1. Papulosquamous skin disease marked by a history of waxing and waning in severity and scaling in perinasal area manifested in this patient.

Diagnosis: Seborrheic dermatitis presenting as erythema with scaling on the perinasal and perioral area. Similar to rosacea, seborrheic dermatitis is a chronic and relapsing erythematous rash with well-demarcated erythematous patches, papules, or plaques; however, unlike rosacea, the distribution varies from minimal asymptomatic scaliness of the scalp to more widespread involvement (eg, scalp, ears, upper aspect of the trunk, intertriginous areas). Also, although macular erythema and scaling involving the perinasal area may be seen in either rosacea or seborrheic dermatitis, a greasy quality to the scales and involvement of other sites such as the scalp, retroauricular skin, and eyebrows suggest a diagnosis of seborrheic dermatitis

Read more about seborrheic dermatitis at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

For the next photograph, proceed to the next page >>

2. The patient had a painful, erythematous skin rash over the bridge of her nose, spreading to the malar area, eyelids, and forehead.

Diagnosis: Erysipelas is an acute superficial cellulitis with lymphatic involvement. It is characterized by the abrupt onset of a warm, erythematous rash with a sharply demarcated, indurated, elevated margin. There are no suppurative foci; sometimes, however, there are bullae or vesicles.

In facial “butterfly” erysipelas (which this patient had), the plaques may involve the eyelids, cheeks, nose, and forehead. Upon palpation, the skin is hot and tender. As the process develops, the color becomes a dark, fiery red and vesicles appear at the advancing border and over the surface. Associated regional lymphadenopathy may be present. There is no necrosis.¹

Read more about erysipelas at Painful rash on face. J Fam Pract. 2010 August;59(8):459-462.

For the next photograph, proceed to the next page >>

3. Shortly after she started taking Bikram yoga classes, this 30-year-old patient developed inflammatory papules and pustules. Her symptoms worsened after each 1-hour session. On physical exam, there were erythematous, inflammatory papules and pustules concentrated on her forehead. No comedones were present.

Diagnosis: Rosacea, an inflammatory condition of the skin that typically affects the convex portions of the central face. This chronic cutaneous disorder usually starts after age 30 in both men and women, and is more prevalent in those with fairer skin.² In fact, an epidemiologic study showed the prevalence to be as high as 10% in the Swedish population.³ The condition, which is not life threatening, can be controlled, although not cured. Its effect on appearance may have a negative impact on a patient’s quality of life.

Read more about Rosacea at Pustular eruption on face. J Fam Pract. 2010 July;59(7):399-401.

For the next photograph, proceed to the next page >>

4. Erythematous papules, papulovesicles, and plaques appeared on sun-exposed surfaces of the skin.

Diagnosis: Polymorphous light eruption (PMLE) manifesting as erythematous papules over the cheek and dorsal aspect of the nose. Similarities between PMLE and rosacea include exacerbation by sun exposure and a higher prevalence in fair-skinned individuals.⁴ Also, in both conditions erythematous papules appear on the face and may be pruritic and in some instances painful; however, unlike rosacea, which is chronic, PMLE tends to be intermittent and recurrent, typically occurring in the spring and early summer months.

Read more about PMLE at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

For the next photograph, proceed to the next page >>

5. This patient presented with isolated, grouped, and multiple erythematous to violaceous papules, plaques, or nodules, in an asymmetric distribution.

Diagnosis: B-cell neoplasms with skin involvement can present as primary cutaneous lymphomas or as secondary processes, including specific infiltrates of nodal or extranodal lymphoma or leukemia.⁵ B-cell lymphomas involving the skin have a distinct clinical appearance, presenting as isolated, grouped, or multiple erythematous to violaceous papules, plaques, or nodules, usually in an asymmetric distribution. B-cell lymphoproliferative diseases simulating rosacea are extremely rare.⁵ Nevertheless, B-cell lymphoma mimicking rhinophyma has been documented in the literature.^5-11

Read more about B-cell neoplasms at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

Figures 1, 4, 5 reprinted with permission from Cutis. 2014;94(1):39-45; photographs for Figures 4 and 5 courtesy of Marc Silverstein, MD. Figure 2 reprinted with permission from J Fam Pract. 2010 August;59(8):459-462; photograph courtesy of Felix B. Chang, MD. Figure 3 reprinted courtesy of J Fam Pract. 2010 July;59(7):399-401; photograph courtesy of Nikki N. Kim, MD, Heather W. Wickless, MD, MPH.

REFERENCES
1. Chang F, Lopes A. Erysipelas. In: Domino FJ, ed. The 5-Minute Clinical Consult 2008. 16th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2008:448–449.
2. Gupta AK, Chaudhry MM. Rosacea and its management: an overview. J Eur Acad Dermatol Venereol. 2005;19:273-285.
3. Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol. 1989;69:419-423.
4. Tutrone WD. Polymorphic light eruption. Dermatol Ther. 2003;16:28-39.
5. Barzilai A, Feuerman H, Quaglino P, et al. Cutaneous B-cell neoplasms mimicking granulomatous rosacea or rhinophyma. Arch Dermatol. 2012;148:824-831.
6. Moulonguet I, Ghnassia M, Molina T, et al. Miliarial-type perifollicular B-cell pseudolymphoma (lymphocytoma cutis): a misleading eruption in two women. J Cutan Pathol. 2012;39:1016-1021.
7. Soon CW, Pincus LB, Ai WZ, et al. Acneiform presentation of primary cutaneous follicle center lymphoma. J Am Acad Dermatol. 2011;65:887-889.
8. Rosmaninho A, Alves R, Lima M, et al. Red nose: primary cutaneous marginal zone B-cell lymphoma. Leuk Res.2010;34:682-684.
9. Ogden S, Coulson IH. B-cell lymphoma mimicking rhinophyma. Clin Exp Dermatol. 2008;33:213-214.
10. Seward JL, Malone JC, Callen JP. Rhinophymalike swelling in an 86-year-old woman. Primary cutaneous B-cell lymphoma of the nose. Arch Dermatol. 2004;140:751-756.
11. Colvin JH, Lamerson CL, Cualing H, et al. Cutaneous lymphoplasmacytoid lymphoma (immunocytoma) with Waldenström’s macroglobulinemia mimicking rosacea. J Am Acad Dermatol. 2003;49:1159-1162.

1. Papulosquamous skin disease marked by a history of waxing and waning in severity and scaling in perinasal area manifested in this patient.

Diagnosis: Seborrheic dermatitis presenting as erythema with scaling on the perinasal and perioral area. Similar to rosacea, seborrheic dermatitis is a chronic and relapsing erythematous rash with well-demarcated erythematous patches, papules, or plaques; however, unlike rosacea, the distribution varies from minimal asymptomatic scaliness of the scalp to more widespread involvement (eg, scalp, ears, upper aspect of the trunk, intertriginous areas). Also, although macular erythema and scaling involving the perinasal area may be seen in either rosacea or seborrheic dermatitis, a greasy quality to the scales and involvement of other sites such as the scalp, retroauricular skin, and eyebrows suggest a diagnosis of seborrheic dermatitis

Read more about seborrheic dermatitis at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

For the next photograph, proceed to the next page >>

2. The patient had a painful, erythematous skin rash over the bridge of her nose, spreading to the malar area, eyelids, and forehead.

Diagnosis: Erysipelas is an acute superficial cellulitis with lymphatic involvement. It is characterized by the abrupt onset of a warm, erythematous rash with a sharply demarcated, indurated, elevated margin. There are no suppurative foci; sometimes, however, there are bullae or vesicles.

