For the purpose of classifying patients with axial spondyloarthritis with radiographic sacroiliitis, the modified New York (mNY) criteria and the Assessment of Spondyloarthritis international Society (ASAS) criteria should be considered interchangeable, according to a comparative study first presented at the 2019 European League Against Rheumatism and now published.

“The major finding is that patients classified with one set of the criteria are essentially the same as those classified with the other,” according to Anne Boel, a researcher in the department of rheumatology at Leiden (the Netherlands) University Medical Center, and first author of the study.

The study addresses a controversy that has persisted since the introduction of ASAS criteria for defining axial spondyloarthritis (axSpA) with definite structural changes on conventional radiographs. It was unclear whether this ASAS diagnosis, called radiographic axSpA (r-axSpA), was the same as ankylosing spondylitis (AS) as defined by the older modified New York (mNY) criteria.

In this study, patients from eight cohorts were evaluated with the two classification sets. In addition to having radiographic sacroiliitis, all patients had to have back pain for at least 3 months, which is also mandatory for both classification sets.

Of the 3,434 fulfilling the ASAS criteria for r-axSpA, 96% fulfilled the mNY criteria for AS. Of the 3,882 meeting the mNY criteria for AS, 93% fulfilled the ASAS criteria for r-axSpA.

On the basis of this level of agreement, the authors called the terms r-axSpA and AS “interchangeable.” In the small proportion of cases when there was disagreement, the reason was considered to be minor and not to alter the conclusion that the disease entities are the same.

“Patients cannot be classified according to the ASAS criteria if they first develop back pain at age 45 years or older, so this is one difference between the two criteria sets that would affect classification,” Ms. Boel explained in an interview.

When tallied, 7% of the 4,041 patients with axSpA with radiographic sacroiliitis evaluated met only the mNY criteria, 3% met only the ASAS criteria, 89% met both sets of criteria, and 1% met neither, according to the published data.

Of those who met the mNY criteria but not the ASAS criteria, 99.7% would have potentially fulfilled the ASAS criteria for r-axSpA except for older age at onset. The remainder was attributed to an absence of inflammatory back pain or another spondyloarthritis feature.

Of the 3,434 patients fulfilling the ASAS criteria, 90% fulfilled the mNY criteria because of the presence of inflammatory back pain. Most of those without inflammatory back pain had a mobility restriction and so still met the mNY criteria. A small proportion without inflammatory back pain or mobility restriction fulfilled the ASAS criteria because of other SpA features.

The study resolves a persistent debate over whether AS patients identified by mNY criteria are the same as r-axSpA identified by ASAS criteria, according to the authors, reiterating that these data show that they can be considered the same disease.

This finding is particularly relevant when evaluating studies that have classified patients by either the mNY or the ASAS criteria.

This finding “has important implications for the axSpA research field,” the authors concluded. “Acknowledging that both criteria sets identify the same patients implies that older literature on AS and newer literature on r-axSpA can be directly compared.”

The study had no specific funding source. Ms. Boel reported having no potential conflicts of interest. Coauthors reported ties with pharmaceutical companies outside of this study.

SOURCE: Boel A et al. Ann Rheum Dis. 2019 Jul 30. doi: 10.1136/annrheumdis-2019-215707.

For the purpose of classifying patients with axial spondyloarthritis with radiographic sacroiliitis, the modified New York (mNY) criteria and the Assessment of Spondyloarthritis international Society (ASAS) criteria should be considered interchangeable, according to a comparative study first presented at the 2019 European League Against Rheumatism and now published.

“The major finding is that patients classified with one set of the criteria are essentially the same as those classified with the other,” according to Anne Boel, a researcher in the department of rheumatology at Leiden (the Netherlands) University Medical Center, and first author of the study.

The study addresses a controversy that has persisted since the introduction of ASAS criteria for defining axial spondyloarthritis (axSpA) with definite structural changes on conventional radiographs. It was unclear whether this ASAS diagnosis, called radiographic axSpA (r-axSpA), was the same as ankylosing spondylitis (AS) as defined by the older modified New York (mNY) criteria.

In this study, patients from eight cohorts were evaluated with the two classification sets. In addition to having radiographic sacroiliitis, all patients had to have back pain for at least 3 months, which is also mandatory for both classification sets.

Of the 3,434 fulfilling the ASAS criteria for r-axSpA, 96% fulfilled the mNY criteria for AS. Of the 3,882 meeting the mNY criteria for AS, 93% fulfilled the ASAS criteria for r-axSpA.

On the basis of this level of agreement, the authors called the terms r-axSpA and AS “interchangeable.” In the small proportion of cases when there was disagreement, the reason was considered to be minor and not to alter the conclusion that the disease entities are the same.

“Patients cannot be classified according to the ASAS criteria if they first develop back pain at age 45 years or older, so this is one difference between the two criteria sets that would affect classification,” Ms. Boel explained in an interview.

When tallied, 7% of the 4,041 patients with axSpA with radiographic sacroiliitis evaluated met only the mNY criteria, 3% met only the ASAS criteria, 89% met both sets of criteria, and 1% met neither, according to the published data.

Of those who met the mNY criteria but not the ASAS criteria, 99.7% would have potentially fulfilled the ASAS criteria for r-axSpA except for older age at onset. The remainder was attributed to an absence of inflammatory back pain or another spondyloarthritis feature.

Of the 3,434 patients fulfilling the ASAS criteria, 90% fulfilled the mNY criteria because of the presence of inflammatory back pain. Most of those without inflammatory back pain had a mobility restriction and so still met the mNY criteria. A small proportion without inflammatory back pain or mobility restriction fulfilled the ASAS criteria because of other SpA features.

The study resolves a persistent debate over whether AS patients identified by mNY criteria are the same as r-axSpA identified by ASAS criteria, according to the authors, reiterating that these data show that they can be considered the same disease.

