Pulmonology

When making prescribing decisions, health care professionals should assume that apps for depression and smoking cessation will share user data with third parties despite claims made in privacy policy statements, recent research shows.

“Mechanisms that potentially enable a small number of dominant online service providers to link information about the use of mental health apps, without either user consent or awareness, appear to be prevalent,” Kit Huckvale, MB ChB, MSc, PhD, of Black Dog Institute at the University of New South Wales Sydney in Randwick, New South Wales, Australia, and colleagues wrote in their study. “Mismatches between declared privacy policies and observed behavior highlight the continuing need for innovation around trust and transparency for health apps.” The study was published in JAMA Network Open.

Dr. Huckvale and colleagues examined the top 36 depression and smoking cessation apps for Android and iOS in the United States accessed in January 2018; Of the apps downloaded, 15 apps were Android-only, 14 apps were iOS-only, and 7 apps were available on both platforms. The apps were assessed over a series of two sessions while network traffic was captured during use, which allowed researchers to determine what personal information was in each data transmission and where the information was going.

There were 25 apps with a privacy policy (69%), 22 of 25 apps (88%) described how that app primarily collected data, and only 16 of 25 apps (64%) provided information on secondary uses of data. Despite 23 of 25 apps (92%) addressing “the possibility of transmission of data to any third party,” 33 of 36 apps overall (92%) transmitted data to third parties. The two most common entities that received third-party data for marketing, advertising, or analytic purposes were Google and Facebook (29 of 36 apps; 81%). However, 12 of 28 apps (43%) that sent data to Google and 6 of 12 apps (50%) that sent data to Facebook disclosed that they would share data with those companies.

The type of data sent to Google and Facebook consisted of a strong identifier to the device or a username (9 of 33 apps; 27%), or a weak identifier in the form of an advertising identifier or a pseudonymous profile that can link users to their behavior on the app and on other products and platforms (26 of 33 apps; 79%).

“As smartphones continue to gain capabilities to collect new forms of personal, biometric, and health information, it is imperative for the health care community to respond with new methods and processes to review apps and ensure they remain safe and protect personal health information,” the researchers concluded.

One of the investigators, Mark E. Larsen, DPhil, reported receiving grants from National Health and Medical Research Council. The other authors reported no relevant conflicts of interest.

SOURCE: Huckvale K et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.2542.

When making prescribing decisions, health care professionals should assume that apps for depression and smoking cessation will share user data with third parties despite claims made in privacy policy statements, recent research shows.

“Mechanisms that potentially enable a small number of dominant online service providers to link information about the use of mental health apps, without either user consent or awareness, appear to be prevalent,” Kit Huckvale, MB ChB, MSc, PhD, of Black Dog Institute at the University of New South Wales Sydney in Randwick, New South Wales, Australia, and colleagues wrote in their study. “Mismatches between declared privacy policies and observed behavior highlight the continuing need for innovation around trust and transparency for health apps.” The study was published in JAMA Network Open.

Dr. Huckvale and colleagues examined the top 36 depression and smoking cessation apps for Android and iOS in the United States accessed in January 2018; Of the apps downloaded, 15 apps were Android-only, 14 apps were iOS-only, and 7 apps were available on both platforms. The apps were assessed over a series of two sessions while network traffic was captured during use, which allowed researchers to determine what personal information was in each data transmission and where the information was going.

There were 25 apps with a privacy policy (69%), 22 of 25 apps (88%) described how that app primarily collected data, and only 16 of 25 apps (64%) provided information on secondary uses of data. Despite 23 of 25 apps (92%) addressing “the possibility of transmission of data to any third party,” 33 of 36 apps overall (92%) transmitted data to third parties. The two most common entities that received third-party data for marketing, advertising, or analytic purposes were Google and Facebook (29 of 36 apps; 81%). However, 12 of 28 apps (43%) that sent data to Google and 6 of 12 apps (50%) that sent data to Facebook disclosed that they would share data with those companies.

The type of data sent to Google and Facebook consisted of a strong identifier to the device or a username (9 of 33 apps; 27%), or a weak identifier in the form of an advertising identifier or a pseudonymous profile that can link users to their behavior on the app and on other products and platforms (26 of 33 apps; 79%).

“As smartphones continue to gain capabilities to collect new forms of personal, biometric, and health information, it is imperative for the health care community to respond with new methods and processes to review apps and ensure they remain safe and protect personal health information,” the researchers concluded.

One of the investigators, Mark E. Larsen, DPhil, reported receiving grants from National Health and Medical Research Council. The other authors reported no relevant conflicts of interest.

SOURCE: Huckvale K et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.2542.

When making prescribing decisions, health care professionals should assume that apps for depression and smoking cessation will share user data with third parties despite claims made in privacy policy statements, recent research shows.

“Mechanisms that potentially enable a small number of dominant online service providers to link information about the use of mental health apps, without either user consent or awareness, appear to be prevalent,” Kit Huckvale, MB ChB, MSc, PhD, of Black Dog Institute at the University of New South Wales Sydney in Randwick, New South Wales, Australia, and colleagues wrote in their study. “Mismatches between declared privacy policies and observed behavior highlight the continuing need for innovation around trust and transparency for health apps.” The study was published in JAMA Network Open.

Dr. Huckvale and colleagues examined the top 36 depression and smoking cessation apps for Android and iOS in the United States accessed in January 2018; Of the apps downloaded, 15 apps were Android-only, 14 apps were iOS-only, and 7 apps were available on both platforms. The apps were assessed over a series of two sessions while network traffic was captured during use, which allowed researchers to determine what personal information was in each data transmission and where the information was going.

There were 25 apps with a privacy policy (69%), 22 of 25 apps (88%) described how that app primarily collected data, and only 16 of 25 apps (64%) provided information on secondary uses of data. Despite 23 of 25 apps (92%) addressing “the possibility of transmission of data to any third party,” 33 of 36 apps overall (92%) transmitted data to third parties. The two most common entities that received third-party data for marketing, advertising, or analytic purposes were Google and Facebook (29 of 36 apps; 81%). However, 12 of 28 apps (43%) that sent data to Google and 6 of 12 apps (50%) that sent data to Facebook disclosed that they would share data with those companies.

The type of data sent to Google and Facebook consisted of a strong identifier to the device or a username (9 of 33 apps; 27%), or a weak identifier in the form of an advertising identifier or a pseudonymous profile that can link users to their behavior on the app and on other products and platforms (26 of 33 apps; 79%).

“As smartphones continue to gain capabilities to collect new forms of personal, biometric, and health information, it is imperative for the health care community to respond with new methods and processes to review apps and ensure they remain safe and protect personal health information,” the researchers concluded.

One of the investigators, Mark E. Larsen, DPhil, reported receiving grants from National Health and Medical Research Council. The other authors reported no relevant conflicts of interest.

SOURCE: Huckvale K et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.2542.

See Mangione and Aronowitz editorials

Mechanical pressure induced by friction of the elbows on the thighs may result in proliferation of the stratum corneum and the release of hemosiderin from erythrocytes, resulting in the skin changes seen in this patient, which because of the tripod positioning are known as “thinker’s sign,” a term coined in 1963 by Rothenberg¹ to describe findings in patients with chronic pulmonary disease and advanced respiratory insufficiency. It is also referred to as the Dahl sign, based on a report by Dahl of similar findings in patients with emphysema.²

See Mangione and Aronowitz editorials

Mechanical pressure induced by friction of the elbows on the thighs may result in proliferation of the stratum corneum and the release of hemosiderin from erythrocytes, resulting in the skin changes seen in this patient, which because of the tripod positioning are known as “thinker’s sign,” a term coined in 1963 by Rothenberg¹ to describe findings in patients with chronic pulmonary disease and advanced respiratory insufficiency. It is also referred to as the Dahl sign, based on a report by Dahl of similar findings in patients with emphysema.²

See Mangione and Aronowitz editorials

Mechanical pressure induced by friction of the elbows on the thighs may result in proliferation of the stratum corneum and the release of hemosiderin from erythrocytes, resulting in the skin changes seen in this patient, which because of the tripod positioning are known as “thinker’s sign,” a term coined in 1963 by Rothenberg¹ to describe findings in patients with chronic pulmonary disease and advanced respiratory insufficiency. It is also referred to as the Dahl sign, based on a report by Dahl of similar findings in patients with emphysema.²

Pneumocystis jirovecii (previously carinii) pneumonia (PCP) is rare in patients taking biologic response modifiers for rheumatic disease.^1–10 However, prophylaxis should be considered in patients who have granulomatosis with polyangiitis or underlying pulmonary disease, or who are concomitantly receiving glucocorticoids in high doses. There is some risk of adverse reactions to the prophylactic medicine.^1,11–21 Until clear guidelines are available, the decision to initiate PCP prophylaxis and the choice of agent should be individualized.

THE BURDEN OF PCP

In a meta-analysis²³ of 867 patients who developed PCP and did not have HIV infection, 20.1% had autoimmune or chronic inflammatory disease and the rest were transplant recipients or had malignancies. The mortality rate was 30.6%.

PHARMACOLOGIC RISK FACTORS FOR PCP

Treatment with glucocorticoids

Treatment with glucocorticoids is an important risk factor for PCP, independent of biologic therapy.

Calero-Bernal et al¹¹ reported on 128 patients with non-HIV PCP, of whom 114 (89%) had received a glucocorticoid for more than 4 weeks, and 98 (76%) were currently receiving one. The mean daily dose was equivalent to 27.73 mg of prednisone per day in those on glucocorticoids only, and 21.34 mg in those receiving glucocorticoids in combination with other immunosuppressants.

Park et al,¹² in a retrospective study of Korean patients treated for rheumatic disease with high-dose glucocorticoids (≥ 30 mg/day of prednisone or equivalent for more than 4 weeks), reported an incidence rate of PCP of 2.37 per 100 patient-years in those not on prophylaxis.