In facial “butterfly” erysipelas (which this patient had), the plaques may involve the eyelids, cheeks, nose, and forehead. Upon palpation, the skin is hot and tender. As the process develops, the color becomes a dark, fiery red and vesicles appear at the advancing border and over the surface. Associated regional lymphadenopathy may be present. There is no necrosis.¹

Read more about erysipelas at Painful rash on face. J Fam Pract. 2010 August;59(8):459-462.

For the next photograph, proceed to the next page >>

3. Shortly after she started taking Bikram yoga classes, this 30-year-old patient developed inflammatory papules and pustules. Her symptoms worsened after each 1-hour session. On physical exam, there were erythematous, inflammatory papules and pustules concentrated on her forehead. No comedones were present.

Diagnosis: Rosacea, an inflammatory condition of the skin that typically affects the convex portions of the central face. This chronic cutaneous disorder usually starts after age 30 in both men and women, and is more prevalent in those with fairer skin.² In fact, an epidemiologic study showed the prevalence to be as high as 10% in the Swedish population.³ The condition, which is not life threatening, can be controlled, although not cured. Its effect on appearance may have a negative impact on a patient’s quality of life.

Read more about Rosacea at Pustular eruption on face. J Fam Pract. 2010 July;59(7):399-401.

For the next photograph, proceed to the next page >>

4. Erythematous papules, papulovesicles, and plaques appeared on sun-exposed surfaces of the skin.

Diagnosis: Polymorphous light eruption (PMLE) manifesting as erythematous papules over the cheek and dorsal aspect of the nose. Similarities between PMLE and rosacea include exacerbation by sun exposure and a higher prevalence in fair-skinned individuals.⁴ Also, in both conditions erythematous papules appear on the face and may be pruritic and in some instances painful; however, unlike rosacea, which is chronic, PMLE tends to be intermittent and recurrent, typically occurring in the spring and early summer months.

Read more about PMLE at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

For the next photograph, proceed to the next page >>

5. This patient presented with isolated, grouped, and multiple erythematous to violaceous papules, plaques, or nodules, in an asymmetric distribution.

Diagnosis: B-cell neoplasms with skin involvement can present as primary cutaneous lymphomas or as secondary processes, including specific infiltrates of nodal or extranodal lymphoma or leukemia.⁵ B-cell lymphomas involving the skin have a distinct clinical appearance, presenting as isolated, grouped, or multiple erythematous to violaceous papules, plaques, or nodules, usually in an asymmetric distribution. B-cell lymphoproliferative diseases simulating rosacea are extremely rare.⁵ Nevertheless, B-cell lymphoma mimicking rhinophyma has been documented in the literature.^5-11

Read more about B-cell neoplasms at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

Figures 1, 4, 5 reprinted with permission from Cutis. 2014;94(1):39-45; photographs for Figures 4 and 5 courtesy of Marc Silverstein, MD. Figure 2 reprinted with permission from J Fam Pract. 2010 August;59(8):459-462; photograph courtesy of Felix B. Chang, MD. Figure 3 reprinted courtesy of J Fam Pract. 2010 July;59(7):399-401; photograph courtesy of Nikki N. Kim, MD, Heather W. Wickless, MD, MPH.

REFERENCES
1. Chang F, Lopes A. Erysipelas. In: Domino FJ, ed. The 5-Minute Clinical Consult 2008. 16th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2008:448–449.
2. Gupta AK, Chaudhry MM. Rosacea and its management: an overview. J Eur Acad Dermatol Venereol. 2005;19:273-285.
3. Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol. 1989;69:419-423.
4. Tutrone WD. Polymorphic light eruption. Dermatol Ther. 2003;16:28-39.
5. Barzilai A, Feuerman H, Quaglino P, et al. Cutaneous B-cell neoplasms mimicking granulomatous rosacea or rhinophyma. Arch Dermatol. 2012;148:824-831.
6. Moulonguet I, Ghnassia M, Molina T, et al. Miliarial-type perifollicular B-cell pseudolymphoma (lymphocytoma cutis): a misleading eruption in two women. J Cutan Pathol. 2012;39:1016-1021.
7. Soon CW, Pincus LB, Ai WZ, et al. Acneiform presentation of primary cutaneous follicle center lymphoma. J Am Acad Dermatol. 2011;65:887-889.
8. Rosmaninho A, Alves R, Lima M, et al. Red nose: primary cutaneous marginal zone B-cell lymphoma. Leuk Res.2010;34:682-684.
9. Ogden S, Coulson IH. B-cell lymphoma mimicking rhinophyma. Clin Exp Dermatol. 2008;33:213-214.
10. Seward JL, Malone JC, Callen JP. Rhinophymalike swelling in an 86-year-old woman. Primary cutaneous B-cell lymphoma of the nose. Arch Dermatol. 2004;140:751-756.
11. Colvin JH, Lamerson CL, Cualing H, et al. Cutaneous lymphoplasmacytoid lymphoma (immunocytoma) with Waldenström’s macroglobulinemia mimicking rosacea. J Am Acad Dermatol. 2003;49:1159-1162.

1. Papulosquamous skin disease marked by a history of waxing and waning in severity and scaling in perinasal area manifested in this patient.

Diagnosis: Seborrheic dermatitis presenting as erythema with scaling on the perinasal and perioral area. Similar to rosacea, seborrheic dermatitis is a chronic and relapsing erythematous rash with well-demarcated erythematous patches, papules, or plaques; however, unlike rosacea, the distribution varies from minimal asymptomatic scaliness of the scalp to more widespread involvement (eg, scalp, ears, upper aspect of the trunk, intertriginous areas). Also, although macular erythema and scaling involving the perinasal area may be seen in either rosacea or seborrheic dermatitis, a greasy quality to the scales and involvement of other sites such as the scalp, retroauricular skin, and eyebrows suggest a diagnosis of seborrheic dermatitis

Read more about seborrheic dermatitis at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

For the next photograph, proceed to the next page >>

2. The patient had a painful, erythematous skin rash over the bridge of her nose, spreading to the malar area, eyelids, and forehead.

Diagnosis: Erysipelas is an acute superficial cellulitis with lymphatic involvement. It is characterized by the abrupt onset of a warm, erythematous rash with a sharply demarcated, indurated, elevated margin. There are no suppurative foci; sometimes, however, there are bullae or vesicles.

In facial “butterfly” erysipelas (which this patient had), the plaques may involve the eyelids, cheeks, nose, and forehead. Upon palpation, the skin is hot and tender. As the process develops, the color becomes a dark, fiery red and vesicles appear at the advancing border and over the surface. Associated regional lymphadenopathy may be present. There is no necrosis.¹

Read more about erysipelas at Painful rash on face. J Fam Pract. 2010 August;59(8):459-462.

For the next photograph, proceed to the next page >>

3. Shortly after she started taking Bikram yoga classes, this 30-year-old patient developed inflammatory papules and pustules. Her symptoms worsened after each 1-hour session. On physical exam, there were erythematous, inflammatory papules and pustules concentrated on her forehead. No comedones were present.

Diagnosis: Rosacea, an inflammatory condition of the skin that typically affects the convex portions of the central face. This chronic cutaneous disorder usually starts after age 30 in both men and women, and is more prevalent in those with fairer skin.² In fact, an epidemiologic study showed the prevalence to be as high as 10% in the Swedish population.³ The condition, which is not life threatening, can be controlled, although not cured. Its effect on appearance may have a negative impact on a patient’s quality of life.

Read more about Rosacea at Pustular eruption on face. J Fam Pract. 2010 July;59(7):399-401.