This finding is particularly relevant when evaluating studies that have classified patients by either the mNY or the ASAS criteria.

This finding “has important implications for the axSpA research field,” the authors concluded. “Acknowledging that both criteria sets identify the same patients implies that older literature on AS and newer literature on r-axSpA can be directly compared.”

The study had no specific funding source. Ms. Boel reported having no potential conflicts of interest. Coauthors reported ties with pharmaceutical companies outside of this study.

SOURCE: Boel A et al. Ann Rheum Dis. 2019 Jul 30. doi: 10.1136/annrheumdis-2019-215707.

For the purpose of classifying patients with axial spondyloarthritis with radiographic sacroiliitis, the modified New York (mNY) criteria and the Assessment of Spondyloarthritis international Society (ASAS) criteria should be considered interchangeable, according to a comparative study first presented at the 2019 European League Against Rheumatism and now published.

“The major finding is that patients classified with one set of the criteria are essentially the same as those classified with the other,” according to Anne Boel, a researcher in the department of rheumatology at Leiden (the Netherlands) University Medical Center, and first author of the study.

The study addresses a controversy that has persisted since the introduction of ASAS criteria for defining axial spondyloarthritis (axSpA) with definite structural changes on conventional radiographs. It was unclear whether this ASAS diagnosis, called radiographic axSpA (r-axSpA), was the same as ankylosing spondylitis (AS) as defined by the older modified New York (mNY) criteria.

In this study, patients from eight cohorts were evaluated with the two classification sets. In addition to having radiographic sacroiliitis, all patients had to have back pain for at least 3 months, which is also mandatory for both classification sets.

Of the 3,434 fulfilling the ASAS criteria for r-axSpA, 96% fulfilled the mNY criteria for AS. Of the 3,882 meeting the mNY criteria for AS, 93% fulfilled the ASAS criteria for r-axSpA.

On the basis of this level of agreement, the authors called the terms r-axSpA and AS “interchangeable.” In the small proportion of cases when there was disagreement, the reason was considered to be minor and not to alter the conclusion that the disease entities are the same.

“Patients cannot be classified according to the ASAS criteria if they first develop back pain at age 45 years or older, so this is one difference between the two criteria sets that would affect classification,” Ms. Boel explained in an interview.

When tallied, 7% of the 4,041 patients with axSpA with radiographic sacroiliitis evaluated met only the mNY criteria, 3% met only the ASAS criteria, 89% met both sets of criteria, and 1% met neither, according to the published data.

Of those who met the mNY criteria but not the ASAS criteria, 99.7% would have potentially fulfilled the ASAS criteria for r-axSpA except for older age at onset. The remainder was attributed to an absence of inflammatory back pain or another spondyloarthritis feature.

Of the 3,434 patients fulfilling the ASAS criteria, 90% fulfilled the mNY criteria because of the presence of inflammatory back pain. Most of those without inflammatory back pain had a mobility restriction and so still met the mNY criteria. A small proportion without inflammatory back pain or mobility restriction fulfilled the ASAS criteria because of other SpA features.

The study resolves a persistent debate over whether AS patients identified by mNY criteria are the same as r-axSpA identified by ASAS criteria, according to the authors, reiterating that these data show that they can be considered the same disease.

This finding is particularly relevant when evaluating studies that have classified patients by either the mNY or the ASAS criteria.

This finding “has important implications for the axSpA research field,” the authors concluded. “Acknowledging that both criteria sets identify the same patients implies that older literature on AS and newer literature on r-axSpA can be directly compared.”

The study had no specific funding source. Ms. Boel reported having no potential conflicts of interest. Coauthors reported ties with pharmaceutical companies outside of this study.

SOURCE: Boel A et al. Ann Rheum Dis. 2019 Jul 30. doi: 10.1136/annrheumdis-2019-215707.

Historically, aspergillosis in patients with hematopoietic stem cell transplantation (HSCT) has carried a high mortality rate. However, recent data demonstrate a dramatic improvement in outcomes for patients with HSCT: 90-day survival increased from 22% before 2000 to 45% over the past 15 years.¹ Improved outcomes coincide with changes in transplant immunosuppression practices, use of cross-sectional imaging for early disease identification, galactomannan screening, and the development of novel treatment options.

Voriconazole is an azole drug that blocks the synthesis of ergosterol, a vital component of the cellular membrane of fungi. Voriconazole was approved in 2002 after a clinical trial demonstrated an improvement in 50% of patients with invasive aspergillosis in the voriconazole arm vs 30% in the amphotericin B arm at 12 weeks.² Amphotericin B is a polyene antifungal drug that binds with ergosterol, creating leaks in the cell membrane that lead to cellular demise. Voriconazole quickly became the first-line therapy for invasive aspergillosis and is recommended by both the Infectious Disease Society of American (IDSA) and the European Conference on Infections in Leukemia.³

Case Presentation

A 55-year-old man with high-risk chronic myelogenous leukemia (CML) underwent a 10 of 10 human leukocyte antigen allele and antigen-matched peripheral blood allogeneic HSCT with a myeloablative-conditioning regimen of busulfan and cyclophosphamide, along with prophylactic voriconazole, sulfamethoxazole/trimethoprim, and acyclovir. After successful engraftment (without significant neutropenia), his posttransplant course was complicated by grade 2 graft vs host disease (GVHD) of the skin, eyes, and liver, which responded well to steroids and tacrolimus. Voriconazole was continued for 5 months until immunosuppression was minimized (tacrolimus 1 mg twice daily). Two months later, the patient’s GVHD worsened, necessitating treatment at an outside hospital with high-dose prednisone (2 mg/kg/d) and cyclosporine (300 mg twice daily). Voriconazole prophylaxis was not reinitiated at that time.