Other studies^13,14 have also found a prednisone dose greater than 15 to 20 mg per day for more than 4 weeks or concomitant use of 2 or more disease-modifying antirheumatic drugs to be a significant risk factor.^13,14

Tumor necrosis factor alpha antagonists

A US Food and Drug Administration review¹ of voluntary reports of adverse drug events estimated the incidence of PCP to be 2.3 per 100,000 patient-years with infliximab and 1.6 per 100,000 patient-years with etanercept. In most cases, other immunosuppressants were used concomitantly.¹

Postmarketing surveillance² of 5,000 patients with rheumatoid arthritis showed an incidence of suspected PCP of 0.4% within the first 6 months of starting infliximab therapy.

Komano et al,¹⁵ in a case-control study of patients with rheumatoid arthritis treated with infliximab, reported that all 21 patients with PCP were also on methotrexate (median dosage 8 mg per week) and prednisolone (median dosage 7.5 mg per day).

PCP has also been reported after adalimumab use in combination with prednisone, azathioprine, and methotrexate, as well as with certolizumab, golimumab, tocilizumab, abatacept, and rituximab.^{3–6,24–26}

Rituximab

Calero-Bernal et al¹¹ reported that 23% of patients with non-HIV PCP who were receiving immunosuppressant drugs were on rituximab.

Alexandre et al¹⁶ performed a retrospective review of 11 cases of PCP complicating rituximab therapy for autoimmune disease, in which 10 (91%) of the patients were also on corticosteroids, with a median dosage of 30 mg of prednisone daily. A literature review of an additional 18 cases revealed similar findings.

 

 

PATIENT RISK FACTORS FOR PCP

Pulmonary disease, age, other factors

Komano et al,¹⁵ in their study of patients with rheumatoid arthritis treated with infliximab, found that 10 (48%) of 21 patients with PCP had preexisting pulmonary disease, compared with 11 (10.8%) of 102 patients without PCP (P < .001). Patients with PCP were older (mean age 64 vs 54, P < .001), were on higher median doses of prednisolone per day (7.5 vs 5 mg, P = .001), and had lower median serum immunoglobulin G (IgG) levels (944 vs 1,394 mg/dL, P < .001).¹⁵ 

Tadros et al¹³ performed a case-control study that also showed that patients with autoimmune disease who developed PCP had lower lymphocyte counts than controls on admission. Other risk factors included low CD4 counts and age older than 50.

Li et al¹⁷ found that patients with autoimmune or inflammatory disease with PCP were more likely to have low CD3, CD4, and CD8 cell counts, as well as albumin levels less than 28 g/L. They therefore suggested that lymphocyte subtyping may be a useful tool to guide PCP prophylaxis.

Granulomatosis with polyangiitis

Patients with granulomatosis with polyangiitis have a significantly higher incidence of PCP than patients with other connective tissue diseases.

Ward and Donald¹⁸ reviewed 223 cases of PCP in patients with connective tissue disease. The highest frequency (89 cases per 10,000 hospitalizations per year) was in patients with granulomatosis with polyangiitis, followed by 65 per 10,000 hospitalizations per year for patients with polyarteritis nodosa. The lowest frequency was in rheumatoid arthritis patients, at 2 per 10,000 hospitalizations per year. In decreasing order, diseases with significant associations with PCP were:

• Polyarteritis nodosa (odds ratio [OR] 10.20, 95% confidence interval [CI] 5.69–18.29)
• Granulomatosis with polyangiitis (OR 7.81, 95% CI 4.71–13.05)
• Inflammatory myopathy (OR 4.44, 95% CI 2.67–7.38)
• Systemic lupus erythematosus (OR 2.52, 95% CI 1.66–3.82).

Vallabhaneni and Chiller,²⁶ in a meta-analysis including rheumatoid arthritis patients on biologics, did not find an increased risk of PCP (OR 1.77, 95% CI 0.42–7.47).

Park et al¹² found that the highest incidences of PCP were in patients with granulomatosis with polyangiitis, microscopic polyangiitis, and systemic sclerosis. For systemic sclerosis, the main reason for giving high-dose glucocorticoids was interstitial lung disease.

Other studies^19,20,28 also found an association with coexisting pulmonary disease in patients with rheumatoid arthritis.

CURRENT GUIDELINES

There are guidelines for primary and secondary prophylaxis of PCP in HIV-positive patients with CD4 counts less than 200/mm³ or a history of acquired immunodeficiency syndrome (AIDS)-defining illness.²⁷ Additionally, patients with a CD4 cell percentage less than 14% should be considered for prophylaxis.²⁷

Unfortunately, there are no guidelines for prophylaxis in patients taking immunosuppressants for rheumatic disease.

The recommended regimen for PCP prophylaxis in HIV-infected patients is trimethoprim-sulfamethoxazole, 1 double-strength or 1 single-strength tablet daily. Alternative regimens include 1 double-strength tablet 3 times per week, dapsone, aerosolized pentamidine, and atovaquone.²⁷

There are also guidelines for prophylaxis in kidney transplant recipients, as well as for patients with hematologic malignancies and solid-organ malignancies, particularly those on chemotherapeutic agents and the T-cell-depleting agent alemtuzumab.^29–31

Italian clinical practice guidelines for the use of tumor necrosis factor antagonists in inflammatory bowel disease recommend consideration of PCP prophylaxis in patients who are also on other immunosuppressants, particularly high-dose glucocorticoids.³²

Prophylaxis has been shown to increase life expectancy and quality-adjusted life-years and to reduce cost for patients on immunosuppressive therapy for granulomatosis with polyangiitis.²¹ The European Society of Clinical Microbiology and Infectious Diseases recently produced consensus statements recommending PCP prophylaxis for patients on rituximab with other concomitant immunosuppressants such as the equivalent of prednisone 20 mg daily for more than 4 weeks.³³ Prophylaxis was not recommended for other biologic therapies.^34,35

THE RISKS OF PROPHYLAXIS

The risk of PCP should be weighed against the risk of prophylaxis in patients with rheumatic disease. Adverse reactions to sulfonamide antibiotics including disease flares have been reported in patients with systemic lupus erythematosus.^36,37 Other studies have found no increased risk of flares in patients taking trimethoprim-sulfamethoxazole for PCP prophylaxis.^12,38 A retrospective analysis of patients with vasculitis found no increased risk of combining methotrexate and trimethoprim-sulfamethoxazole.³⁹

KEY POINTS

• PCP is an opportunistic infection with a high risk of death.
• PCP has been reported with biologics used as immunomodulators in rheumatic disease.
• PCP prophylaxis should be considered in patients at high risk of PCP, such as those who have granulomatosis with polyangiitis, underlying pulmonary disease or who are concomitantly taking glucocorticoids.

Pneumocystis jirovecii (previously carinii) pneumonia (PCP) is rare in patients taking biologic response modifiers for rheumatic disease.^1–10 However, prophylaxis should be considered in patients who have granulomatosis with polyangiitis or underlying pulmonary disease, or who are concomitantly receiving glucocorticoids in high doses. There is some risk of adverse reactions to the prophylactic medicine.^1,11–21 Until clear guidelines are available, the decision to initiate PCP prophylaxis and the choice of agent should be individualized.

THE BURDEN OF PCP

In a meta-analysis²³ of 867 patients who developed PCP and did not have HIV infection, 20.1% had autoimmune or chronic inflammatory disease and the rest were transplant recipients or had malignancies. The mortality rate was 30.6%.

PHARMACOLOGIC RISK FACTORS FOR PCP

Treatment with glucocorticoids

Treatment with glucocorticoids is an important risk factor for PCP, independent of biologic therapy.

Calero-Bernal et al¹¹ reported on 128 patients with non-HIV PCP, of whom 114 (89%) had received a glucocorticoid for more than 4 weeks, and 98 (76%) were currently receiving one. The mean daily dose was equivalent to 27.73 mg of prednisone per day in those on glucocorticoids only, and 21.34 mg in those receiving glucocorticoids in combination with other immunosuppressants.

Park et al,¹² in a retrospective study of Korean patients treated for rheumatic disease with high-dose glucocorticoids (≥ 30 mg/day of prednisone or equivalent for more than 4 weeks), reported an incidence rate of PCP of 2.37 per 100 patient-years in those not on prophylaxis.

Other studies^13,14 have also found a prednisone dose greater than 15 to 20 mg per day for more than 4 weeks or concomitant use of 2 or more disease-modifying antirheumatic drugs to be a significant risk factor.^13,14

Tumor necrosis factor alpha antagonists

A US Food and Drug Administration review¹ of voluntary reports of adverse drug events estimated the incidence of PCP to be 2.3 per 100,000 patient-years with infliximab and 1.6 per 100,000 patient-years with etanercept. In most cases, other immunosuppressants were used concomitantly.¹

Postmarketing surveillance² of 5,000 patients with rheumatoid arthritis showed an incidence of suspected PCP of 0.4% within the first 6 months of starting infliximab therapy.

Komano et al,¹⁵ in a case-control study of patients with rheumatoid arthritis treated with infliximab, reported that all 21 patients with PCP were also on methotrexate (median dosage 8 mg per week) and prednisolone (median dosage 7.5 mg per day).

PCP has also been reported after adalimumab use in combination with prednisone, azathioprine, and methotrexate, as well as with certolizumab, golimumab, tocilizumab, abatacept, and rituximab.^{3–6,24–26}

Rituximab

Calero-Bernal et al¹¹ reported that 23% of patients with non-HIV PCP who were receiving immunosuppressant drugs were on rituximab.

Alexandre et al¹⁶ performed a retrospective review of 11 cases of PCP complicating rituximab therapy for autoimmune disease, in which 10 (91%) of the patients were also on corticosteroids, with a median dosage of 30 mg of prednisone daily. A literature review of an additional 18 cases revealed similar findings.

 

 

PATIENT RISK FACTORS FOR PCP

Pulmonary disease, age, other factors

Komano et al,¹⁵ in their study of patients with rheumatoid arthritis treated with infliximab, found that 10 (48%) of 21 patients with PCP had preexisting pulmonary disease, compared with 11 (10.8%) of 102 patients without PCP (P < .001). Patients with PCP were older (mean age 64 vs 54, P < .001), were on higher median doses of prednisolone per day (7.5 vs 5 mg, P = .001), and had lower median serum immunoglobulin G (IgG) levels (944 vs 1,394 mg/dL, P < .001).¹⁵ 

Tadros et al¹³ performed a case-control study that also showed that patients with autoimmune disease who developed PCP had lower lymphocyte counts than controls on admission. Other risk factors included low CD4 counts and age older than 50.

