnosis, other than by stopping smoking, that may not be the case for subsets of patients such as those with alpha-1 antitrypsin deficiency. But COPD generally has to be suspected in order to prompt appropriate screening for it.

COPD is still diagnosed by spirometry, with findings demonstrating incompletely reversible airway obstruction. The forced expiratory volume in 1 second (FEV₁), a spirometric measure required to make the diagnosis, has been a useful surrogate marker of drug efficacy, but it is far from the ideal measure of disease progression and risk of death. Patients who have frequent exacerbations requiring hospitalization tend to have a tumultuous clinical course. The best predictor of future exacerbations is the patient’s history of exacerbations. Reducing the exacerbation rate improves the quality of life but may not translate to a benefit in terms of the mortality risk.

A lower risk of death is most consistently attained by helping patients stop smoking and, if they have sustained hypoxemia, giving them supplemental oxygen. The former intervention is the population game-changer—yet the US Centers for Disease Control and Prevention reports that 18% of American adults still smoke cigarettes, a number that dropped only slightly between 2005 and 2012. Americans with less education and less income more frequently smoke cigarettes, and it is estimated that one in 13 Americans currently 17 years or younger will die prematurely from the effects of cigarette smoking.

As for newer therapies, many that are applicable to most patients with COPD represent a fine-tuning of drug therapies we have been using for decades. Thus, it is not surprising that no dramatic increase in survival rates has been achieved. The advantage of several of the newer therapies in terms of FEV₁ or exacerbation rate is statistically significant but relatively modest in terms of clinical impact. Their clinical promise (including specific antibiotics in low doses), revealed in recent studies, may be dependent upon using them in the most appropriate patients. Reducing the exacerbation rate is a significant advantage, but I would also like to know which drugs or drug combinations are most likely to permit major reductions in patients’ corticosteroid requirements. Hopefully, these data will come from real-world comparative efficacy studies.

Reading the article by Hatipoğlu and Aboussouan, I was reminded that utilizing our pulmonary colleagues’ expertise is of particular value in individualizing therapy for our patients with COPD—using newer drugs and combinations when most appropriate, not just because they are readily available. As physicians who are not pulmonary specialists, we need to be vigilant in recognizing the treatable comorbidities that contribute to dyspnea and poor outcome in patients with COPD, such as obstructive sleep apnea, congestive heart failure, obesity, and thromboembolism.

But to make the largest impact on the mortality rate, we need to continue to engage in and expand the ongoing war against cigarette use.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.