For the next photograph, proceed to the next page >>

4. Erythematous papules, papulovesicles, and plaques appeared on sun-exposed surfaces of the skin.

Diagnosis: Polymorphous light eruption (PMLE) manifesting as erythematous papules over the cheek and dorsal aspect of the nose. Similarities between PMLE and rosacea include exacerbation by sun exposure and a higher prevalence in fair-skinned individuals.⁴ Also, in both conditions erythematous papules appear on the face and may be pruritic and in some instances painful; however, unlike rosacea, which is chronic, PMLE tends to be intermittent and recurrent, typically occurring in the spring and early summer months.

Read more about PMLE at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

For the next photograph, proceed to the next page >>

5. This patient presented with isolated, grouped, and multiple erythematous to violaceous papules, plaques, or nodules, in an asymmetric distribution.

Diagnosis: B-cell neoplasms with skin involvement can present as primary cutaneous lymphomas or as secondary processes, including specific infiltrates of nodal or extranodal lymphoma or leukemia.⁵ B-cell lymphomas involving the skin have a distinct clinical appearance, presenting as isolated, grouped, or multiple erythematous to violaceous papules, plaques, or nodules, usually in an asymmetric distribution. B-cell lymphoproliferative diseases simulating rosacea are extremely rare.⁵ Nevertheless, B-cell lymphoma mimicking rhinophyma has been documented in the literature.^5-11

Read more about B-cell neoplasms at The great mimickers of rosacea. Cutis. 2014;94(1):39-45.

Figures 1, 4, 5 reprinted with permission from Cutis. 2014;94(1):39-45; photographs for Figures 4 and 5 courtesy of Marc Silverstein, MD. Figure 2 reprinted with permission from J Fam Pract. 2010 August;59(8):459-462; photograph courtesy of Felix B. Chang, MD. Figure 3 reprinted courtesy of J Fam Pract. 2010 July;59(7):399-401; photograph courtesy of Nikki N. Kim, MD, Heather W. Wickless, MD, MPH.

REFERENCES
1. Chang F, Lopes A. Erysipelas. In: Domino FJ, ed. The 5-Minute Clinical Consult 2008. 16th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2008:448–449.
2. Gupta AK, Chaudhry MM. Rosacea and its management: an overview. J Eur Acad Dermatol Venereol. 2005;19:273-285.
3. Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol. 1989;69:419-423.
4. Tutrone WD. Polymorphic light eruption. Dermatol Ther. 2003;16:28-39.
5. Barzilai A, Feuerman H, Quaglino P, et al. Cutaneous B-cell neoplasms mimicking granulomatous rosacea or rhinophyma. Arch Dermatol. 2012;148:824-831.
6. Moulonguet I, Ghnassia M, Molina T, et al. Miliarial-type perifollicular B-cell pseudolymphoma (lymphocytoma cutis): a misleading eruption in two women. J Cutan Pathol. 2012;39:1016-1021.
7. Soon CW, Pincus LB, Ai WZ, et al. Acneiform presentation of primary cutaneous follicle center lymphoma. J Am Acad Dermatol. 2011;65:887-889.
8. Rosmaninho A, Alves R, Lima M, et al. Red nose: primary cutaneous marginal zone B-cell lymphoma. Leuk Res.2010;34:682-684.
9. Ogden S, Coulson IH. B-cell lymphoma mimicking rhinophyma. Clin Exp Dermatol. 2008;33:213-214.
10. Seward JL, Malone JC, Callen JP. Rhinophymalike swelling in an 86-year-old woman. Primary cutaneous B-cell lymphoma of the nose. Arch Dermatol. 2004;140:751-756.
11. Colvin JH, Lamerson CL, Cualing H, et al. Cutaneous lymphoplasmacytoid lymphoma (immunocytoma) with Waldenström’s macroglobulinemia mimicking rosacea. J Am Acad Dermatol. 2003;49:1159-1162.

No significant difference in combination therapy vs ICS alone

In 2013, a Cochrane review analyzed the risk of mortality and nonfatal serious adverse events in patients treated with the LABA salmeterol in combination with ICS, compared with patients receiving the same dose of ICS alone.¹ The review included 35 RCTs of moderate quality with 13,447 adolescents and adults and 5 RCTs with 1862 children. Patients had all stages of asthma; mean study duration was 34 weeks in adult trials and 15 weeks in trials of children.

Seven deaths from all causes occurred in both the salmeterol-plus-ICS group and the ICS-alone group (35 trials, N=13,447; Peto odds ratio [OR]=0.90; 95% confidence interval [CI], 0.31-2.6). No deaths in children and no asthma-related deaths occurred in any study participants (40 trials, N=15,309).

Adults treated with ICS alone showed no significant difference from adults receiving combination therapy in the frequency of serious adverse events (defined as life threatening, requiring hospitalization or prolongation of existing hospitalization, or resulting in persistent or significant disability or incapacity). Adults on ICS had 21 events per 1000 compared with 24 per 1000 in adults on combination treatment (35 trials, N=13,447; Peto OR=1.2; 95% CI, 0.91-1.4).

Asthma-related serious adverse events were reported in 29 of 6986 adults in the combination group and 23 of 6461 in the ICS-alone group, a nonsignificant difference (35 trials, N=13,447; Peto OR=1.1; 95% CI, 0.65-1.9).

Only one serious asthma-related adverse event occurred in each group of children (ICS- and combination-treated); (5 trials, N=1862; Peto OR=0.99; 95% CI, 0.6-16). Because the number of events was so small and the results were so imprecise, a relative increase in all-cause mortality or nonfatal adverse events can’t be completely ruled out.

Inconsistent dosages mar trials that show more catastrophic events

A systematic review of 7 RCTs with 7253 asthmatic patients compared LABA plus ICS or ICS alone at various doses. All of the trials included at least one catastrophic event, defined as an asthma-related intubation or death.² The mean ages of the patients varied from 11 to 48 years, and the length of the studies from 12 to 52 weeks. The risk of catastrophic events was greater in the LABA plus ICS groups than ICS alone (OR=3.7; 95% CI, 1.4-9.6).

Only one of the 7 trials was included in the 2013 Cochrane review. The others were excluded because the control groups used different doses of ICS than the LABA-plus-ICS groups. In one trial, for example, the ICS group used 4 times the dose of budesonide used in the LABA-plus-ICS group. The difference in outcomes may therefore reflect the variation in ICS dose rather than the presence or absence of LABA.

Because of these conflicting results, the US Food and Drug Administration has mandated continued evaluation of LABAs by manufacturers.³ Five clinical trials that are multinational, randomized, double-blind, and lasting at least 6 months will evaluate the safety of LABAs plus fixed-dose ICS compared with fixed-dose ICS alone. A total of 6200 children and 46,800 adults will be enrolled in the studies, whose results should be available in 2017.

No significant difference in combination therapy vs ICS alone

In 2013, a Cochrane review analyzed the risk of mortality and nonfatal serious adverse events in patients treated with the LABA salmeterol in combination with ICS, compared with patients receiving the same dose of ICS alone.¹ The review included 35 RCTs of moderate quality with 13,447 adolescents and adults and 5 RCTs with 1862 children. Patients had all stages of asthma; mean study duration was 34 weeks in adult trials and 15 weeks in trials of children.

Seven deaths from all causes occurred in both the salmeterol-plus-ICS group and the ICS-alone group (35 trials, N=13,447; Peto odds ratio [OR]=0.90; 95% confidence interval [CI], 0.31-2.6). No deaths in children and no asthma-related deaths occurred in any study participants (40 trials, N=15,309).

Adults treated with ICS alone showed no significant difference from adults receiving combination therapy in the frequency of serious adverse events (defined as life threatening, requiring hospitalization or prolongation of existing hospitalization, or resulting in persistent or significant disability or incapacity). Adults on ICS had 21 events per 1000 compared with 24 per 1000 in adults on combination treatment (35 trials, N=13,447; Peto OR=1.2; 95% CI, 0.91-1.4).