One year later, at a routine follow-up appointment, the patient endorsed several weeks of malaise, weight loss, and nonproductive cough. The patient’s immunosuppression recently had been reduced to 1 mg/kg/d of prednisone and 100 mg of cyclosporine twice daily. A chest X-ray demonstrated multiple pulmonary nodules; follow-up chest computed tomography (CT) confirmed multiple nodular infiltrates with surrounding ground-glass opacities suspicious with a fungal infection (Figure 1). 

Treatment with oral voriconazole (300 mg twice daily) was initiated for probable pulmonary aspergillosis. Cyclosporine (150 mg twice daily) and prednisone (1 mg/kg/d) were continued throughout treatment out of concern for hepatic GVHD. The patient’s symptoms improved over the next 10 days, and follow-up chest imaging demonstrated improvement.

Two weeks after initiation of voriconazole treatment, the patient developed a new productive cough and dyspnea, associated with fevers and chills. Repeat imaging revealed right lower-lobe pneumonia. The serum voriconazole trough level was checked and was 3.1 mg/L, suggesting therapeutic dosing. The patient subsequently developed acute respiratory distress syndrome and required intubation and mechanical ventilation. Repeat BAL sampling demonstrated multidrug-resistant Escherichia coli, a BAL galactomannan level of 2.0 ODI, and negative fungal cultures. The patient’s hospital course was complicated by profound hypoxemia, requiring prone positioning and neuromuscular blockade. He was treated with meropenem and voriconazole. His immunosuppression was reduced, but he rapidly developed acute liver injury from hepatic GVHD that resolved after reinitiation of cyclosporine and prednisone at 0.75 mg/kg/d.

The patient improved over the next 3 weeks and was successfully extubated. Repeat chest CT imaging demonstrated numerous pneumatoceles in the location of previous nodules, consistent with healing necrotic fungal disease, and a new right lower-lobe cavitary mass (Figure 2). Two days after transferring out of the intensive care unit, the patient again developed hypoxemia and fevers to 39° C. Bronchoscopy with BAL of the right lower lobe revealed positive A fumigatus and Rhizopus sp polymerase chain reaction (PCR) assays, although fungal cultures were positive only for A fumigatus. Liposomal amphotericin B (5 mg/kg) was added to voriconazole therapy to treat mucormycosis and to provide a second active agent against A fumigatus.

Unfortunately, the patient’s clinical status continued to deteriorate with signs of progressive respiratory failure and infection despite empiric, broad-spectrum antibiotics and dual antifungal therapy. His serum voriconazole level continued to be therapeutic at 1.9 mg/L. The patient declined reintubation and invasive mechanical ventilation, and he ultimately transitioned to comfort measures and died with his family at the bedside.

Autopsy demonstrated widely disseminated Aspergillus infection as the cause of death, with evidence of myocardial, neural, and vascular invasion of A fumigatus (Figures 3 and 4). 

Discussion

This case of fatal, progressive, invasive, pulmonary aspergillosis demonstrates several important factors in the treatment of patients with this disease. Treatment failure usually relates to any of 4 possible factors: host immune status, severity or burden of disease, appropriate dosing of antifungal agents, and drug resistance. This patient’s immune system was heavily suppressed for a prolonged period. Attempts at reducing immunosuppression to the minimal required dosage to prevent a GVHD flare were unsuccessful and became an unmodifiable risk factor, a major contributor to his demise.

The risks of continuous high-dose immunosuppression in steroid-refractory GVHD is well understood and has been previously demonstrated to have up to 50% 4-year nonrelapse mortality, mainly due to overwhelming bacterial, viral, and fungal infections.⁴ All attempts should be made to cease or reduce immunosuppression in the setting of a severe infection, although this is sometimes impossible as in this case.

The patient’s disease burden was significant as evidenced by the bilateral, multifocal pulmonary nodules seen on chest imaging and the disseminated disease found at postmortem examination. His initial improvement in symptoms with voriconazole and the evolution of his images (with many of his initial pulmonary nodules becoming pneumatoceles) suggested a temporary positive immune response. The authors believe that the Rhizopus in his sputum represents noninvasive colonization of one of his pneumatoceles, because postmortem examination failed to reveal Rhizopus at any other location.

Voriconazole has excellent pulmonary and central nervous system penetration: In this patient serum levels were well within the therapeutic range. His peculiar drug resistance pattern (sensitivity to azoles and resistance to amphotericin) is unusual. Azole resistance in leukemia and patients with HSCT is more common than is amphotericin resistance, with current estimates of azole resistance close to 5%, ranging between 1% and 30%.^5,6 Widespread use of antifungal prophylaxis with azoles likely selects for azole resistance.⁶

Despite this concern of azole resistance, current IDSA guidelines recommend against routine susceptibility testing of Aspergillus to azole therapy because of the current lack of consensus between the European Committee on Antibiotic Susceptibility Testing and Clinical and Laboratory Standards Institute on break points for resistance patterns.^3,7 This is an area of emerging research, and proposed cut points for declaration of resistance do exist in the literature even if not globally agreed on.⁸

Combination antifungal therapy is an option for treatment in cases of possible drug resistance. Nonetheless, a recent randomized, double-blind, placebo-controlled, multicenter trial comparing voriconazole monotherapy with the combination of voriconazole and anidulafungin failed to demonstrate an overall mortality benefit in the primary analysis, although secondary analysis showed a mortality benefit with combination therapy in patients at highest risk for death.⁹

Despite the lack of unified standards with susceptibility testing, it may be reasonable to perform such tests in patients with demonstrating progressive disease. In this patient’s case, amphotericin B was added to treat the Rhizopus species found in his sputum, and while not the combination studied in the previously mentioned study, the drug should have provided an additional active agent for Aspergillus should this patient have had azole resistance.