Li et al¹⁷ found that patients with autoimmune or inflammatory disease with PCP were more likely to have low CD3, CD4, and CD8 cell counts, as well as albumin levels less than 28 g/L. They therefore suggested that lymphocyte subtyping may be a useful tool to guide PCP prophylaxis.

Granulomatosis with polyangiitis

Patients with granulomatosis with polyangiitis have a significantly higher incidence of PCP than patients with other connective tissue diseases.

Ward and Donald¹⁸ reviewed 223 cases of PCP in patients with connective tissue disease. The highest frequency (89 cases per 10,000 hospitalizations per year) was in patients with granulomatosis with polyangiitis, followed by 65 per 10,000 hospitalizations per year for patients with polyarteritis nodosa. The lowest frequency was in rheumatoid arthritis patients, at 2 per 10,000 hospitalizations per year. In decreasing order, diseases with significant associations with PCP were:

• Polyarteritis nodosa (odds ratio [OR] 10.20, 95% confidence interval [CI] 5.69–18.29)
• Granulomatosis with polyangiitis (OR 7.81, 95% CI 4.71–13.05)
• Inflammatory myopathy (OR 4.44, 95% CI 2.67–7.38)
• Systemic lupus erythematosus (OR 2.52, 95% CI 1.66–3.82).

Vallabhaneni and Chiller,²⁶ in a meta-analysis including rheumatoid arthritis patients on biologics, did not find an increased risk of PCP (OR 1.77, 95% CI 0.42–7.47).

Park et al¹² found that the highest incidences of PCP were in patients with granulomatosis with polyangiitis, microscopic polyangiitis, and systemic sclerosis. For systemic sclerosis, the main reason for giving high-dose glucocorticoids was interstitial lung disease.

Other studies^19,20,28 also found an association with coexisting pulmonary disease in patients with rheumatoid arthritis.

CURRENT GUIDELINES

There are guidelines for primary and secondary prophylaxis of PCP in HIV-positive patients with CD4 counts less than 200/mm³ or a history of acquired immunodeficiency syndrome (AIDS)-defining illness.²⁷ Additionally, patients with a CD4 cell percentage less than 14% should be considered for prophylaxis.²⁷

Unfortunately, there are no guidelines for prophylaxis in patients taking immunosuppressants for rheumatic disease.

The recommended regimen for PCP prophylaxis in HIV-infected patients is trimethoprim-sulfamethoxazole, 1 double-strength or 1 single-strength tablet daily. Alternative regimens include 1 double-strength tablet 3 times per week, dapsone, aerosolized pentamidine, and atovaquone.²⁷

There are also guidelines for prophylaxis in kidney transplant recipients, as well as for patients with hematologic malignancies and solid-organ malignancies, particularly those on chemotherapeutic agents and the T-cell-depleting agent alemtuzumab.^29–31

Italian clinical practice guidelines for the use of tumor necrosis factor antagonists in inflammatory bowel disease recommend consideration of PCP prophylaxis in patients who are also on other immunosuppressants, particularly high-dose glucocorticoids.³²

Prophylaxis has been shown to increase life expectancy and quality-adjusted life-years and to reduce cost for patients on immunosuppressive therapy for granulomatosis with polyangiitis.²¹ The European Society of Clinical Microbiology and Infectious Diseases recently produced consensus statements recommending PCP prophylaxis for patients on rituximab with other concomitant immunosuppressants such as the equivalent of prednisone 20 mg daily for more than 4 weeks.³³ Prophylaxis was not recommended for other biologic therapies.^34,35

THE RISKS OF PROPHYLAXIS

The risk of PCP should be weighed against the risk of prophylaxis in patients with rheumatic disease. Adverse reactions to sulfonamide antibiotics including disease flares have been reported in patients with systemic lupus erythematosus.^36,37 Other studies have found no increased risk of flares in patients taking trimethoprim-sulfamethoxazole for PCP prophylaxis.^12,38 A retrospective analysis of patients with vasculitis found no increased risk of combining methotrexate and trimethoprim-sulfamethoxazole.³⁹

KEY POINTS

• PCP is an opportunistic infection with a high risk of death.
• PCP has been reported with biologics used as immunomodulators in rheumatic disease.
• PCP prophylaxis should be considered in patients at high risk of PCP, such as those who have granulomatosis with polyangiitis, underlying pulmonary disease or who are concomitantly taking glucocorticoids.

Pneumocystis jirovecii (previously carinii) pneumonia (PCP) is rare in patients taking biologic response modifiers for rheumatic disease.^1–10 However, prophylaxis should be considered in patients who have granulomatosis with polyangiitis or underlying pulmonary disease, or who are concomitantly receiving glucocorticoids in high doses. There is some risk of adverse reactions to the prophylactic medicine.^1,11–21 Until clear guidelines are available, the decision to initiate PCP prophylaxis and the choice of agent should be individualized.

THE BURDEN OF PCP

In a meta-analysis²³ of 867 patients who developed PCP and did not have HIV infection, 20.1% had autoimmune or chronic inflammatory disease and the rest were transplant recipients or had malignancies. The mortality rate was 30.6%.

PHARMACOLOGIC RISK FACTORS FOR PCP

Treatment with glucocorticoids

Treatment with glucocorticoids is an important risk factor for PCP, independent of biologic therapy.

Calero-Bernal et al¹¹ reported on 128 patients with non-HIV PCP, of whom 114 (89%) had received a glucocorticoid for more than 4 weeks, and 98 (76%) were currently receiving one. The mean daily dose was equivalent to 27.73 mg of prednisone per day in those on glucocorticoids only, and 21.34 mg in those receiving glucocorticoids in combination with other immunosuppressants.

Park et al,¹² in a retrospective study of Korean patients treated for rheumatic disease with high-dose glucocorticoids (≥ 30 mg/day of prednisone or equivalent for more than 4 weeks), reported an incidence rate of PCP of 2.37 per 100 patient-years in those not on prophylaxis.

Other studies^13,14 have also found a prednisone dose greater than 15 to 20 mg per day for more than 4 weeks or concomitant use of 2 or more disease-modifying antirheumatic drugs to be a significant risk factor.^13,14

Tumor necrosis factor alpha antagonists

A US Food and Drug Administration review¹ of voluntary reports of adverse drug events estimated the incidence of PCP to be 2.3 per 100,000 patient-years with infliximab and 1.6 per 100,000 patient-years with etanercept. In most cases, other immunosuppressants were used concomitantly.¹

Postmarketing surveillance² of 5,000 patients with rheumatoid arthritis showed an incidence of suspected PCP of 0.4% within the first 6 months of starting infliximab therapy.

Komano et al,¹⁵ in a case-control study of patients with rheumatoid arthritis treated with infliximab, reported that all 21 patients with PCP were also on methotrexate (median dosage 8 mg per week) and prednisolone (median dosage 7.5 mg per day).

PCP has also been reported after adalimumab use in combination with prednisone, azathioprine, and methotrexate, as well as with certolizumab, golimumab, tocilizumab, abatacept, and rituximab.^{3–6,24–26}

Rituximab

Calero-Bernal et al¹¹ reported that 23% of patients with non-HIV PCP who were receiving immunosuppressant drugs were on rituximab.

Alexandre et al¹⁶ performed a retrospective review of 11 cases of PCP complicating rituximab therapy for autoimmune disease, in which 10 (91%) of the patients were also on corticosteroids, with a median dosage of 30 mg of prednisone daily. A literature review of an additional 18 cases revealed similar findings.

 

 

PATIENT RISK FACTORS FOR PCP

Pulmonary disease, age, other factors

Komano et al,¹⁵ in their study of patients with rheumatoid arthritis treated with infliximab, found that 10 (48%) of 21 patients with PCP had preexisting pulmonary disease, compared with 11 (10.8%) of 102 patients without PCP (P < .001). Patients with PCP were older (mean age 64 vs 54, P < .001), were on higher median doses of prednisolone per day (7.5 vs 5 mg, P = .001), and had lower median serum immunoglobulin G (IgG) levels (944 vs 1,394 mg/dL, P < .001).¹⁵ 

Tadros et al¹³ performed a case-control study that also showed that patients with autoimmune disease who developed PCP had lower lymphocyte counts than controls on admission. Other risk factors included low CD4 counts and age older than 50.

Li et al¹⁷ found that patients with autoimmune or inflammatory disease with PCP were more likely to have low CD3, CD4, and CD8 cell counts, as well as albumin levels less than 28 g/L. They therefore suggested that lymphocyte subtyping may be a useful tool to guide PCP prophylaxis.

Granulomatosis with polyangiitis

Patients with granulomatosis with polyangiitis have a significantly higher incidence of PCP than patients with other connective tissue diseases.

Ward and Donald¹⁸ reviewed 223 cases of PCP in patients with connective tissue disease. The highest frequency (89 cases per 10,000 hospitalizations per year) was in patients with granulomatosis with polyangiitis, followed by 65 per 10,000 hospitalizations per year for patients with polyarteritis nodosa. The lowest frequency was in rheumatoid arthritis patients, at 2 per 10,000 hospitalizations per year. In decreasing order, diseases with significant associations with PCP were:

• Polyarteritis nodosa (odds ratio [OR] 10.20, 95% confidence interval [CI] 5.69–18.29)
• Granulomatosis with polyangiitis (OR 7.81, 95% CI 4.71–13.05)
• Inflammatory myopathy (OR 4.44, 95% CI 2.67–7.38)
• Systemic lupus erythematosus (OR 2.52, 95% CI 1.66–3.82).

Vallabhaneni and Chiller,²⁶ in a meta-analysis including rheumatoid arthritis patients on biologics, did not find an increased risk of PCP (OR 1.77, 95% CI 0.42–7.47).

Park et al¹² found that the highest incidences of PCP were in patients with granulomatosis with polyangiitis, microscopic polyangiitis, and systemic sclerosis. For systemic sclerosis, the main reason for giving high-dose glucocorticoids was interstitial lung disease.