Asthma-related serious adverse events were reported in 29 of 6986 adults in the combination group and 23 of 6461 in the ICS-alone group, a nonsignificant difference (35 trials, N=13,447; Peto OR=1.1; 95% CI, 0.65-1.9).

Only one serious asthma-related adverse event occurred in each group of children (ICS- and combination-treated); (5 trials, N=1862; Peto OR=0.99; 95% CI, 0.6-16). Because the number of events was so small and the results were so imprecise, a relative increase in all-cause mortality or nonfatal adverse events can’t be completely ruled out.

Inconsistent dosages mar trials that show more catastrophic events

A systematic review of 7 RCTs with 7253 asthmatic patients compared LABA plus ICS or ICS alone at various doses. All of the trials included at least one catastrophic event, defined as an asthma-related intubation or death.² The mean ages of the patients varied from 11 to 48 years, and the length of the studies from 12 to 52 weeks. The risk of catastrophic events was greater in the LABA plus ICS groups than ICS alone (OR=3.7; 95% CI, 1.4-9.6).

Only one of the 7 trials was included in the 2013 Cochrane review. The others were excluded because the control groups used different doses of ICS than the LABA-plus-ICS groups. In one trial, for example, the ICS group used 4 times the dose of budesonide used in the LABA-plus-ICS group. The difference in outcomes may therefore reflect the variation in ICS dose rather than the presence or absence of LABA.

Because of these conflicting results, the US Food and Drug Administration has mandated continued evaluation of LABAs by manufacturers.³ Five clinical trials that are multinational, randomized, double-blind, and lasting at least 6 months will evaluate the safety of LABAs plus fixed-dose ICS compared with fixed-dose ICS alone. A total of 6200 children and 46,800 adults will be enrolled in the studies, whose results should be available in 2017.

No significant difference in combination therapy vs ICS alone

In 2013, a Cochrane review analyzed the risk of mortality and nonfatal serious adverse events in patients treated with the LABA salmeterol in combination with ICS, compared with patients receiving the same dose of ICS alone.¹ The review included 35 RCTs of moderate quality with 13,447 adolescents and adults and 5 RCTs with 1862 children. Patients had all stages of asthma; mean study duration was 34 weeks in adult trials and 15 weeks in trials of children.

Seven deaths from all causes occurred in both the salmeterol-plus-ICS group and the ICS-alone group (35 trials, N=13,447; Peto odds ratio [OR]=0.90; 95% confidence interval [CI], 0.31-2.6). No deaths in children and no asthma-related deaths occurred in any study participants (40 trials, N=15,309).

Adults treated with ICS alone showed no significant difference from adults receiving combination therapy in the frequency of serious adverse events (defined as life threatening, requiring hospitalization or prolongation of existing hospitalization, or resulting in persistent or significant disability or incapacity). Adults on ICS had 21 events per 1000 compared with 24 per 1000 in adults on combination treatment (35 trials, N=13,447; Peto OR=1.2; 95% CI, 0.91-1.4).

Asthma-related serious adverse events were reported in 29 of 6986 adults in the combination group and 23 of 6461 in the ICS-alone group, a nonsignificant difference (35 trials, N=13,447; Peto OR=1.1; 95% CI, 0.65-1.9).

Only one serious asthma-related adverse event occurred in each group of children (ICS- and combination-treated); (5 trials, N=1862; Peto OR=0.99; 95% CI, 0.6-16). Because the number of events was so small and the results were so imprecise, a relative increase in all-cause mortality or nonfatal adverse events can’t be completely ruled out.

Inconsistent dosages mar trials that show more catastrophic events

A systematic review of 7 RCTs with 7253 asthmatic patients compared LABA plus ICS or ICS alone at various doses. All of the trials included at least one catastrophic event, defined as an asthma-related intubation or death.² The mean ages of the patients varied from 11 to 48 years, and the length of the studies from 12 to 52 weeks. The risk of catastrophic events was greater in the LABA plus ICS groups than ICS alone (OR=3.7; 95% CI, 1.4-9.6).

Only one of the 7 trials was included in the 2013 Cochrane review. The others were excluded because the control groups used different doses of ICS than the LABA-plus-ICS groups. In one trial, for example, the ICS group used 4 times the dose of budesonide used in the LABA-plus-ICS group. The difference in outcomes may therefore reflect the variation in ICS dose rather than the presence or absence of LABA.

Because of these conflicting results, the US Food and Drug Administration has mandated continued evaluation of LABAs by manufacturers.³ Five clinical trials that are multinational, randomized, double-blind, and lasting at least 6 months will evaluate the safety of LABAs plus fixed-dose ICS compared with fixed-dose ICS alone. A total of 6200 children and 46,800 adults will be enrolled in the studies, whose results should be available in 2017.

To the Editor: We read the review on enterovirus D68¹ (EV-D68) with great interest, and we thought it merited comment.

During the current influenza season, we have had several adult cases of EV-D68 presenting as an influenza-like illness. EV-D68 was diagnosed by nasal swab viral film array polymerase chain reaction (PCR) testing. We agree with the authors that the clinical spectrum of enteroviral infection includes a variety of extraintestinal manifestations, eg, acute pancreatitis. As more cases of EV-D68 are described, the range of clinical manifestations will be increased.^2–5

We recently saw a 27-year-old woman who presented with an influenza-like illness, but with a main complaint of right-upper-quadrant abdominal pain. She denied recent travel or contacts with sick children or adults. Her past medical history was unremarkable, and she was not taking any medications. The physical examination was unremarkable except for moderately severe tenderness in the right upper quadrant, with no rebound or guarding.

Results of laboratory testing at hospital admission included a white blood cell count of 7.3 × 10⁹/L (49% neutrophils, 41% lymphocytes, 7% monocytes, 3% eosinophils), a normal platelet count, serum lipase 73 U/L (reference range 5.6–51.3 U/L), and serum amylase 211 U/L (37–121 U/L). Serum aminotransferase and alkaline phosphatase levels were normal. Abdominal ultrasonography was unremarkable. Nasal swab for multiplex PCR testing for respiratory viruses was positive for human rhinovirus-enterovirus. Further PCR testing was positive for EV-D68 (New York State Department of Health, Wadsworth Laboratory). Her abdominal pain was treated symptomatically; she gradually improved and was discharged.

This instance of EV-D68 in a healthy 27-year-old woman presenting with influenza-like illness and acute pain in the right upper quadrant is the first we have seen of EV-D68 presenting as acute pancreatitis. Clinicians should be aware that EV-D68, like influenza, may present with gastrointestinal manifestations.

To the Editor: We read the review on enterovirus D68¹ (EV-D68) with great interest, and we thought it merited comment.

During the current influenza season, we have had several adult cases of EV-D68 presenting as an influenza-like illness. EV-D68 was diagnosed by nasal swab viral film array polymerase chain reaction (PCR) testing. We agree with the authors that the clinical spectrum of enteroviral infection includes a variety of extraintestinal manifestations, eg, acute pancreatitis. As more cases of EV-D68 are described, the range of clinical manifestations will be increased.^2–5

We recently saw a 27-year-old woman who presented with an influenza-like illness, but with a main complaint of right-upper-quadrant abdominal pain. She denied recent travel or contacts with sick children or adults. Her past medical history was unremarkable, and she was not taking any medications. The physical examination was unremarkable except for moderately severe tenderness in the right upper quadrant, with no rebound or guarding.