Surprisingly, subsequent testing demonstrated the Aspergillus species to be resistant to amphotericin B. De novo amphotericin B-resistant A fumigates is extremely rare, with an expected incidence of 1% or less.¹⁰ The authors believe the patient may have demonstrated induction of amphotericin-B resistance through activation of fungal stress pathways by prior treatment with voriconazole. This has been demonstrated in vitro and should be considered should combination salvage therapy be required for the treatment of a refractory Aspergillus infection especially if patients have received prior treatment with voriconazole.¹¹

Conclusion

This fatal case of invasive pulmonary aspergillosis illustrates the importance of considering the 4 main causes of treatment failure in an infection. Although the patient had a high burden of disease with a rare resistance pattern, he was treated with appropriate and well-dosed therapy. Ultimately, his unmodifiable immunosuppression was likely the driving factor leading to treatment failure and death. The indication for and number of bone marrow transplants continues to increase, thus exposure to and treatment of invasive fungal infections will increase accordingly. As such, providers should ensure that all causes of treatment failure are considered and addressed.

Historically, aspergillosis in patients with hematopoietic stem cell transplantation (HSCT) has carried a high mortality rate. However, recent data demonstrate a dramatic improvement in outcomes for patients with HSCT: 90-day survival increased from 22% before 2000 to 45% over the past 15 years.¹ Improved outcomes coincide with changes in transplant immunosuppression practices, use of cross-sectional imaging for early disease identification, galactomannan screening, and the development of novel treatment options.

Voriconazole is an azole drug that blocks the synthesis of ergosterol, a vital component of the cellular membrane of fungi. Voriconazole was approved in 2002 after a clinical trial demonstrated an improvement in 50% of patients with invasive aspergillosis in the voriconazole arm vs 30% in the amphotericin B arm at 12 weeks.² Amphotericin B is a polyene antifungal drug that binds with ergosterol, creating leaks in the cell membrane that lead to cellular demise. Voriconazole quickly became the first-line therapy for invasive aspergillosis and is recommended by both the Infectious Disease Society of American (IDSA) and the European Conference on Infections in Leukemia.³

Case Presentation

A 55-year-old man with high-risk chronic myelogenous leukemia (CML) underwent a 10 of 10 human leukocyte antigen allele and antigen-matched peripheral blood allogeneic HSCT with a myeloablative-conditioning regimen of busulfan and cyclophosphamide, along with prophylactic voriconazole, sulfamethoxazole/trimethoprim, and acyclovir. After successful engraftment (without significant neutropenia), his posttransplant course was complicated by grade 2 graft vs host disease (GVHD) of the skin, eyes, and liver, which responded well to steroids and tacrolimus. Voriconazole was continued for 5 months until immunosuppression was minimized (tacrolimus 1 mg twice daily). Two months later, the patient’s GVHD worsened, necessitating treatment at an outside hospital with high-dose prednisone (2 mg/kg/d) and cyclosporine (300 mg twice daily). Voriconazole prophylaxis was not reinitiated at that time.

One year later, at a routine follow-up appointment, the patient endorsed several weeks of malaise, weight loss, and nonproductive cough. The patient’s immunosuppression recently had been reduced to 1 mg/kg/d of prednisone and 100 mg of cyclosporine twice daily. A chest X-ray demonstrated multiple pulmonary nodules; follow-up chest computed tomography (CT) confirmed multiple nodular infiltrates with surrounding ground-glass opacities suspicious with a fungal infection (Figure 1). 

Treatment with oral voriconazole (300 mg twice daily) was initiated for probable pulmonary aspergillosis. Cyclosporine (150 mg twice daily) and prednisone (1 mg/kg/d) were continued throughout treatment out of concern for hepatic GVHD. The patient’s symptoms improved over the next 10 days, and follow-up chest imaging demonstrated improvement.

Two weeks after initiation of voriconazole treatment, the patient developed a new productive cough and dyspnea, associated with fevers and chills. Repeat imaging revealed right lower-lobe pneumonia. The serum voriconazole trough level was checked and was 3.1 mg/L, suggesting therapeutic dosing. The patient subsequently developed acute respiratory distress syndrome and required intubation and mechanical ventilation. Repeat BAL sampling demonstrated multidrug-resistant Escherichia coli, a BAL galactomannan level of 2.0 ODI, and negative fungal cultures. The patient’s hospital course was complicated by profound hypoxemia, requiring prone positioning and neuromuscular blockade. He was treated with meropenem and voriconazole. His immunosuppression was reduced, but he rapidly developed acute liver injury from hepatic GVHD that resolved after reinitiation of cyclosporine and prednisone at 0.75 mg/kg/d.

The patient improved over the next 3 weeks and was successfully extubated. Repeat chest CT imaging demonstrated numerous pneumatoceles in the location of previous nodules, consistent with healing necrotic fungal disease, and a new right lower-lobe cavitary mass (Figure 2). Two days after transferring out of the intensive care unit, the patient again developed hypoxemia and fevers to 39° C. Bronchoscopy with BAL of the right lower lobe revealed positive A fumigatus and Rhizopus sp polymerase chain reaction (PCR) assays, although fungal cultures were positive only for A fumigatus. Liposomal amphotericin B (5 mg/kg) was added to voriconazole therapy to treat mucormycosis and to provide a second active agent against A fumigatus.

Unfortunately, the patient’s clinical status continued to deteriorate with signs of progressive respiratory failure and infection despite empiric, broad-spectrum antibiotics and dual antifungal therapy. His serum voriconazole level continued to be therapeutic at 1.9 mg/L. The patient declined reintubation and invasive mechanical ventilation, and he ultimately transitioned to comfort measures and died with his family at the bedside.