Other studies^19,20,28 also found an association with coexisting pulmonary disease in patients with rheumatoid arthritis.

CURRENT GUIDELINES

There are guidelines for primary and secondary prophylaxis of PCP in HIV-positive patients with CD4 counts less than 200/mm³ or a history of acquired immunodeficiency syndrome (AIDS)-defining illness.²⁷ Additionally, patients with a CD4 cell percentage less than 14% should be considered for prophylaxis.²⁷

Unfortunately, there are no guidelines for prophylaxis in patients taking immunosuppressants for rheumatic disease.

The recommended regimen for PCP prophylaxis in HIV-infected patients is trimethoprim-sulfamethoxazole, 1 double-strength or 1 single-strength tablet daily. Alternative regimens include 1 double-strength tablet 3 times per week, dapsone, aerosolized pentamidine, and atovaquone.²⁷

There are also guidelines for prophylaxis in kidney transplant recipients, as well as for patients with hematologic malignancies and solid-organ malignancies, particularly those on chemotherapeutic agents and the T-cell-depleting agent alemtuzumab.^29–31

Italian clinical practice guidelines for the use of tumor necrosis factor antagonists in inflammatory bowel disease recommend consideration of PCP prophylaxis in patients who are also on other immunosuppressants, particularly high-dose glucocorticoids.³²

Prophylaxis has been shown to increase life expectancy and quality-adjusted life-years and to reduce cost for patients on immunosuppressive therapy for granulomatosis with polyangiitis.²¹ The European Society of Clinical Microbiology and Infectious Diseases recently produced consensus statements recommending PCP prophylaxis for patients on rituximab with other concomitant immunosuppressants such as the equivalent of prednisone 20 mg daily for more than 4 weeks.³³ Prophylaxis was not recommended for other biologic therapies.^34,35

THE RISKS OF PROPHYLAXIS

The risk of PCP should be weighed against the risk of prophylaxis in patients with rheumatic disease. Adverse reactions to sulfonamide antibiotics including disease flares have been reported in patients with systemic lupus erythematosus.^36,37 Other studies have found no increased risk of flares in patients taking trimethoprim-sulfamethoxazole for PCP prophylaxis.^12,38 A retrospective analysis of patients with vasculitis found no increased risk of combining methotrexate and trimethoprim-sulfamethoxazole.³⁹

KEY POINTS

• PCP is an opportunistic infection with a high risk of death.
• PCP has been reported with biologics used as immunomodulators in rheumatic disease.
• PCP prophylaxis should be considered in patients at high risk of PCP, such as those who have granulomatosis with polyangiitis, underlying pulmonary disease or who are concomitantly taking glucocorticoids.

"I have trained myself to see what others overlook."
—Sherlock Holmes¹

The article by Grandjean and Huber in this issue² is a timely reminder of the importance of skilled observation in medical care. Osler³ considered observation to represent “the whole art of medicine,” but warned that “for some men it is quite as difficult to record an observation in brief and plain language.” This insight captures not only the never-ending feud between written and visual communication, but also the higher efficiency of images. Leonardo da Vinci, a visual thinker with a touch of dyslexia,⁴ often boasted in colorful terms about the superiority of the visual. Next to his amazing rendition of a bovine heart he scribbled, “[Writer] how could you describe this heart in words without filling a whole book? So, don’t bother with words unless you are speaking to the blind…you will always be overruled by the painter.”⁵

See related article and editorial

Ironically, physicians have often preferred the written over the visual. Oliver Wendell Holmes Sr., professor of anatomy at Harvard Medical School and renowned essayist, once wrote a scathing review of a new anatomy textbook that, according to him, had just too many pictures. “Let a student have illustrations,” he thundered “and just so surely will he use them at the expense of the text.”⁶ The book was Gray’s Anatomy, but Holmes’ tirade exemplifies the conundrum of our profession: to become physicians we must read (and memorize) lots of written text, with little emphasis on how much more efficiently information might be conveyed through a single picture.

This trend is probably worsening. When I first came to the United States 43 years ago, I was amazed at how many of my professors immediately grabbed a sheet of paper and started drawing their explanations to my questions. But I have not seen much of this lately, and that is a pity, since pictures are undoubtedly a better way of communicating.

OBSERVING A PATIENT WITH COPD

Netter’s patient is also exhaling through pursed lips. This reduces the respiratory rate and carbon dioxide level, while improving distribution of ventilation,^9,10 oxygen saturation, tidal volume, inspiratory muscle strength, and diaphragmatic efficiency.^11,12 Since less inspiratory force is required for each breath, dyspnea is also improved.^13,14 Diagnostically, pursed‑lip breathing increases the probability of chronic obstructive pulmonary disease (COPD), with a likelihood ratio of 5.05.¹⁵

The man in The Pink Puffer is using accessory respiratory muscles, which not only represents one of the earliest signs of airway obstruction, but also reflects severe disease. In fact, use of accessory respiratory muscles occurs in more than 90% of COPD patients admitted for acute exacerbations.⁷

Lastly, Netter’s patient exhibits inspiratory retraction of supraclavicular fossae and interspaces (tirage), which indicates increased airway resistance and reduced forced expiratory volume in 1 second (FEV₁).^16,17 A clavicular “lift” of more than 5 mm correlates with an FEV₁ of 0.6 L.¹⁸

But what is odd about this patient is what Netter did not portray: clubbing. This goes against the conventional wisdom of the time but is actually correct, since we now know that clubbing is more a feature of chronic bronchitis than emphysema.¹⁹ In fact, if present in a “pink puffer,” it should suggest an underlying malignancy. Hence, Netter reminds us that we should never convince ourselves that we see something simply because we know it should be there. Instead, we should always rely on what we see. This is, after all, how Vesalius debunked Galen’s anatomic errors: by seeing for himself. Tom McCrae, Osler’s right-hand man at Johns Hopkins, used to warn his students that one misses more by not seeing than by not knowing. Leonardo put it simply: “Wisdom is the daughter of [visual] experience.”²⁰ In the end, Netter’s drawing reminds us that a picture is truly worth a thousand words.

 

 

TEACHING STUDENTS TO OBSERVE

Unfortunately, detecting detail is difficult. It is also very difficult to teach. For the past few months I’ve been asking astute clinicians how they observe, and most of them seem befuddled, as if I had asked which muscles they contract in order to walk. They just walk. And they just observe.

So, how can we rekindle this important but underappreciated component of the physician’s skill set? First of all, by becoming cognizant of its fundamental role in medicine. Second, by accepting that this is something that cannot be easily tested by single-best- answer, black-and-white, multiple-choice exams. Recognizing the complexity of clinical skills reminds us that not all that counts in medicine can be counted, and not all that can be counted counts. Yet it also provides a hurdle, since testing typically drives curriculum. If we cannot assess observation, how can we reincorporate it in the curriculum? Lastly, we need to regain ownership of the teaching of this skill. No art instructor can properly identify and interpret clinical findings. Hence, physicians ought to teach it. In the end, learning how to properly observe is a personal and lifelong effort. As Osler put it, “There is no more difficult art to acquire than the art of observation.”²¹

Leonardo used to quip that “There are three classes of people: those who see, those who see when they are shown, and those who do not see.”²² Yet this time Leonardo might have been wrong. There are really only two kinds of people: those who have been taught how to observe and those who have not. Leonardo was lucky enough to have been apprenticed to an artist whose nickname was Verrocchio, which resembles the Italian words vero occhio, a “fine eye.” Without Verrocchio, even Leonardo might not have become such a skilled observer. How many Verrocchios are around today?

"I have trained myself to see what others overlook."
—Sherlock Holmes¹

The article by Grandjean and Huber in this issue² is a timely reminder of the importance of skilled observation in medical care. Osler³ considered observation to represent “the whole art of medicine,” but warned that “for some men it is quite as difficult to record an observation in brief and plain language.” This insight captures not only the never-ending feud between written and visual communication, but also the higher efficiency of images. Leonardo da Vinci, a visual thinker with a touch of dyslexia,⁴ often boasted in colorful terms about the superiority of the visual. Next to his amazing rendition of a bovine heart he scribbled, “[Writer] how could you describe this heart in words without filling a whole book? So, don’t bother with words unless you are speaking to the blind…you will always be overruled by the painter.”⁵

See related article and editorial

Ironically, physicians have often preferred the written over the visual. Oliver Wendell Holmes Sr., professor of anatomy at Harvard Medical School and renowned essayist, once wrote a scathing review of a new anatomy textbook that, according to him, had just too many pictures. “Let a student have illustrations,” he thundered “and just so surely will he use them at the expense of the text.”⁶ The book was Gray’s Anatomy, but Holmes’ tirade exemplifies the conundrum of our profession: to become physicians we must read (and memorize) lots of written text, with little emphasis on how much more efficiently information might be conveyed through a single picture.

This trend is probably worsening. When I first came to the United States 43 years ago, I was amazed at how many of my professors immediately grabbed a sheet of paper and started drawing their explanations to my questions. But I have not seen much of this lately, and that is a pity, since pictures are undoubtedly a better way of communicating.

OBSERVING A PATIENT WITH COPD

Netter’s patient is also exhaling through pursed lips. This reduces the respiratory rate and carbon dioxide level, while improving distribution of ventilation,^9,10 oxygen saturation, tidal volume, inspiratory muscle strength, and diaphragmatic efficiency.^11,12 Since less inspiratory force is required for each breath, dyspnea is also improved.^13,14 Diagnostically, pursed‑lip breathing increases the probability of chronic obstructive pulmonary disease (COPD), with a likelihood ratio of 5.05.¹⁵

The man in The Pink Puffer is using accessory respiratory muscles, which not only represents one of the earliest signs of airway obstruction, but also reflects severe disease. In fact, use of accessory respiratory muscles occurs in more than 90% of COPD patients admitted for acute exacerbations.⁷

Lastly, Netter’s patient exhibits inspiratory retraction of supraclavicular fossae and interspaces (tirage), which indicates increased airway resistance and reduced forced expiratory volume in 1 second (FEV₁).^16,17 A clavicular “lift” of more than 5 mm correlates with an FEV₁ of 0.6 L.¹⁸

But what is odd about this patient is what Netter did not portray: clubbing. This goes against the conventional wisdom of the time but is actually correct, since we now know that clubbing is more a feature of chronic bronchitis than emphysema.¹⁹ In fact, if present in a “pink puffer,” it should suggest an underlying malignancy. Hence, Netter reminds us that we should never convince ourselves that we see something simply because we know it should be there. Instead, we should always rely on what we see. This is, after all, how Vesalius debunked Galen’s anatomic errors: by seeing for himself. Tom McCrae, Osler’s right-hand man at Johns Hopkins, used to warn his students that one misses more by not seeing than by not knowing. Leonardo put it simply: “Wisdom is the daughter of [visual] experience.”²⁰ In the end, Netter’s drawing reminds us that a picture is truly worth a thousand words.