Results of laboratory testing at hospital admission included a white blood cell count of 7.3 × 10⁹/L (49% neutrophils, 41% lymphocytes, 7% monocytes, 3% eosinophils), a normal platelet count, serum lipase 73 U/L (reference range 5.6–51.3 U/L), and serum amylase 211 U/L (37–121 U/L). Serum aminotransferase and alkaline phosphatase levels were normal. Abdominal ultrasonography was unremarkable. Nasal swab for multiplex PCR testing for respiratory viruses was positive for human rhinovirus-enterovirus. Further PCR testing was positive for EV-D68 (New York State Department of Health, Wadsworth Laboratory). Her abdominal pain was treated symptomatically; she gradually improved and was discharged.

This instance of EV-D68 in a healthy 27-year-old woman presenting with influenza-like illness and acute pain in the right upper quadrant is the first we have seen of EV-D68 presenting as acute pancreatitis. Clinicians should be aware that EV-D68, like influenza, may present with gastrointestinal manifestations.

To the Editor: We read the review on enterovirus D68¹ (EV-D68) with great interest, and we thought it merited comment.

During the current influenza season, we have had several adult cases of EV-D68 presenting as an influenza-like illness. EV-D68 was diagnosed by nasal swab viral film array polymerase chain reaction (PCR) testing. We agree with the authors that the clinical spectrum of enteroviral infection includes a variety of extraintestinal manifestations, eg, acute pancreatitis. As more cases of EV-D68 are described, the range of clinical manifestations will be increased.^2–5

We recently saw a 27-year-old woman who presented with an influenza-like illness, but with a main complaint of right-upper-quadrant abdominal pain. She denied recent travel or contacts with sick children or adults. Her past medical history was unremarkable, and she was not taking any medications. The physical examination was unremarkable except for moderately severe tenderness in the right upper quadrant, with no rebound or guarding.

Results of laboratory testing at hospital admission included a white blood cell count of 7.3 × 10⁹/L (49% neutrophils, 41% lymphocytes, 7% monocytes, 3% eosinophils), a normal platelet count, serum lipase 73 U/L (reference range 5.6–51.3 U/L), and serum amylase 211 U/L (37–121 U/L). Serum aminotransferase and alkaline phosphatase levels were normal. Abdominal ultrasonography was unremarkable. Nasal swab for multiplex PCR testing for respiratory viruses was positive for human rhinovirus-enterovirus. Further PCR testing was positive for EV-D68 (New York State Department of Health, Wadsworth Laboratory). Her abdominal pain was treated symptomatically; she gradually improved and was discharged.

This instance of EV-D68 in a healthy 27-year-old woman presenting with influenza-like illness and acute pain in the right upper quadrant is the first we have seen of EV-D68 presenting as acute pancreatitis. Clinicians should be aware that EV-D68, like influenza, may present with gastrointestinal manifestations.

To the Editor: In the February 2015 issue of Cleveland Clinic Journal of Medicine, Dr. David A. Katzka reviewed the major clinical features of eosinophilic esophagitis and, having presented its allergic component, rightly assessed the inherent difficulties of detecting and eliminating food allergens involved in the development and course of this disease.¹ The inadequacies of serologic testing were mentioned, as well as the difficulties of endoscopy and biopsy “painstakingly performed with the removal and reintroduction of every suspected food allergen, requiring multiple biopsies weekly, which is impractical for safety and economic reasons.”¹

In a meta-analysis, Arias et al² showed that such an individualized approach for each food is not really necessary. Elemental diets with graded reintroduction of grouped foods were effective in detecting and treating the responsible food allergies in 90.8% of cases (95% confidence interval [CI] 84.7–95.5). In fact, the more pragmatic, simple, and inexpensive six-food-elimination diet was also reasonably effective (72.1% of cases, 95% CI 65.8–78.1). Both outcomes are far superior to elimination strategies directed at immunoglobulin E (IgE), which were effective in only 45.5% of cases (95% CI 35.4–55.7%).²

Franciosi and Liacouras³ described a practical and comprehensive elimination-reintroduction protocol consisting of four steps that, in combination with symptom diaries, can easily identify responsible foods.

In our practice, graded elimination-reintroduction diets—which, depending on history, may range from the basic six-food-elimination diet to the fully developed Franciosi-Liacouras protocol—along with food IgE testing and judicial use of IgG testing against selected foods, have yielded detection and successful treatment rates comparable to the 90.8% rate reported by Arias et al.² Upon identification of food allergens, a dual approach of diet restrictions and food immunotherapy is initiated. As a result of this approach, patients only need to undergo a single endoscopy and biopsy to demonstrate decreased eosinophil counts, usually 1 year after initiation of allergy treatment.

Of course, pharmacologic management is necessary in the treatment of eosinophilic esophagitis. However, the inclusion of montelukast in the standard first-line regimen for eosinophilic esophagitis is not yet a firmly established practice. Not all eosinophilia can be equated to allergy, and not all allergic inflammation is leukotriene-dependent. Furthermore, too little is known about the secondary effects of leukotrienes on immune regulation and whether their blockade is really desirable in eosinophilic esophagitis. But it is known that leukotriene receptor antagonists, especially montelukast, can trigger Churg-Strauss vasculitis, a syndrome whose eosinophil activation, homing pattern, and subsequent proliferation—as well as its exclusive prevalence in allergic patients with asthma and chronic sinusitis—bear some similarity to those of eosinophilic esophagitis.

To the Editor: In the February 2015 issue of Cleveland Clinic Journal of Medicine, Dr. David A. Katzka reviewed the major clinical features of eosinophilic esophagitis and, having presented its allergic component, rightly assessed the inherent difficulties of detecting and eliminating food allergens involved in the development and course of this disease.¹ The inadequacies of serologic testing were mentioned, as well as the difficulties of endoscopy and biopsy “painstakingly performed with the removal and reintroduction of every suspected food allergen, requiring multiple biopsies weekly, which is impractical for safety and economic reasons.”¹

In a meta-analysis, Arias et al² showed that such an individualized approach for each food is not really necessary. Elemental diets with graded reintroduction of grouped foods were effective in detecting and treating the responsible food allergies in 90.8% of cases (95% confidence interval [CI] 84.7–95.5). In fact, the more pragmatic, simple, and inexpensive six-food-elimination diet was also reasonably effective (72.1% of cases, 95% CI 65.8–78.1). Both outcomes are far superior to elimination strategies directed at immunoglobulin E (IgE), which were effective in only 45.5% of cases (95% CI 35.4–55.7%).²

Franciosi and Liacouras³ described a practical and comprehensive elimination-reintroduction protocol consisting of four steps that, in combination with symptom diaries, can easily identify responsible foods.

In our practice, graded elimination-reintroduction diets—which, depending on history, may range from the basic six-food-elimination diet to the fully developed Franciosi-Liacouras protocol—along with food IgE testing and judicial use of IgG testing against selected foods, have yielded detection and successful treatment rates comparable to the 90.8% rate reported by Arias et al.² Upon identification of food allergens, a dual approach of diet restrictions and food immunotherapy is initiated. As a result of this approach, patients only need to undergo a single endoscopy and biopsy to demonstrate decreased eosinophil counts, usually 1 year after initiation of allergy treatment.

Of course, pharmacologic management is necessary in the treatment of eosinophilic esophagitis. However, the inclusion of montelukast in the standard first-line regimen for eosinophilic esophagitis is not yet a firmly established practice. Not all eosinophilia can be equated to allergy, and not all allergic inflammation is leukotriene-dependent. Furthermore, too little is known about the secondary effects of leukotrienes on immune regulation and whether their blockade is really desirable in eosinophilic esophagitis. But it is known that leukotriene receptor antagonists, especially montelukast, can trigger Churg-Strauss vasculitis, a syndrome whose eosinophil activation, homing pattern, and subsequent proliferation—as well as its exclusive prevalence in allergic patients with asthma and chronic sinusitis—bear some similarity to those of eosinophilic esophagitis.