Autopsy demonstrated widely disseminated Aspergillus infection as the cause of death, with evidence of myocardial, neural, and vascular invasion of A fumigatus (Figures 3 and 4). 

Discussion

This case of fatal, progressive, invasive, pulmonary aspergillosis demonstrates several important factors in the treatment of patients with this disease. Treatment failure usually relates to any of 4 possible factors: host immune status, severity or burden of disease, appropriate dosing of antifungal agents, and drug resistance. This patient’s immune system was heavily suppressed for a prolonged period. Attempts at reducing immunosuppression to the minimal required dosage to prevent a GVHD flare were unsuccessful and became an unmodifiable risk factor, a major contributor to his demise.

The risks of continuous high-dose immunosuppression in steroid-refractory GVHD is well understood and has been previously demonstrated to have up to 50% 4-year nonrelapse mortality, mainly due to overwhelming bacterial, viral, and fungal infections.⁴ All attempts should be made to cease or reduce immunosuppression in the setting of a severe infection, although this is sometimes impossible as in this case.

The patient’s disease burden was significant as evidenced by the bilateral, multifocal pulmonary nodules seen on chest imaging and the disseminated disease found at postmortem examination. His initial improvement in symptoms with voriconazole and the evolution of his images (with many of his initial pulmonary nodules becoming pneumatoceles) suggested a temporary positive immune response. The authors believe that the Rhizopus in his sputum represents noninvasive colonization of one of his pneumatoceles, because postmortem examination failed to reveal Rhizopus at any other location.

Voriconazole has excellent pulmonary and central nervous system penetration: In this patient serum levels were well within the therapeutic range. His peculiar drug resistance pattern (sensitivity to azoles and resistance to amphotericin) is unusual. Azole resistance in leukemia and patients with HSCT is more common than is amphotericin resistance, with current estimates of azole resistance close to 5%, ranging between 1% and 30%.^5,6 Widespread use of antifungal prophylaxis with azoles likely selects for azole resistance.⁶

Despite this concern of azole resistance, current IDSA guidelines recommend against routine susceptibility testing of Aspergillus to azole therapy because of the current lack of consensus between the European Committee on Antibiotic Susceptibility Testing and Clinical and Laboratory Standards Institute on break points for resistance patterns.^3,7 This is an area of emerging research, and proposed cut points for declaration of resistance do exist in the literature even if not globally agreed on.⁸

Combination antifungal therapy is an option for treatment in cases of possible drug resistance. Nonetheless, a recent randomized, double-blind, placebo-controlled, multicenter trial comparing voriconazole monotherapy with the combination of voriconazole and anidulafungin failed to demonstrate an overall mortality benefit in the primary analysis, although secondary analysis showed a mortality benefit with combination therapy in patients at highest risk for death.⁹

Despite the lack of unified standards with susceptibility testing, it may be reasonable to perform such tests in patients with demonstrating progressive disease. In this patient’s case, amphotericin B was added to treat the Rhizopus species found in his sputum, and while not the combination studied in the previously mentioned study, the drug should have provided an additional active agent for Aspergillus should this patient have had azole resistance.

Surprisingly, subsequent testing demonstrated the Aspergillus species to be resistant to amphotericin B. De novo amphotericin B-resistant A fumigates is extremely rare, with an expected incidence of 1% or less.¹⁰ The authors believe the patient may have demonstrated induction of amphotericin-B resistance through activation of fungal stress pathways by prior treatment with voriconazole. This has been demonstrated in vitro and should be considered should combination salvage therapy be required for the treatment of a refractory Aspergillus infection especially if patients have received prior treatment with voriconazole.¹¹

Conclusion

This fatal case of invasive pulmonary aspergillosis illustrates the importance of considering the 4 main causes of treatment failure in an infection. Although the patient had a high burden of disease with a rare resistance pattern, he was treated with appropriate and well-dosed therapy. Ultimately, his unmodifiable immunosuppression was likely the driving factor leading to treatment failure and death. The indication for and number of bone marrow transplants continues to increase, thus exposure to and treatment of invasive fungal infections will increase accordingly. As such, providers should ensure that all causes of treatment failure are considered and addressed.

Historically, aspergillosis in patients with hematopoietic stem cell transplantation (HSCT) has carried a high mortality rate. However, recent data demonstrate a dramatic improvement in outcomes for patients with HSCT: 90-day survival increased from 22% before 2000 to 45% over the past 15 years.¹ Improved outcomes coincide with changes in transplant immunosuppression practices, use of cross-sectional imaging for early disease identification, galactomannan screening, and the development of novel treatment options.

Voriconazole is an azole drug that blocks the synthesis of ergosterol, a vital component of the cellular membrane of fungi. Voriconazole was approved in 2002 after a clinical trial demonstrated an improvement in 50% of patients with invasive aspergillosis in the voriconazole arm vs 30% in the amphotericin B arm at 12 weeks.² Amphotericin B is a polyene antifungal drug that binds with ergosterol, creating leaks in the cell membrane that lead to cellular demise. Voriconazole quickly became the first-line therapy for invasive aspergillosis and is recommended by both the Infectious Disease Society of American (IDSA) and the European Conference on Infections in Leukemia.³

Case Presentation

A 55-year-old man with high-risk chronic myelogenous leukemia (CML) underwent a 10 of 10 human leukocyte antigen allele and antigen-matched peripheral blood allogeneic HSCT with a myeloablative-conditioning regimen of busulfan and cyclophosphamide, along with prophylactic voriconazole, sulfamethoxazole/trimethoprim, and acyclovir. After successful engraftment (without significant neutropenia), his posttransplant course was complicated by grade 2 graft vs host disease (GVHD) of the skin, eyes, and liver, which responded well to steroids and tacrolimus. Voriconazole was continued for 5 months until immunosuppression was minimized (tacrolimus 1 mg twice daily). Two months later, the patient’s GVHD worsened, necessitating treatment at an outside hospital with high-dose prednisone (2 mg/kg/d) and cyclosporine (300 mg twice daily). Voriconazole prophylaxis was not reinitiated at that time.