 

 

TEACHING STUDENTS TO OBSERVE

Unfortunately, detecting detail is difficult. It is also very difficult to teach. For the past few months I’ve been asking astute clinicians how they observe, and most of them seem befuddled, as if I had asked which muscles they contract in order to walk. They just walk. And they just observe.

So, how can we rekindle this important but underappreciated component of the physician’s skill set? First of all, by becoming cognizant of its fundamental role in medicine. Second, by accepting that this is something that cannot be easily tested by single-best- answer, black-and-white, multiple-choice exams. Recognizing the complexity of clinical skills reminds us that not all that counts in medicine can be counted, and not all that can be counted counts. Yet it also provides a hurdle, since testing typically drives curriculum. If we cannot assess observation, how can we reincorporate it in the curriculum? Lastly, we need to regain ownership of the teaching of this skill. No art instructor can properly identify and interpret clinical findings. Hence, physicians ought to teach it. In the end, learning how to properly observe is a personal and lifelong effort. As Osler put it, “There is no more difficult art to acquire than the art of observation.”²¹

Leonardo used to quip that “There are three classes of people: those who see, those who see when they are shown, and those who do not see.”²² Yet this time Leonardo might have been wrong. There are really only two kinds of people: those who have been taught how to observe and those who have not. Leonardo was lucky enough to have been apprenticed to an artist whose nickname was Verrocchio, which resembles the Italian words vero occhio, a “fine eye.” Without Verrocchio, even Leonardo might not have become such a skilled observer. How many Verrocchios are around today?

"I have trained myself to see what others overlook."
—Sherlock Holmes¹

The article by Grandjean and Huber in this issue² is a timely reminder of the importance of skilled observation in medical care. Osler³ considered observation to represent “the whole art of medicine,” but warned that “for some men it is quite as difficult to record an observation in brief and plain language.” This insight captures not only the never-ending feud between written and visual communication, but also the higher efficiency of images. Leonardo da Vinci, a visual thinker with a touch of dyslexia,⁴ often boasted in colorful terms about the superiority of the visual. Next to his amazing rendition of a bovine heart he scribbled, “[Writer] how could you describe this heart in words without filling a whole book? So, don’t bother with words unless you are speaking to the blind…you will always be overruled by the painter.”⁵

See related article and editorial

Ironically, physicians have often preferred the written over the visual. Oliver Wendell Holmes Sr., professor of anatomy at Harvard Medical School and renowned essayist, once wrote a scathing review of a new anatomy textbook that, according to him, had just too many pictures. “Let a student have illustrations,” he thundered “and just so surely will he use them at the expense of the text.”⁶ The book was Gray’s Anatomy, but Holmes’ tirade exemplifies the conundrum of our profession: to become physicians we must read (and memorize) lots of written text, with little emphasis on how much more efficiently information might be conveyed through a single picture.

This trend is probably worsening. When I first came to the United States 43 years ago, I was amazed at how many of my professors immediately grabbed a sheet of paper and started drawing their explanations to my questions. But I have not seen much of this lately, and that is a pity, since pictures are undoubtedly a better way of communicating.

OBSERVING A PATIENT WITH COPD

Netter’s patient is also exhaling through pursed lips. This reduces the respiratory rate and carbon dioxide level, while improving distribution of ventilation,^9,10 oxygen saturation, tidal volume, inspiratory muscle strength, and diaphragmatic efficiency.^11,12 Since less inspiratory force is required for each breath, dyspnea is also improved.^13,14 Diagnostically, pursed‑lip breathing increases the probability of chronic obstructive pulmonary disease (COPD), with a likelihood ratio of 5.05.¹⁵

The man in The Pink Puffer is using accessory respiratory muscles, which not only represents one of the earliest signs of airway obstruction, but also reflects severe disease. In fact, use of accessory respiratory muscles occurs in more than 90% of COPD patients admitted for acute exacerbations.⁷

Lastly, Netter’s patient exhibits inspiratory retraction of supraclavicular fossae and interspaces (tirage), which indicates increased airway resistance and reduced forced expiratory volume in 1 second (FEV₁).^16,17 A clavicular “lift” of more than 5 mm correlates with an FEV₁ of 0.6 L.¹⁸

But what is odd about this patient is what Netter did not portray: clubbing. This goes against the conventional wisdom of the time but is actually correct, since we now know that clubbing is more a feature of chronic bronchitis than emphysema.¹⁹ In fact, if present in a “pink puffer,” it should suggest an underlying malignancy. Hence, Netter reminds us that we should never convince ourselves that we see something simply because we know it should be there. Instead, we should always rely on what we see. This is, after all, how Vesalius debunked Galen’s anatomic errors: by seeing for himself. Tom McCrae, Osler’s right-hand man at Johns Hopkins, used to warn his students that one misses more by not seeing than by not knowing. Leonardo put it simply: “Wisdom is the daughter of [visual] experience.”²⁰ In the end, Netter’s drawing reminds us that a picture is truly worth a thousand words.

 

 

TEACHING STUDENTS TO OBSERVE

Unfortunately, detecting detail is difficult. It is also very difficult to teach. For the past few months I’ve been asking astute clinicians how they observe, and most of them seem befuddled, as if I had asked which muscles they contract in order to walk. They just walk. And they just observe.

So, how can we rekindle this important but underappreciated component of the physician’s skill set? First of all, by becoming cognizant of its fundamental role in medicine. Second, by accepting that this is something that cannot be easily tested by single-best- answer, black-and-white, multiple-choice exams. Recognizing the complexity of clinical skills reminds us that not all that counts in medicine can be counted, and not all that can be counted counts. Yet it also provides a hurdle, since testing typically drives curriculum. If we cannot assess observation, how can we reincorporate it in the curriculum? Lastly, we need to regain ownership of the teaching of this skill. No art instructor can properly identify and interpret clinical findings. Hence, physicians ought to teach it. In the end, learning how to properly observe is a personal and lifelong effort. As Osler put it, “There is no more difficult art to acquire than the art of observation.”²¹

Leonardo used to quip that “There are three classes of people: those who see, those who see when they are shown, and those who do not see.”²² Yet this time Leonardo might have been wrong. There are really only two kinds of people: those who have been taught how to observe and those who have not. Leonardo was lucky enough to have been apprenticed to an artist whose nickname was Verrocchio, which resembles the Italian words vero occhio, a “fine eye.” Without Verrocchio, even Leonardo might not have become such a skilled observer. How many Verrocchios are around today?

Today’s most prominent medical journals have a “clinical images” section. High- quality, readily accessible digital photography can transport a patient to the journal’s pages, as demonstrated by Grandjean and Huber’s “Thinker sign” images in this issue of the Journal.¹ Images challenge healthcare practitioners to recall diseases via pattern recognition, or to deduce them by higher-order cognition. Images can reinforce prior learning, change perspective, and challenge preconceived notions.

See related article and editorial

I have used clinical images—physical examination findings, skin rashes, blood smears, radiography—for more than 20 years as a medical educator. I have dimmed the lights in conference rooms and lecture halls from Maine to Northern California, challenging students, residents, and faculty to contemplate a snippet of history and describe what they see to arrive at a diagnosis. Images are compelling teaching tools for first-year medical students beginning to make clinical observations, and for seasoned clinicians who have seen thousands of patients.

In my experience, clinical image presentations are consistently engaging. Introducing an audience to 8 to 10 patients in an hour loosely mimics the experience of seeing patients over the course of morning hospital rounds or clinic. The images I use are assembled from a collection of images of patients I have seen during my career in medical education. Showing images of patients I’ve personally cared for consistently prompts people to engage. “Here is a patient I saw last week on the medicine wards” reignites the sagging eyes and fading attention of the audience. In retelling a patient encounter, I create a human connection between a picture on the screen—my patient—and the listener. My patient becomes a patient of anyone in the room, a patient someone might see tomorrow on hospital rounds or in clinic.

Sometimes, instead of presenting a brief clinical history or select physical findings, I tell a story about the patient in the image. Whether sad or funny, these stories often bring learners together, prompting them to wonder how there could ever be a better job than the one they have. A prominent educator once approached me after a clinical images presentation to opine, “What you did with us today is the cure for physician burnout.” Hyperbole, perhaps, but I understood what he meant. Over the course of an hour, the audience had been transported to numerous bedsides and examination rooms, witnessing the interesting and delightfully mundane jewels our patients often bring—true pearls, indeed.

However, as educational, fun, and intellectually challenging as clinical images can be, they can never replace the experience of being at the bedside. There is nothing as engaging as the stories the patients themselves tell us. Unfiltered musings come to life, physical findings are indelibly seared into memory.

But unfortunately, even as trainees spend less time than ever before with their patients,^2,3 bedside rounding has dramatically faded, replaced by rounds in conference rooms and hospital hallways.⁴ The underlying cause is multifactorial—declining physical examination skills, increasing use of radiography and other advanced imaging, the electronic health record, and the overwhelming volume of clinical tasks carried out at a distance from the patient.

But this is not the whole story. I also believe that teachers and leaders fear the “thin ice” of rounding at the patient’s bedside. One never knows what will happen there—what will be said, what will be asked, what will be uncovered. What if, while talking to and examining the patient with the Dahl sign shown in Grandjean and Huber,¹ the patient’s condition would suddenly deteriorate, urgently requiring nebulized beta-2 agonists and transfer to the medical intensive care unit? What if the patient rambles for 5 minutes about extraneous details not relevant to his or her disease? What if the nurse needs to dispense scheduled medications or hang the next dose of antibiotics? What if the patient asks to use the bedpan at the moment digital clubbing was to be pointed out and discussed?