To the Editor: In the February 2015 issue of Cleveland Clinic Journal of Medicine, Dr. David A. Katzka reviewed the major clinical features of eosinophilic esophagitis and, having presented its allergic component, rightly assessed the inherent difficulties of detecting and eliminating food allergens involved in the development and course of this disease.¹ The inadequacies of serologic testing were mentioned, as well as the difficulties of endoscopy and biopsy “painstakingly performed with the removal and reintroduction of every suspected food allergen, requiring multiple biopsies weekly, which is impractical for safety and economic reasons.”¹

In a meta-analysis, Arias et al² showed that such an individualized approach for each food is not really necessary. Elemental diets with graded reintroduction of grouped foods were effective in detecting and treating the responsible food allergies in 90.8% of cases (95% confidence interval [CI] 84.7–95.5). In fact, the more pragmatic, simple, and inexpensive six-food-elimination diet was also reasonably effective (72.1% of cases, 95% CI 65.8–78.1). Both outcomes are far superior to elimination strategies directed at immunoglobulin E (IgE), which were effective in only 45.5% of cases (95% CI 35.4–55.7%).²

Franciosi and Liacouras³ described a practical and comprehensive elimination-reintroduction protocol consisting of four steps that, in combination with symptom diaries, can easily identify responsible foods.

In our practice, graded elimination-reintroduction diets—which, depending on history, may range from the basic six-food-elimination diet to the fully developed Franciosi-Liacouras protocol—along with food IgE testing and judicial use of IgG testing against selected foods, have yielded detection and successful treatment rates comparable to the 90.8% rate reported by Arias et al.² Upon identification of food allergens, a dual approach of diet restrictions and food immunotherapy is initiated. As a result of this approach, patients only need to undergo a single endoscopy and biopsy to demonstrate decreased eosinophil counts, usually 1 year after initiation of allergy treatment.

Of course, pharmacologic management is necessary in the treatment of eosinophilic esophagitis. However, the inclusion of montelukast in the standard first-line regimen for eosinophilic esophagitis is not yet a firmly established practice. Not all eosinophilia can be equated to allergy, and not all allergic inflammation is leukotriene-dependent. Furthermore, too little is known about the secondary effects of leukotrienes on immune regulation and whether their blockade is really desirable in eosinophilic esophagitis. But it is known that leukotriene receptor antagonists, especially montelukast, can trigger Churg-Strauss vasculitis, a syndrome whose eosinophil activation, homing pattern, and subsequent proliferation—as well as its exclusive prevalence in allergic patients with asthma and chronic sinusitis—bear some similarity to those of eosinophilic esophagitis.

In Reply: I am most grateful to Drs. Theodoropoulos and Morris for their letter. I fully agree that we are getting smarter with diet elimination therapies by introducing more than one food at a time in the hope that we can lessen the number of endoscopies needed to isolate specific antigenic causes of eosinophilic esophagitis. This is not always successful, but in some of the more fortunate patients, we can get by with one or two endoscopies. It is my hope that with less-invasive tools such as the Cytosponge, the esophageal string test, and perhaps even serum evaluations, we can further embrace diet therapy as a standard treatment in more patients with eosinophilic esophagitis.

I think it is also important to note that although traditional radioallergosorbent and skin testing was only 45% accurate for eosinophilic esophagitis in the meta-analysis cited, this testing is still important, given the number of IgE-related allergies additionally uncovered in patients with eosinophilic esophagitis.

In Reply: I am most grateful to Drs. Theodoropoulos and Morris for their letter. I fully agree that we are getting smarter with diet elimination therapies by introducing more than one food at a time in the hope that we can lessen the number of endoscopies needed to isolate specific antigenic causes of eosinophilic esophagitis. This is not always successful, but in some of the more fortunate patients, we can get by with one or two endoscopies. It is my hope that with less-invasive tools such as the Cytosponge, the esophageal string test, and perhaps even serum evaluations, we can further embrace diet therapy as a standard treatment in more patients with eosinophilic esophagitis.

I think it is also important to note that although traditional radioallergosorbent and skin testing was only 45% accurate for eosinophilic esophagitis in the meta-analysis cited, this testing is still important, given the number of IgE-related allergies additionally uncovered in patients with eosinophilic esophagitis.

In Reply: I am most grateful to Drs. Theodoropoulos and Morris for their letter. I fully agree that we are getting smarter with diet elimination therapies by introducing more than one food at a time in the hope that we can lessen the number of endoscopies needed to isolate specific antigenic causes of eosinophilic esophagitis. This is not always successful, but in some of the more fortunate patients, we can get by with one or two endoscopies. It is my hope that with less-invasive tools such as the Cytosponge, the esophageal string test, and perhaps even serum evaluations, we can further embrace diet therapy as a standard treatment in more patients with eosinophilic esophagitis.

I think it is also important to note that although traditional radioallergosorbent and skin testing was only 45% accurate for eosinophilic esophagitis in the meta-analysis cited, this testing is still important, given the number of IgE-related allergies additionally uncovered in patients with eosinophilic esophagitis.

To the Editor: In his article, Dr. Lehman¹ argued that because the Patient Protection and Affordable Care Act (PPACA) attempts to break the healthcare “iron triangle” by simultaneously improving access and quality while reducing costs, it may paradoxically make the situation worse on all three fronts. However, this line of argument fails to provide a comparison—that is, worse compared to what? While Dr. Lehman does not suggest a comparison, two come to mind that could be implied from his arguments: 1) doing nothing, or 2) targeting reform at only two sides of the triangle.

Prior to the PPACA, the US healthcare system had serious problems with access, quality, and cost.² While it is true that any reform could potentially be worse than doing nothing, none of the three seemed to be getting any better under the status quo. Both candidates for president in 2008 agreed that doing nothing was no longer an option.^3,4 Alternatively, trying to improve two legs of the triangle (say, access and quality) while acknowledging that the third (cost) would suffer would have been just as politically untenable.

The true explanation for how the PPACA could expect to (and may still) improve access and quality while reducing healthcare costs (compared to no reform) is that the PPACA is not a single intervention, as is obvious from the 2,000-plus pages of the law. No single component of the law needs to do all three. For example, expanding Medicaid improves access and quality (especially for those without prior coverage) but undoubtedly raises costs. On the other hand, accountable care organizations should decrease costs by incentivizing providers to be more efficient and reduce waste (and ideally would also improve quality).⁵ Given the low bar set prior to implementation of the PPACA, it was not a stretch to have expected any major reform to improve (not fix) our problems with access, quality, and cost.

To the Editor: In his article, Dr. Lehman¹ argued that because the Patient Protection and Affordable Care Act (PPACA) attempts to break the healthcare “iron triangle” by simultaneously improving access and quality while reducing costs, it may paradoxically make the situation worse on all three fronts. However, this line of argument fails to provide a comparison—that is, worse compared to what? While Dr. Lehman does not suggest a comparison, two come to mind that could be implied from his arguments: 1) doing nothing, or 2) targeting reform at only two sides of the triangle.

Prior to the PPACA, the US healthcare system had serious problems with access, quality, and cost.² While it is true that any reform could potentially be worse than doing nothing, none of the three seemed to be getting any better under the status quo. Both candidates for president in 2008 agreed that doing nothing was no longer an option.^3,4 Alternatively, trying to improve two legs of the triangle (say, access and quality) while acknowledging that the third (cost) would suffer would have been just as politically untenable.

The true explanation for how the PPACA could expect to (and may still) improve access and quality while reducing healthcare costs (compared to no reform) is that the PPACA is not a single intervention, as is obvious from the 2,000-plus pages of the law. No single component of the law needs to do all three. For example, expanding Medicaid improves access and quality (especially for those without prior coverage) but undoubtedly raises costs. On the other hand, accountable care organizations should decrease costs by incentivizing providers to be more efficient and reduce waste (and ideally would also improve quality).⁵ Given the low bar set prior to implementation of the PPACA, it was not a stretch to have expected any major reform to improve (not fix) our problems with access, quality, and cost.