One year later, at a routine follow-up appointment, the patient endorsed several weeks of malaise, weight loss, and nonproductive cough. The patient’s immunosuppression recently had been reduced to 1 mg/kg/d of prednisone and 100 mg of cyclosporine twice daily. A chest X-ray demonstrated multiple pulmonary nodules; follow-up chest computed tomography (CT) confirmed multiple nodular infiltrates with surrounding ground-glass opacities suspicious with a fungal infection (Figure 1). 

Treatment with oral voriconazole (300 mg twice daily) was initiated for probable pulmonary aspergillosis. Cyclosporine (150 mg twice daily) and prednisone (1 mg/kg/d) were continued throughout treatment out of concern for hepatic GVHD. The patient’s symptoms improved over the next 10 days, and follow-up chest imaging demonstrated improvement.

Two weeks after initiation of voriconazole treatment, the patient developed a new productive cough and dyspnea, associated with fevers and chills. Repeat imaging revealed right lower-lobe pneumonia. The serum voriconazole trough level was checked and was 3.1 mg/L, suggesting therapeutic dosing. The patient subsequently developed acute respiratory distress syndrome and required intubation and mechanical ventilation. Repeat BAL sampling demonstrated multidrug-resistant Escherichia coli, a BAL galactomannan level of 2.0 ODI, and negative fungal cultures. The patient’s hospital course was complicated by profound hypoxemia, requiring prone positioning and neuromuscular blockade. He was treated with meropenem and voriconazole. His immunosuppression was reduced, but he rapidly developed acute liver injury from hepatic GVHD that resolved after reinitiation of cyclosporine and prednisone at 0.75 mg/kg/d.

The patient improved over the next 3 weeks and was successfully extubated. Repeat chest CT imaging demonstrated numerous pneumatoceles in the location of previous nodules, consistent with healing necrotic fungal disease, and a new right lower-lobe cavitary mass (Figure 2). Two days after transferring out of the intensive care unit, the patient again developed hypoxemia and fevers to 39° C. Bronchoscopy with BAL of the right lower lobe revealed positive A fumigatus and Rhizopus sp polymerase chain reaction (PCR) assays, although fungal cultures were positive only for A fumigatus. Liposomal amphotericin B (5 mg/kg) was added to voriconazole therapy to treat mucormycosis and to provide a second active agent against A fumigatus.

Unfortunately, the patient’s clinical status continued to deteriorate with signs of progressive respiratory failure and infection despite empiric, broad-spectrum antibiotics and dual antifungal therapy. His serum voriconazole level continued to be therapeutic at 1.9 mg/L. The patient declined reintubation and invasive mechanical ventilation, and he ultimately transitioned to comfort measures and died with his family at the bedside.

Autopsy demonstrated widely disseminated Aspergillus infection as the cause of death, with evidence of myocardial, neural, and vascular invasion of A fumigatus (Figures 3 and 4). 

Discussion

This case of fatal, progressive, invasive, pulmonary aspergillosis demonstrates several important factors in the treatment of patients with this disease. Treatment failure usually relates to any of 4 possible factors: host immune status, severity or burden of disease, appropriate dosing of antifungal agents, and drug resistance. This patient’s immune system was heavily suppressed for a prolonged period. Attempts at reducing immunosuppression to the minimal required dosage to prevent a GVHD flare were unsuccessful and became an unmodifiable risk factor, a major contributor to his demise.

The risks of continuous high-dose immunosuppression in steroid-refractory GVHD is well understood and has been previously demonstrated to have up to 50% 4-year nonrelapse mortality, mainly due to overwhelming bacterial, viral, and fungal infections.⁴ All attempts should be made to cease or reduce immunosuppression in the setting of a severe infection, although this is sometimes impossible as in this case.

The patient’s disease burden was significant as evidenced by the bilateral, multifocal pulmonary nodules seen on chest imaging and the disseminated disease found at postmortem examination. His initial improvement in symptoms with voriconazole and the evolution of his images (with many of his initial pulmonary nodules becoming pneumatoceles) suggested a temporary positive immune response. The authors believe that the Rhizopus in his sputum represents noninvasive colonization of one of his pneumatoceles, because postmortem examination failed to reveal Rhizopus at any other location.

Voriconazole has excellent pulmonary and central nervous system penetration: In this patient serum levels were well within the therapeutic range. His peculiar drug resistance pattern (sensitivity to azoles and resistance to amphotericin) is unusual. Azole resistance in leukemia and patients with HSCT is more common than is amphotericin resistance, with current estimates of azole resistance close to 5%, ranging between 1% and 30%.^5,6 Widespread use of antifungal prophylaxis with azoles likely selects for azole resistance.⁶

Despite this concern of azole resistance, current IDSA guidelines recommend against routine susceptibility testing of Aspergillus to azole therapy because of the current lack of consensus between the European Committee on Antibiotic Susceptibility Testing and Clinical and Laboratory Standards Institute on break points for resistance patterns.^3,7 This is an area of emerging research, and proposed cut points for declaration of resistance do exist in the literature even if not globally agreed on.⁸

Combination antifungal therapy is an option for treatment in cases of possible drug resistance. Nonetheless, a recent randomized, double-blind, placebo-controlled, multicenter trial comparing voriconazole monotherapy with the combination of voriconazole and anidulafungin failed to demonstrate an overall mortality benefit in the primary analysis, although secondary analysis showed a mortality benefit with combination therapy in patients at highest risk for death.⁹

Despite the lack of unified standards with susceptibility testing, it may be reasonable to perform such tests in patients with demonstrating progressive disease. In this patient’s case, amphotericin B was added to treat the Rhizopus species found in his sputum, and while not the combination studied in the previously mentioned study, the drug should have provided an additional active agent for Aspergillus should this patient have had azole resistance.