Of course, the patient may have lots to say, or nothing at all. But in those moments when the ice does not break, when the patient is not suddenly wheeled away to radiology, key clinical findings are seen and remembered, often for an entire career. If the ice does not break, the patient, the story, and the clinical finding—otherwise seen on a large screen in a dark room or on a page in a textbook or journal—come together in that moment, in a way nothing else ever quite can.

In this golden age of technology, we must remember that these images portray real patients with stories to tell, sometimes mundane and sometimes profound, but always worth hearing.

Acknowledgment: The author wishes to thank Mark C. Henderson, MD, for his helpful comments on this manuscript.

Today’s most prominent medical journals have a “clinical images” section. High- quality, readily accessible digital photography can transport a patient to the journal’s pages, as demonstrated by Grandjean and Huber’s “Thinker sign” images in this issue of the Journal.¹ Images challenge healthcare practitioners to recall diseases via pattern recognition, or to deduce them by higher-order cognition. Images can reinforce prior learning, change perspective, and challenge preconceived notions.

See related article and editorial

I have used clinical images—physical examination findings, skin rashes, blood smears, radiography—for more than 20 years as a medical educator. I have dimmed the lights in conference rooms and lecture halls from Maine to Northern California, challenging students, residents, and faculty to contemplate a snippet of history and describe what they see to arrive at a diagnosis. Images are compelling teaching tools for first-year medical students beginning to make clinical observations, and for seasoned clinicians who have seen thousands of patients.

In my experience, clinical image presentations are consistently engaging. Introducing an audience to 8 to 10 patients in an hour loosely mimics the experience of seeing patients over the course of morning hospital rounds or clinic. The images I use are assembled from a collection of images of patients I have seen during my career in medical education. Showing images of patients I’ve personally cared for consistently prompts people to engage. “Here is a patient I saw last week on the medicine wards” reignites the sagging eyes and fading attention of the audience. In retelling a patient encounter, I create a human connection between a picture on the screen—my patient—and the listener. My patient becomes a patient of anyone in the room, a patient someone might see tomorrow on hospital rounds or in clinic.

Sometimes, instead of presenting a brief clinical history or select physical findings, I tell a story about the patient in the image. Whether sad or funny, these stories often bring learners together, prompting them to wonder how there could ever be a better job than the one they have. A prominent educator once approached me after a clinical images presentation to opine, “What you did with us today is the cure for physician burnout.” Hyperbole, perhaps, but I understood what he meant. Over the course of an hour, the audience had been transported to numerous bedsides and examination rooms, witnessing the interesting and delightfully mundane jewels our patients often bring—true pearls, indeed.

However, as educational, fun, and intellectually challenging as clinical images can be, they can never replace the experience of being at the bedside. There is nothing as engaging as the stories the patients themselves tell us. Unfiltered musings come to life, physical findings are indelibly seared into memory.

But unfortunately, even as trainees spend less time than ever before with their patients,^2,3 bedside rounding has dramatically faded, replaced by rounds in conference rooms and hospital hallways.⁴ The underlying cause is multifactorial—declining physical examination skills, increasing use of radiography and other advanced imaging, the electronic health record, and the overwhelming volume of clinical tasks carried out at a distance from the patient.

But this is not the whole story. I also believe that teachers and leaders fear the “thin ice” of rounding at the patient’s bedside. One never knows what will happen there—what will be said, what will be asked, what will be uncovered. What if, while talking to and examining the patient with the Dahl sign shown in Grandjean and Huber,¹ the patient’s condition would suddenly deteriorate, urgently requiring nebulized beta-2 agonists and transfer to the medical intensive care unit? What if the patient rambles for 5 minutes about extraneous details not relevant to his or her disease? What if the nurse needs to dispense scheduled medications or hang the next dose of antibiotics? What if the patient asks to use the bedpan at the moment digital clubbing was to be pointed out and discussed?

Of course, the patient may have lots to say, or nothing at all. But in those moments when the ice does not break, when the patient is not suddenly wheeled away to radiology, key clinical findings are seen and remembered, often for an entire career. If the ice does not break, the patient, the story, and the clinical finding—otherwise seen on a large screen in a dark room or on a page in a textbook or journal—come together in that moment, in a way nothing else ever quite can.

In this golden age of technology, we must remember that these images portray real patients with stories to tell, sometimes mundane and sometimes profound, but always worth hearing.

Acknowledgment: The author wishes to thank Mark C. Henderson, MD, for his helpful comments on this manuscript.

Today’s most prominent medical journals have a “clinical images” section. High- quality, readily accessible digital photography can transport a patient to the journal’s pages, as demonstrated by Grandjean and Huber’s “Thinker sign” images in this issue of the Journal.¹ Images challenge healthcare practitioners to recall diseases via pattern recognition, or to deduce them by higher-order cognition. Images can reinforce prior learning, change perspective, and challenge preconceived notions.

See related article and editorial

I have used clinical images—physical examination findings, skin rashes, blood smears, radiography—for more than 20 years as a medical educator. I have dimmed the lights in conference rooms and lecture halls from Maine to Northern California, challenging students, residents, and faculty to contemplate a snippet of history and describe what they see to arrive at a diagnosis. Images are compelling teaching tools for first-year medical students beginning to make clinical observations, and for seasoned clinicians who have seen thousands of patients.

In my experience, clinical image presentations are consistently engaging. Introducing an audience to 8 to 10 patients in an hour loosely mimics the experience of seeing patients over the course of morning hospital rounds or clinic. The images I use are assembled from a collection of images of patients I have seen during my career in medical education. Showing images of patients I’ve personally cared for consistently prompts people to engage. “Here is a patient I saw last week on the medicine wards” reignites the sagging eyes and fading attention of the audience. In retelling a patient encounter, I create a human connection between a picture on the screen—my patient—and the listener. My patient becomes a patient of anyone in the room, a patient someone might see tomorrow on hospital rounds or in clinic.

Sometimes, instead of presenting a brief clinical history or select physical findings, I tell a story about the patient in the image. Whether sad or funny, these stories often bring learners together, prompting them to wonder how there could ever be a better job than the one they have. A prominent educator once approached me after a clinical images presentation to opine, “What you did with us today is the cure for physician burnout.” Hyperbole, perhaps, but I understood what he meant. Over the course of an hour, the audience had been transported to numerous bedsides and examination rooms, witnessing the interesting and delightfully mundane jewels our patients often bring—true pearls, indeed.

However, as educational, fun, and intellectually challenging as clinical images can be, they can never replace the experience of being at the bedside. There is nothing as engaging as the stories the patients themselves tell us. Unfiltered musings come to life, physical findings are indelibly seared into memory.

But unfortunately, even as trainees spend less time than ever before with their patients,^2,3 bedside rounding has dramatically faded, replaced by rounds in conference rooms and hospital hallways.⁴ The underlying cause is multifactorial—declining physical examination skills, increasing use of radiography and other advanced imaging, the electronic health record, and the overwhelming volume of clinical tasks carried out at a distance from the patient.

But this is not the whole story. I also believe that teachers and leaders fear the “thin ice” of rounding at the patient’s bedside. One never knows what will happen there—what will be said, what will be asked, what will be uncovered. What if, while talking to and examining the patient with the Dahl sign shown in Grandjean and Huber,¹ the patient’s condition would suddenly deteriorate, urgently requiring nebulized beta-2 agonists and transfer to the medical intensive care unit? What if the patient rambles for 5 minutes about extraneous details not relevant to his or her disease? What if the nurse needs to dispense scheduled medications or hang the next dose of antibiotics? What if the patient asks to use the bedpan at the moment digital clubbing was to be pointed out and discussed?

Of course, the patient may have lots to say, or nothing at all. But in those moments when the ice does not break, when the patient is not suddenly wheeled away to radiology, key clinical findings are seen and remembered, often for an entire career. If the ice does not break, the patient, the story, and the clinical finding—otherwise seen on a large screen in a dark room or on a page in a textbook or journal—come together in that moment, in a way nothing else ever quite can.

In this golden age of technology, we must remember that these images portray real patients with stories to tell, sometimes mundane and sometimes profound, but always worth hearing.

Acknowledgment: The author wishes to thank Mark C. Henderson, MD, for his helpful comments on this manuscript.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease characterized by irreversible obstructive ventilatory defects.^1-4 It is a major cause of morbidity and mortality, affecting 5% of the population in the United States and ranking as the third leading cause of death in 2008.^5,6 The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. In this 3-part review, we discuss the management of stable COPD in the context of 3 common clinical scenarios: initiating and optimizing therapy, managing acute exacerbations, and managing advanced disease.

Case Presentation

A 65-year-old man with COPD underwent pulmonary function testing (PFT), which demonstrated an obstructive ventilatory defect: forced expiratory volume in 1 second/forced vital capacity ratio (FEV₁/FVC), 0.45; FEV₁, 2 L (65% of predicted); and diffusing capacity of the lung for carbon monoxide, 15 mL/min/mm Hg (65% of predicted). He has dyspnea with strenuous exercise but is comfortable at rest and with minimal exercise. He has had 1 exacerbation in the past year, and this was treated on an outpatient basis with steroids and antibiotics. His medication regimen includes inhaled tiotropium once daily and inhaled albuterol as needed that he uses roughly twice a week.

What determines the appropriate therapy for a given COPD patient?

COPD management is guided by disease severity that is measured using a multimodal staging system developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The initial classification adopted by the GOLD 2011 report encompassed 4 categories based on symptoms, number of exacerbations, and degree of airflow limitation on PFT. However, in 2017 the GOLD ABCD classification was modified to consider only symptoms and risk of exacerbation in classifying patients, regardless of performance on spirometry and FEV₁ (Figure 1).^7,8 This approach was intended to make therapy more individualized based on the patient clinical profile. The Table provides a summary of the recommended treatments according to classification based on the GOLD 2017 report.