To the Editor: In his article, Dr. Lehman¹ argued that because the Patient Protection and Affordable Care Act (PPACA) attempts to break the healthcare “iron triangle” by simultaneously improving access and quality while reducing costs, it may paradoxically make the situation worse on all three fronts. However, this line of argument fails to provide a comparison—that is, worse compared to what? While Dr. Lehman does not suggest a comparison, two come to mind that could be implied from his arguments: 1) doing nothing, or 2) targeting reform at only two sides of the triangle.

Prior to the PPACA, the US healthcare system had serious problems with access, quality, and cost.² While it is true that any reform could potentially be worse than doing nothing, none of the three seemed to be getting any better under the status quo. Both candidates for president in 2008 agreed that doing nothing was no longer an option.^3,4 Alternatively, trying to improve two legs of the triangle (say, access and quality) while acknowledging that the third (cost) would suffer would have been just as politically untenable.

The true explanation for how the PPACA could expect to (and may still) improve access and quality while reducing healthcare costs (compared to no reform) is that the PPACA is not a single intervention, as is obvious from the 2,000-plus pages of the law. No single component of the law needs to do all three. For example, expanding Medicaid improves access and quality (especially for those without prior coverage) but undoubtedly raises costs. On the other hand, accountable care organizations should decrease costs by incentivizing providers to be more efficient and reduce waste (and ideally would also improve quality).⁵ Given the low bar set prior to implementation of the PPACA, it was not a stretch to have expected any major reform to improve (not fix) our problems with access, quality, and cost.

In Reply: Many of the statements made by Dr. Riggs are indisputable. The conclusions drawn from these insights, however, are questionable.

The Patient Protection and Affordable Care Act (PPACA) was introduced under the premise that a patchwork of policies would improve access and quality of care while decreasing overall health expenditures. Dr. Riggs suggests that, since individual components are targeted toward some of these issues, the net effect of the PPACA is its breaking of the healthcare iron triangle.

Nothing could be further from the truth. This line of reasoning requires that the left hand knows not what the right hand is doing, and that each hand (ie, each component of the PPACA) can ignore the effects of the other, with each proclaiming success in its efforts. It is disingenuous to suggest that the PPACA, on the whole, improves upon the problems of access, quality, and cost if each of the program’s tenets addresses only one or two of the triangle’s vertices.

The PPACA suffers from its own lofty expectations. Rather than being a transformative law that shifts a paradigm, the PPACA is simply an evolution of an existing, broken system, cobbling together components everyone readily agrees are dysfunctional. It expands Medicaid, an insufficiently funded program for the most economically and medically disadvantaged Americans. It subsidizes private health insurance, which, for all its advantages, is likely responsible for the overconsumption of discounted healthcare. And it promotes the unproven concept of accountable care organizations, with no rational expectation that this approach would be superior to preferred provider organizations or health maintenance organizations. It is illogical to expect the sum of many broken parts to yield a superior outcome.

Dr. Riggs notes that trying to improve two legs of the triangle (increased access and improved quality) while acknowledging rising costs is politically untenable. On this point, he is absolutely correct. Discussing the harsh reality that healthcare is a scarce commodity is a political nonstarter. Until Americans demand—and politicians provide—difficult answers to the question of how we will provide healthcare in the 21st century, simultaneously improving delivery of care on all three fronts remains a fantasy. Barring truly transformative change, the iron triangle continues to rule the economics of American healthcare.

In Reply: Many of the statements made by Dr. Riggs are indisputable. The conclusions drawn from these insights, however, are questionable.

The Patient Protection and Affordable Care Act (PPACA) was introduced under the premise that a patchwork of policies would improve access and quality of care while decreasing overall health expenditures. Dr. Riggs suggests that, since individual components are targeted toward some of these issues, the net effect of the PPACA is its breaking of the healthcare iron triangle.

Nothing could be further from the truth. This line of reasoning requires that the left hand knows not what the right hand is doing, and that each hand (ie, each component of the PPACA) can ignore the effects of the other, with each proclaiming success in its efforts. It is disingenuous to suggest that the PPACA, on the whole, improves upon the problems of access, quality, and cost if each of the program’s tenets addresses only one or two of the triangle’s vertices.

The PPACA suffers from its own lofty expectations. Rather than being a transformative law that shifts a paradigm, the PPACA is simply an evolution of an existing, broken system, cobbling together components everyone readily agrees are dysfunctional. It expands Medicaid, an insufficiently funded program for the most economically and medically disadvantaged Americans. It subsidizes private health insurance, which, for all its advantages, is likely responsible for the overconsumption of discounted healthcare. And it promotes the unproven concept of accountable care organizations, with no rational expectation that this approach would be superior to preferred provider organizations or health maintenance organizations. It is illogical to expect the sum of many broken parts to yield a superior outcome.

Dr. Riggs notes that trying to improve two legs of the triangle (increased access and improved quality) while acknowledging rising costs is politically untenable. On this point, he is absolutely correct. Discussing the harsh reality that healthcare is a scarce commodity is a political nonstarter. Until Americans demand—and politicians provide—difficult answers to the question of how we will provide healthcare in the 21st century, simultaneously improving delivery of care on all three fronts remains a fantasy. Barring truly transformative change, the iron triangle continues to rule the economics of American healthcare.

In Reply: Many of the statements made by Dr. Riggs are indisputable. The conclusions drawn from these insights, however, are questionable.

The Patient Protection and Affordable Care Act (PPACA) was introduced under the premise that a patchwork of policies would improve access and quality of care while decreasing overall health expenditures. Dr. Riggs suggests that, since individual components are targeted toward some of these issues, the net effect of the PPACA is its breaking of the healthcare iron triangle.

Nothing could be further from the truth. This line of reasoning requires that the left hand knows not what the right hand is doing, and that each hand (ie, each component of the PPACA) can ignore the effects of the other, with each proclaiming success in its efforts. It is disingenuous to suggest that the PPACA, on the whole, improves upon the problems of access, quality, and cost if each of the program’s tenets addresses only one or two of the triangle’s vertices.

The PPACA suffers from its own lofty expectations. Rather than being a transformative law that shifts a paradigm, the PPACA is simply an evolution of an existing, broken system, cobbling together components everyone readily agrees are dysfunctional. It expands Medicaid, an insufficiently funded program for the most economically and medically disadvantaged Americans. It subsidizes private health insurance, which, for all its advantages, is likely responsible for the overconsumption of discounted healthcare. And it promotes the unproven concept of accountable care organizations, with no rational expectation that this approach would be superior to preferred provider organizations or health maintenance organizations. It is illogical to expect the sum of many broken parts to yield a superior outcome.

Dr. Riggs notes that trying to improve two legs of the triangle (increased access and improved quality) while acknowledging rising costs is politically untenable. On this point, he is absolutely correct. Discussing the harsh reality that healthcare is a scarce commodity is a political nonstarter. Until Americans demand—and politicians provide—difficult answers to the question of how we will provide healthcare in the 21st century, simultaneously improving delivery of care on all three fronts remains a fantasy. Barring truly transformative change, the iron triangle continues to rule the economics of American healthcare.

To the Editor: I read with keen interest the high-quality review of the pathogenesis, diagnosis, and management of alcoholic hepatitis by Dugum et al.¹ They clearly emphasized the high morbidity and mortality rates associated with this condition.