Surprisingly, subsequent testing demonstrated the Aspergillus species to be resistant to amphotericin B. De novo amphotericin B-resistant A fumigates is extremely rare, with an expected incidence of 1% or less.¹⁰ The authors believe the patient may have demonstrated induction of amphotericin-B resistance through activation of fungal stress pathways by prior treatment with voriconazole. This has been demonstrated in vitro and should be considered should combination salvage therapy be required for the treatment of a refractory Aspergillus infection especially if patients have received prior treatment with voriconazole.¹¹

Conclusion

This fatal case of invasive pulmonary aspergillosis illustrates the importance of considering the 4 main causes of treatment failure in an infection. Although the patient had a high burden of disease with a rare resistance pattern, he was treated with appropriate and well-dosed therapy. Ultimately, his unmodifiable immunosuppression was likely the driving factor leading to treatment failure and death. The indication for and number of bone marrow transplants continues to increase, thus exposure to and treatment of invasive fungal infections will increase accordingly. As such, providers should ensure that all causes of treatment failure are considered and addressed.

NEW YORK – More patients are inquiring about the antiaging claims made for nicotinamide products, according to Christine DeWitt MD, of the department of dermatology, Georgetown University, Washington. She encouraged attendees at the American Academy of Dermatology summer meeting to gain familiarity with the underlying mechanisms and potential uses of nicotinamide for aging skin and prevention of skin cancer as well as for a variety of dermatologic disorders, including atopic dermatitis and bullous pemphigoid.

Ted Bosworth/MDedge News

The ability of nicotinamide to increase oxidized nicotinamide adenine dinucleotide (NAD+) is credited for most of its dermatologic benefits, according to Dr. DeWitt. She explained that NAD+ has a central role in cell metabolism, including serving as a substrate for sirtuins, which help prevent deterioration of telomeres, now thought to be a critical event in aging.

Downstream effects include an improved barrier function to reduce transdermal water loss in patients with atopic dermatitis and anti-inflammatory effects that are relevant to acne and bullous pemphigoid.

The related but unique forms of vitamin B3, nicotinamide riboside and nicotinamide mononucleotide, appear to increase more directly and effectively NAD+ with the potential to provide more potent enzymatic antiaging effects, according to Dr. DeWitt. Not all of the more than 90 active and recruiting trials listed for these compounds on clinicaltrials.gov relate to aging, but many do list this or a related condition, such as frailty or sarcopenia, as the therapeutic target.

The trials are being conducted even as OTC nicotinamide riboside and nicotinamide mononucleotide products are being promoted with terms such as “antiaging DNA repair” and “sirtuins activator.” Dr. DeWitt said that favorable reviews of these products on Internet forums are leading many patients to ask her specifically about their clinical value.

“Patients are starting to look at aging and longevity as an entity to manage and to treat,” Dr. DeWitt explained. Increasingly, patients bring up terms like autophagy and ask about the science behind antiaging products.

The clinical role of nicotinamide-related products, whether to reduce events related to aging or provide other benefits, remains unproven.

Nevertheless, Dr. DeWitt often offers nicotinamide to her patients for such indications as acne and atopic dermatitis. In patients with bullous pemphigoid, nicotinamide is an adjunct to other therapies “in most of my patients.”

When recommending nicotinamide, Dr. DeWitt specifies a brand, not because there is evidence that one brand is better than another but because of a reputation of quality control with branded OTC products.

In general, nicotinamide, which is not generally associated with the flushing that accompanies niacin, is well tolerated. She recommends 500 mg twice daily for most indications.

Dr. DeWitt advised reviewing published studies on nicotinamide in order to respond appropriately to patient inquiries. She noted that many patients come to the clinician’s office already aware of the science behind the potential role of NAD+ to inhibit aging and will be seeking an objective point of view.

Dr. DeWitt reports no conflicts of interest.

NEW YORK – More patients are inquiring about the antiaging claims made for nicotinamide products, according to Christine DeWitt MD, of the department of dermatology, Georgetown University, Washington. She encouraged attendees at the American Academy of Dermatology summer meeting to gain familiarity with the underlying mechanisms and potential uses of nicotinamide for aging skin and prevention of skin cancer as well as for a variety of dermatologic disorders, including atopic dermatitis and bullous pemphigoid.

Ted Bosworth/MDedge News

The ability of nicotinamide to increase oxidized nicotinamide adenine dinucleotide (NAD+) is credited for most of its dermatologic benefits, according to Dr. DeWitt. She explained that NAD+ has a central role in cell metabolism, including serving as a substrate for sirtuins, which help prevent deterioration of telomeres, now thought to be a critical event in aging.

Downstream effects include an improved barrier function to reduce transdermal water loss in patients with atopic dermatitis and anti-inflammatory effects that are relevant to acne and bullous pemphigoid.

The related but unique forms of vitamin B3, nicotinamide riboside and nicotinamide mononucleotide, appear to increase more directly and effectively NAD+ with the potential to provide more potent enzymatic antiaging effects, according to Dr. DeWitt. Not all of the more than 90 active and recruiting trials listed for these compounds on clinicaltrials.gov relate to aging, but many do list this or a related condition, such as frailty or sarcopenia, as the therapeutic target.

The trials are being conducted even as OTC nicotinamide riboside and nicotinamide mononucleotide products are being promoted with terms such as “antiaging DNA repair” and “sirtuins activator.” Dr. DeWitt said that favorable reviews of these products on Internet forums are leading many patients to ask her specifically about their clinical value.