The patient in our clinical scenario can be classified as GOLD category B.

What is the approach to building a pharmacologic regimen for the patient with COPD?

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta-agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta- agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

Figure 2 presents an approach to building a treatment plan for the patient with stable COPD.

Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms.⁷ Both short-acting beta-agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD^9,10 and seem to have comparative efficacy when compared head-to-head in trials.¹¹ However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with fewer exacerbations compared to albuterol alone.¹² On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate.^11-13 Inhaled short-acting beta-agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function.¹⁴

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta-agonists increased the risk of severe cardiac arrhythmias.¹⁵ Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia.¹⁶ Beta-agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side effects but achieve less than maximal bronchodilation.¹⁷ Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant, especially when combined with long-acting anticholinergic agents.¹⁸

In light of the above discussion, a combination of a short-acting beta-agonist and a muscarinic antagonist is recommended in all patients with COPD, unless the patient is on a long-acting muscarinic antagonist (LAMA).^7,18 In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator, as he was using the LAMA tiotropium.

Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator:^7,19 either a long-acting beta-agonist (LABA) or a LAMA. Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extended-duration of action.²⁰ Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist.²¹ Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in an extended duration of action.²¹ Revefenacin is a new lung-selective LAMA that is under development and has shown promise among those with moderate to very severe COPD. Results are only limited to phase 3 trials, and clinical studies are still underway.²²

The currently available LABAs include salmeterol, formoterol, arformoterol, olodaterol, and indacaterol. The last 2 have the advantage of once-daily dosing rather than twice daily.^23,24 LABAs have been shown to improve lung function, exacerbation rate, and quality of life in multiple clinical trials.^23,25 Vilanterol is another LABA that has a long duration of action and can be used once daily,²⁶ but is only available in a combination with umeclidinium, a LAMA. Several LAMAs are approved for use in COPD, including the prototype tiotropium, in addition to aclidinium, umeclidinium, and glycopyrronium. These have been shown in clinical trials to improve lung function, symptoms, and exacerbation rate.^27-30

Patients can be started on either a LAMA or LABA depending on the individual patient's needs and the agent's adverse effects.⁷ Both have comparable adverse effects and efficacy, as detailed below. Concerning adverse effects, there is conflicting data concerning an association of cardiovascular events with both classes of long-acting bronchodilators. While clinical trials failed to show an increased risk,^25,31,32 several retrospective studies showed an increased risk of emergency room visits and hospitalizations due to tachyarrhythmias, heart failure, myocardial infarction, and stroke upon initiation of long-acting bronchodilators.^33,34 There was no difference in risk for adverse cardiovascular events between LABA and LAMA in 1 Canadian study, and slightly more with LABA in a study using an American database.^33,34 Wang et al reported that the risk of cardiovascular adverse effects, defined as hospitalizations and emergency room visits from heart failure, arrythmia, stroke, or ischemia, was 1.5 times the baseline risk in the first 30 days of starting a LABA or LAMA.³⁵ The risk was subsequently the same as baseline or even lower after that period. Urinary retention is another possible complication of LAMA supported by evidence from meta-analyses and retrospective studies, but not clinical trials; the possibility of urinary retention should be discussed with patients upon initiation.^36,37 Concerns about increased mortality with the soft mist formulation of tiotropium were put to rest by the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial, which showed no increased mortality compared to Handihaler.³⁸

As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations.³⁹ No difference in hospitalization rate or mortality was noted in 1 meta-analysis, although tiotropium was more effective in reducing exacerbations.⁴⁰ The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA, while a LAMA would be a better first agent for a patient with severe tachycardia induced by albuterol.

What is the role of inhaled corticosteroids in COPD?

Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation.⁴¹ ICS should not be used alone for COPD management and are always combined with a LABA.⁷ Several ICS formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations, with modest effect on lung function and no change in mortality.⁴² Side effects include oral candidiasis, dysphonia, and skin bruising.⁴³ There is also an increased risk of pneumonia.⁴⁴ ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS).⁴⁵ ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.⁴⁶

What if the patient is still symptomatic on a LABA or LAMA?

For patients whose symptoms are not controlled on one class of LABA, recommendations are to add a bronchodilator from the other class.⁷ There are also multiple combined LAMA-LABA inhalers that are approved in the United States and can possibly improve adherence to therapy. These include tiotropium-olodaterol, umeclidinium-vilanterol, glycopyrronium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post-bronchodilator FEV₁ and quality of life, with no change in hospital admissions, mortality, or adverse effects.⁴⁷ Interestingly, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not.⁴⁷

Current guidelines recommend that patients in GOLD categories C and D who are not well controlled should receive a combination of LABA-ICS.⁷ However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS.⁴⁸ In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.

Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life.^7,49 Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial.²⁷ In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV₁, and morning symptoms.⁵⁰ A combination of triple therapy with fluticasone furoate, umeclidinium, and vilanterol was recently noted to result in a lower rate of moderate or severe COPD exacerbations, preserve lung function, and maintain health-related quality of life, as compared with fluticasone furoate/vilanterol or umeclidinium/vilanterol combination therapy among those with symptomatic COPD with a history of exacerbations.⁵¹

Is there a role for theophylline? Other agents?

Theophylline

Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways.⁵² Theophylline has a serious adverse-effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor.⁵³ It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials.^54,55

In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in the treatment of COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief.⁵³ If used, the therapeutic range of theophylline for COPD is 8 to 12 mcg/mL peak level measured 3 to 7 hours after morning dose, and this level is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients.⁵⁶

Systemic Steroids

Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients, regardless of disease severity, as they increase morbidity and mortality without improving symptoms or lung function.^57,58 The dose of systemic steroids should be tapered and finally discontinued.

Mucolytics

Classes of mucolytics include thiol derivatives, inhaled dornase alfa, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied.⁵⁹ There is no consistent evidence of beneficial role of mucolytics in COPD patients.^7,59 The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio, 0.78; 95% CI, 0.67-0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers.⁶⁰

Long-Term Antibiotics

There is no role for long-term antibiotics in the management of COPD.⁷ Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patients with frequent exacerbations on optimal therapy and will be discussed later in the review.⁶¹

What nonpharmacologic treatments are recommended for COPD patients?

Smoking cessation, oxygen therapy for severe hypoxemia (resting O₂ saturation ≤ 88% or PaO₂ ≤ 55 mm Hg), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D.⁷ It improves symptoms, quality of life, exercise tolerance, and health care utilization. Beneficial effects last for about 2 years.^62,63

What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?

Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m². He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.

What is the significance of acute exacerbations of COPD?

Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.^1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.³ Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.⁴ Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.

How is AECOPD defined?

COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.⁵ Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.⁶ Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.⁷

What is the underlying pathophysiology?

AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.² With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.¹ Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.⁶

How do acute exacerbations affect the course of the disease?

In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.⁸ Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV₁) per lower respiratory tract infection per year,^9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.¹¹

What are the triggers for COPD exacerbation?

Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.² Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.¹² Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.⁶

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.^24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.⁵ One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.²⁶ In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).²⁷ Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.²⁸ Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.⁵ The prescribing clinician also needs to consider potential of prolongation of the QT interval.²⁶

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD.^29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.⁶ Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.^29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD³¹ found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.⁶

β-Blockers

Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.³² Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.³³

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations.³⁴ Two small, single-center studies,^35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,⁶ which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.³⁷ Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Case Presentation

A 65-year-old man with severe chronic obstructive disease (COPD; forced expiratory volume in 1 second/forced vital capacity ratio [FEV₁/FVC], 27; FEV₁ 25% of predicted; residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest computed tomography (CT) scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively.¹ Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population, as compared with pharmacologic management alone.² However, the procedure is associated with risks, including higher short-term morbidity and mortality.² Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone.² On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone.² Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery.^2,3

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction.^4-9 Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics.^10,11 The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis, and increased frequency of COPD exacerbation in the following 30 days. The fact that a high-heterogeneity subgroup had greater improvements in both the FEV₁ and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy.¹² The HRCT scans also help in identifying those with complete fissures, a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic LVRS.¹³ Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction.^11,14 Unfortunately, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status.¹³

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for more than 15 hours a day is thought to reduce mortality among patients with COPD and severe resting hypoxemia.^15-18 More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status.¹⁹

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease.²⁰ Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources.²¹ A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders.²²

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment.²³ The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to improve his or her quality of life.

What is the current scope of lung transplantation in the management of severe COPD?

There is an indisputable role for lung transplantation in end-stage COPD. However, lung transplantation does not benefit all COPD patients. There is a subset of patients for whom the treatment provides a survival benefit. It has been reported that 79% of patients with an FEV₁ < 16% predicted will survive at least 1 additional year after transplant, but only 11% of patients with an FEV₁ > 25% will do so.²⁴ The pre-transplant BODE (body mass index, airflow obstruction/FEV₁, dyspnea, and exercise capacity) index score is used to identify patients who will benefit from lung transplantation.^25,26 International guidelines for the selection of lung transplant candidates identify the following patient characteristics:²⁷

• The disease is progressive, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy;
• The patient is not a candidate for endoscopic or surgical LVRS;
• BODE index is 5 to 6;
• The PCO₂ is greater than 50 mm Hg (6.6 kPa) and/or PO₂ is less than 60 mm Hg (8 kPa);
• FEV₁ is 25% predicted.

The perioperative mortality of lung transplantation surgery has been reduced to less than 10%. Risk of complications from surgery in the perioperative period, such as bronchial dehiscence, infectious complications, and acute rejection, have also been reduced but do occur. Chronic allograft dysfunction and the risk of lung cancer in cases of single lung transplant should be discussed with the patient before surgery.²⁸

How can we incorporate palliative care into the management plan for patients with COPD?

Among patients with end-stage COPD on home oxygen therapy who have required mechanical ventilation for an exacerbation, only 55% are alive at 1 year.²⁹ COPD patients at high risk of death within the next year of life as well as patients with refractory symptoms and unmet needs are candidates for early palliative care. Palliative care and palliative care specialists can aid in reducing symptom burden and improving quality of life among these patients and their family members, and palliative care is recommended by multiple international societies for patients with advanced COPD.^30,31 In spite of these recommendations, the utilization of palliative care resources has been dismally low.^32,33 Improving physician-patient communication regarding palliative services and patients’ unmet care needs will help ensure that COPD patients receive adequate palliative care services at the appropriate time.