An important consideration for healthcare practitioners is that the presentation of alcoholic hepatitis can mimic an infectious process, eg, presenting with fever and an elevated white blood cell count. Indeed, clinicians should be vigilant and should routinely evaluate for an underlying infection in patients with suspected alcoholic hepatitis, because patients with liver disease are immunocompromised and several problems can potentially coexist in any given patient.

Therefore, clinicians should focus on the clinical history and examination (vital signs, mental status examination, presence of ascites) and should screen for common coinfections such as urinary tract infection and pneumonia with a white blood cell count with differential and other tests. Of particular importance, patients with ascites should undergo diagnostic abdominal paracentesis,² and empiric antimicrobial therapy for spontaneous bacterial peritonitis should be considered on a case-by-case basis.³

To the Editor: I read with keen interest the high-quality review of the pathogenesis, diagnosis, and management of alcoholic hepatitis by Dugum et al.¹ They clearly emphasized the high morbidity and mortality rates associated with this condition.

An important consideration for healthcare practitioners is that the presentation of alcoholic hepatitis can mimic an infectious process, eg, presenting with fever and an elevated white blood cell count. Indeed, clinicians should be vigilant and should routinely evaluate for an underlying infection in patients with suspected alcoholic hepatitis, because patients with liver disease are immunocompromised and several problems can potentially coexist in any given patient.

Therefore, clinicians should focus on the clinical history and examination (vital signs, mental status examination, presence of ascites) and should screen for common coinfections such as urinary tract infection and pneumonia with a white blood cell count with differential and other tests. Of particular importance, patients with ascites should undergo diagnostic abdominal paracentesis,² and empiric antimicrobial therapy for spontaneous bacterial peritonitis should be considered on a case-by-case basis.³

To the Editor: I read with keen interest the high-quality review of the pathogenesis, diagnosis, and management of alcoholic hepatitis by Dugum et al.¹ They clearly emphasized the high morbidity and mortality rates associated with this condition.

An important consideration for healthcare practitioners is that the presentation of alcoholic hepatitis can mimic an infectious process, eg, presenting with fever and an elevated white blood cell count. Indeed, clinicians should be vigilant and should routinely evaluate for an underlying infection in patients with suspected alcoholic hepatitis, because patients with liver disease are immunocompromised and several problems can potentially coexist in any given patient.

Therefore, clinicians should focus on the clinical history and examination (vital signs, mental status examination, presence of ascites) and should screen for common coinfections such as urinary tract infection and pneumonia with a white blood cell count with differential and other tests. Of particular importance, patients with ascites should undergo diagnostic abdominal paracentesis,² and empiric antimicrobial therapy for spontaneous bacterial peritonitis should be considered on a case-by-case basis.³

In Reply: We thank Dr. Mirrakhimov for his interest in our article¹ and for his comments on the importance of infection evaluation and treatment in patients with alcoholic hepatitis. We agree with the points he has raised and emphasized several of them in our article. We highlighted the need to evaluate for infections in these patients, as about a quarter of them are infected at the time of presentation.²

Importantly, patients with alcoholic hepatitis frequently have systemic inflammatory response syndrome criteria, which can be related to the overall inflammatory state of the disease itself or can reflect an active bacterial infection. Therefore, clinical monitoring for symptoms and signs of infection is crucial, and screening for infections is warranted on admission as well as repeatedly during the hospital stay for patients who experience clinical deterioration.³ Obtaining blood and urine cultures and performing paracentesis in patients with ascites to evaluate for bacterial peritonitis are required. Indeed, infections are a leading cause of death in patients with severe alcoholic hepatitis, both directly and indirectly by predisposing to multiorgan failure.⁴

Another factor to consider is the increased susceptibility to infection in these patients treated with corticosteroids. A study by Louvet et al² showed that nonresponse to corticosteroids is the main factor contributing to the development of infection during treatment with corticosteroids, suggesting that infection is likely a consequence of the absence of improvement in liver function. More recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (which evaluated the treatment effect of prednisolone and pentoxifylline in the management of severe alcoholic hepatitis) showed that despite the higher rates of infections in patients treated with prednisolone, the mortality rates attributed to infections were similar across the treatment groups, regardless of whether prednisolone was administered.⁴

Finally, it is important to emphasize that criteria to initiate empiric antibiotics in patients with alcoholic hepatitis are currently lacking, and the decision to start antibiotics empirically in patients without a clear infection is largely based on the clinician’s assessment.

In Reply: We thank Dr. Mirrakhimov for his interest in our article¹ and for his comments on the importance of infection evaluation and treatment in patients with alcoholic hepatitis. We agree with the points he has raised and emphasized several of them in our article. We highlighted the need to evaluate for infections in these patients, as about a quarter of them are infected at the time of presentation.²

Importantly, patients with alcoholic hepatitis frequently have systemic inflammatory response syndrome criteria, which can be related to the overall inflammatory state of the disease itself or can reflect an active bacterial infection. Therefore, clinical monitoring for symptoms and signs of infection is crucial, and screening for infections is warranted on admission as well as repeatedly during the hospital stay for patients who experience clinical deterioration.³ Obtaining blood and urine cultures and performing paracentesis in patients with ascites to evaluate for bacterial peritonitis are required. Indeed, infections are a leading cause of death in patients with severe alcoholic hepatitis, both directly and indirectly by predisposing to multiorgan failure.⁴

Another factor to consider is the increased susceptibility to infection in these patients treated with corticosteroids. A study by Louvet et al² showed that nonresponse to corticosteroids is the main factor contributing to the development of infection during treatment with corticosteroids, suggesting that infection is likely a consequence of the absence of improvement in liver function. More recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (which evaluated the treatment effect of prednisolone and pentoxifylline in the management of severe alcoholic hepatitis) showed that despite the higher rates of infections in patients treated with prednisolone, the mortality rates attributed to infections were similar across the treatment groups, regardless of whether prednisolone was administered.⁴

Finally, it is important to emphasize that criteria to initiate empiric antibiotics in patients with alcoholic hepatitis are currently lacking, and the decision to start antibiotics empirically in patients without a clear infection is largely based on the clinician’s assessment.

In Reply: We thank Dr. Mirrakhimov for his interest in our article¹ and for his comments on the importance of infection evaluation and treatment in patients with alcoholic hepatitis. We agree with the points he has raised and emphasized several of them in our article. We highlighted the need to evaluate for infections in these patients, as about a quarter of them are infected at the time of presentation.²

Importantly, patients with alcoholic hepatitis frequently have systemic inflammatory response syndrome criteria, which can be related to the overall inflammatory state of the disease itself or can reflect an active bacterial infection. Therefore, clinical monitoring for symptoms and signs of infection is crucial, and screening for infections is warranted on admission as well as repeatedly during the hospital stay for patients who experience clinical deterioration.³ Obtaining blood and urine cultures and performing paracentesis in patients with ascites to evaluate for bacterial peritonitis are required. Indeed, infections are a leading cause of death in patients with severe alcoholic hepatitis, both directly and indirectly by predisposing to multiorgan failure.⁴

Another factor to consider is the increased susceptibility to infection in these patients treated with corticosteroids. A study by Louvet et al² showed that nonresponse to corticosteroids is the main factor contributing to the development of infection during treatment with corticosteroids, suggesting that infection is likely a consequence of the absence of improvement in liver function. More recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (which evaluated the treatment effect of prednisolone and pentoxifylline in the management of severe alcoholic hepatitis) showed that despite the higher rates of infections in patients treated with prednisolone, the mortality rates attributed to infections were similar across the treatment groups, regardless of whether prednisolone was administered.⁴

Finally, it is important to emphasize that criteria to initiate empiric antibiotics in patients with alcoholic hepatitis are currently lacking, and the decision to start antibiotics empirically in patients without a clear infection is largely based on the clinician’s assessment.