Conclusion

COPD is a leading cause of morbidity and mortality in the United States and represents a significant economic burden for both individuals and society. The goals in COPD management are to provide symptom relief, improve the quality of life, preserve lung function, and reduce the frequency of exacerbations and mortality. COPD management is guided by disease severity that is measured using the GOLD multimodal staging system and requires a multidisciplinary approach. Several classes of medication are available for treatment, and a step-wise approach should be applied in building an effective pharmacologic regimen. In addition to pharmacologic therapies, nonpharmacologic therapies, including smoking cessation, vaccinations, proper nutrition, and maintaining physical activity, are an important part of long-term management. Those who continue to be symptomatic despite appropriate maximal therapy may be candidates for lung volume reduction. Palliative care services for COPD patients, which can aid in reducing symptom burden and improving quality of life, should not be overlooked.

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Here are 5 articles from the July issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Cloud of inconsistency hangs over cannabis data

To take the posttest, go to: https://bit.ly/2NfjaDS
Expires February 6, 2020

2. Roux-en-Y achieves diabetes remission in majority of patients

To take the posttest, go to: https://bit.ly/2x9hLnE
Expires February 6, 2020

3. Socioeconomic status, race found to impact CPAP compliance

To take the posttest, go to: https://bit.ly/2RBpLa9
Expires February 8, 2020

4. Exercise type matters for fall prevention among elderly

To take the posttest, go to: https://bit.ly/2X26OUh
Expires February 12, 2020

5. Adult HIV patients should receive standard vaccinations, with caveats

To take the posttest, go to: https://bit.ly/2X1S7LV
Expires February 12, 2020

Use of inhaled corticosteroids may lower the risk of lung cancer in patients with chronic obstructive pulmonary disease, and continued use may also reduce lung cancer risk, recent research from the European Respiratory Journal has shown.

“The appropriate use of [inhaled corticosteroids] ICS in [chronic obstructive pulmonary disease] COPD patients is often debated and not all patients might benefit from the use of ICS. The clinical benefits and risk of use in an individual patient must be weighed by the physician,” wrote Adam J.N. Raymakers, MSc, PhD, of the University of British Columbia’s Collaboration for Outcomes Research and Evaluation (CORE), Vancouver, B.C., and colleagues.

“This study, however, indicates that potential benefits may accrue from ICS use in COPD patients in terms of reduced lung cancer risk, and that sustained use may be associated with reduced risk of lung cancer.”

Dr. Raymakers and colleagues did an analysis of 39,676 patients with COPD (mean age, 70.7 years; 53% female) who received ICS between 1997 and 2007 and linked those patients to a registry of cancer patients in British Columbia. The linked databases included the Medical Services Plan (MSP) payment information file, Discharge Abstract Database (DAD), PharmaNet data file, and the British Columbia Cancer Registry (BCCR). The researchers determined a patient had COPD if he or she received three or more prescriptions related to COPD, while ICS exposure was analyzed in the context of a patient’s ICS exposure, cumulative duration, cumulative dose, and weighted cumulative duration and dose.

The analysis revealed 372,075 prescriptions for ICS were dispensed and 71.2% of the patients were “distinct users” of ICS, with patients filling a median of eight prescriptions at mean 5.2 years of follow-up. Fluticasone propionate was the most common ICS prescribed at a dose of 0.64 mg per day, and patients had median 60 days of ICS supplied per person.

Overall, there were 994 cases of lung cancer (2.5%), and exposure to ICS was linked to a 30% reduction in lung cancer risk (hazard ratio, 0.70; 95% confidence interval, 0.61-0.80), while recency-weighted duration of ICS exposure was linked to a 26% reduction in lung cancer risk (HR, 0.74; 95% CI, 0.66-0.87). There was a 43% reduced risk of lung cancer per gram of ICS when the data were measured by recency-weighted cumulative dosage.

In a multivariate analysis, ICS use was associated with a 30% reduction in risk of non–small cell lung cancer (HR, 0.70; 95% CI, 0.60-0.82), which the researchers said suggests ICS provides a protective effect for patients against lung cancer. “These results highlight the importance of properly identifying which patients might be at the highest risk of lung cancer, to enhance the therapeutic benefits of ICS in these COPD patients,” they wrote.

This study received funding from the Canadian Institutes of Health Research. The authors report no conflicts of interest.

SOURCE: Raymakers A, et al. Eur Respir J. 2019. doi: 10.1183/13993003.01257-2018.

Use of inhaled corticosteroids may lower the risk of lung cancer in patients with chronic obstructive pulmonary disease, and continued use may also reduce lung cancer risk, recent research from the European Respiratory Journal has shown.

“The appropriate use of [inhaled corticosteroids] ICS in [chronic obstructive pulmonary disease] COPD patients is often debated and not all patients might benefit from the use of ICS. The clinical benefits and risk of use in an individual patient must be weighed by the physician,” wrote Adam J.N. Raymakers, MSc, PhD, of the University of British Columbia’s Collaboration for Outcomes Research and Evaluation (CORE), Vancouver, B.C., and colleagues.

“This study, however, indicates that potential benefits may accrue from ICS use in COPD patients in terms of reduced lung cancer risk, and that sustained use may be associated with reduced risk of lung cancer.”

Dr. Raymakers and colleagues did an analysis of 39,676 patients with COPD (mean age, 70.7 years; 53% female) who received ICS between 1997 and 2007 and linked those patients to a registry of cancer patients in British Columbia. The linked databases included the Medical Services Plan (MSP) payment information file, Discharge Abstract Database (DAD), PharmaNet data file, and the British Columbia Cancer Registry (BCCR). The researchers determined a patient had COPD if he or she received three or more prescriptions related to COPD, while ICS exposure was analyzed in the context of a patient’s ICS exposure, cumulative duration, cumulative dose, and weighted cumulative duration and dose.

The analysis revealed 372,075 prescriptions for ICS were dispensed and 71.2% of the patients were “distinct users” of ICS, with patients filling a median of eight prescriptions at mean 5.2 years of follow-up. Fluticasone propionate was the most common ICS prescribed at a dose of 0.64 mg per day, and patients had median 60 days of ICS supplied per person.

Overall, there were 994 cases of lung cancer (2.5%), and exposure to ICS was linked to a 30% reduction in lung cancer risk (hazard ratio, 0.70; 95% confidence interval, 0.61-0.80), while recency-weighted duration of ICS exposure was linked to a 26% reduction in lung cancer risk (HR, 0.74; 95% CI, 0.66-0.87). There was a 43% reduced risk of lung cancer per gram of ICS when the data were measured by recency-weighted cumulative dosage.

In a multivariate analysis, ICS use was associated with a 30% reduction in risk of non–small cell lung cancer (HR, 0.70; 95% CI, 0.60-0.82), which the researchers said suggests ICS provides a protective effect for patients against lung cancer. “These results highlight the importance of properly identifying which patients might be at the highest risk of lung cancer, to enhance the therapeutic benefits of ICS in these COPD patients,” they wrote.

This study received funding from the Canadian Institutes of Health Research. The authors report no conflicts of interest.

SOURCE: Raymakers A, et al. Eur Respir J. 2019. doi: 10.1183/13993003.01257-2018.

Use of inhaled corticosteroids may lower the risk of lung cancer in patients with chronic obstructive pulmonary disease, and continued use may also reduce lung cancer risk, recent research from the European Respiratory Journal has shown.

“The appropriate use of [inhaled corticosteroids] ICS in [chronic obstructive pulmonary disease] COPD patients is often debated and not all patients might benefit from the use of ICS. The clinical benefits and risk of use in an individual patient must be weighed by the physician,” wrote Adam J.N. Raymakers, MSc, PhD, of the University of British Columbia’s Collaboration for Outcomes Research and Evaluation (CORE), Vancouver, B.C., and colleagues.

“This study, however, indicates that potential benefits may accrue from ICS use in COPD patients in terms of reduced lung cancer risk, and that sustained use may be associated with reduced risk of lung cancer.”

Dr. Raymakers and colleagues did an analysis of 39,676 patients with COPD (mean age, 70.7 years; 53% female) who received ICS between 1997 and 2007 and linked those patients to a registry of cancer patients in British Columbia. The linked databases included the Medical Services Plan (MSP) payment information file, Discharge Abstract Database (DAD), PharmaNet data file, and the British Columbia Cancer Registry (BCCR). The researchers determined a patient had COPD if he or she received three or more prescriptions related to COPD, while ICS exposure was analyzed in the context of a patient’s ICS exposure, cumulative duration, cumulative dose, and weighted cumulative duration and dose.

The analysis revealed 372,075 prescriptions for ICS were dispensed and 71.2% of the patients were “distinct users” of ICS, with patients filling a median of eight prescriptions at mean 5.2 years of follow-up. Fluticasone propionate was the most common ICS prescribed at a dose of 0.64 mg per day, and patients had median 60 days of ICS supplied per person.

Overall, there were 994 cases of lung cancer (2.5%), and exposure to ICS was linked to a 30% reduction in lung cancer risk (hazard ratio, 0.70; 95% confidence interval, 0.61-0.80), while recency-weighted duration of ICS exposure was linked to a 26% reduction in lung cancer risk (HR, 0.74; 95% CI, 0.66-0.87). There was a 43% reduced risk of lung cancer per gram of ICS when the data were measured by recency-weighted cumulative dosage.

In a multivariate analysis, ICS use was associated with a 30% reduction in risk of non–small cell lung cancer (HR, 0.70; 95% CI, 0.60-0.82), which the researchers said suggests ICS provides a protective effect for patients against lung cancer. “These results highlight the importance of properly identifying which patients might be at the highest risk of lung cancer, to enhance the therapeutic benefits of ICS in these COPD patients,” they wrote.

This study received funding from the Canadian Institutes of Health Research. The authors report no conflicts of interest.

SOURCE: Raymakers A, et al. Eur Respir J. 2019. doi: 10.1183/13993003.01257-2018.