“Patients are starting to look at aging and longevity as an entity to manage and to treat,” Dr. DeWitt explained. Increasingly, patients bring up terms like autophagy and ask about the science behind antiaging products.

The clinical role of nicotinamide-related products, whether to reduce events related to aging or provide other benefits, remains unproven.

Nevertheless, Dr. DeWitt often offers nicotinamide to her patients for such indications as acne and atopic dermatitis. In patients with bullous pemphigoid, nicotinamide is an adjunct to other therapies “in most of my patients.”

When recommending nicotinamide, Dr. DeWitt specifies a brand, not because there is evidence that one brand is better than another but because of a reputation of quality control with branded OTC products.

In general, nicotinamide, which is not generally associated with the flushing that accompanies niacin, is well tolerated. She recommends 500 mg twice daily for most indications.

Dr. DeWitt advised reviewing published studies on nicotinamide in order to respond appropriately to patient inquiries. She noted that many patients come to the clinician’s office already aware of the science behind the potential role of NAD+ to inhibit aging and will be seeking an objective point of view.

Dr. DeWitt reports no conflicts of interest.

NEW YORK – More patients are inquiring about the antiaging claims made for nicotinamide products, according to Christine DeWitt MD, of the department of dermatology, Georgetown University, Washington. She encouraged attendees at the American Academy of Dermatology summer meeting to gain familiarity with the underlying mechanisms and potential uses of nicotinamide for aging skin and prevention of skin cancer as well as for a variety of dermatologic disorders, including atopic dermatitis and bullous pemphigoid.

Ted Bosworth/MDedge News

The ability of nicotinamide to increase oxidized nicotinamide adenine dinucleotide (NAD+) is credited for most of its dermatologic benefits, according to Dr. DeWitt. She explained that NAD+ has a central role in cell metabolism, including serving as a substrate for sirtuins, which help prevent deterioration of telomeres, now thought to be a critical event in aging.

Downstream effects include an improved barrier function to reduce transdermal water loss in patients with atopic dermatitis and anti-inflammatory effects that are relevant to acne and bullous pemphigoid.

The related but unique forms of vitamin B3, nicotinamide riboside and nicotinamide mononucleotide, appear to increase more directly and effectively NAD+ with the potential to provide more potent enzymatic antiaging effects, according to Dr. DeWitt. Not all of the more than 90 active and recruiting trials listed for these compounds on clinicaltrials.gov relate to aging, but many do list this or a related condition, such as frailty or sarcopenia, as the therapeutic target.

The trials are being conducted even as OTC nicotinamide riboside and nicotinamide mononucleotide products are being promoted with terms such as “antiaging DNA repair” and “sirtuins activator.” Dr. DeWitt said that favorable reviews of these products on Internet forums are leading many patients to ask her specifically about their clinical value.

“Patients are starting to look at aging and longevity as an entity to manage and to treat,” Dr. DeWitt explained. Increasingly, patients bring up terms like autophagy and ask about the science behind antiaging products.

The clinical role of nicotinamide-related products, whether to reduce events related to aging or provide other benefits, remains unproven.

Nevertheless, Dr. DeWitt often offers nicotinamide to her patients for such indications as acne and atopic dermatitis. In patients with bullous pemphigoid, nicotinamide is an adjunct to other therapies “in most of my patients.”

When recommending nicotinamide, Dr. DeWitt specifies a brand, not because there is evidence that one brand is better than another but because of a reputation of quality control with branded OTC products.

In general, nicotinamide, which is not generally associated with the flushing that accompanies niacin, is well tolerated. She recommends 500 mg twice daily for most indications.

Dr. DeWitt advised reviewing published studies on nicotinamide in order to respond appropriately to patient inquiries. She noted that many patients come to the clinician’s office already aware of the science behind the potential role of NAD+ to inhibit aging and will be seeking an objective point of view.

Dr. DeWitt reports no conflicts of interest.

NEW YORK – In patients receiving first-time botulinum toxin injections for cosmetic enhancements, it is prudent to use a relatively low dose, Gary Goldenberg, MD, advised at the American Academy of Dermatology summer meeting.

Ted Bosworth/MDedge News

Optimal dosing varies by individual, and undertreatment is easier to correct than is excess treatment. “This is a pearl. I always undercorrect, especially if I am injecting a patient for the first time,” said Dr. Goldenberg, an assistant clinical professor of dermatology and pathology at the Icahn School of Medicine at Mount Sinai, New York.

All patients are invited to return 2 weeks after their initial treatments, when the maximum effect is reached. Dr. Goldenberg does not charge for touch-ups administered at that time. “I want the patient to have the best possible experience,” he said.

The demand for botulinum toxin injections is skyrocketing, even among patients in their 20s. Also, men now represent a substantial proportion of those seeking cosmetic botulinum toxin injections.

Botulinum toxin injections are a source of high levels of patient satisfaction, according to Dr. Goldenberg. They are also a good way to get started in performing cosmetic procedures as skills in the injection of botulinum toxin are readily acquired, While some primary care physicians and gynecologists also are offering botulinum toxin injections for cosmetic purposes, dermatologists “are going to do a better job because we know the anatomy the best,” he said.

Dr. Goldenberg said botulinum toxin injections should be offered as a service in promotional efforts for one’s practice, but any mention to patients should be tactful. Patients should be informed that there are solutions for damaged or wrinkled skin, but the topic should be dropped if there is no apparent interest.

“I only suggest. I do not push,” he said. “I never talk about money. If they want to know how much (injections) will cost, they must speak to my office staff.”

With the recent approval of prabotulinumtoxinA (Jeuveau), there are four botulinum toxin injection products available in the United States. These include the original product, onabotulinumtoxinA (Botox), incobotulinumtoxinA (Xeomin), and abobotulinumtoxinA (Dysport). Dr. Goldenberg, who has administered them all, is not so far convinced there are important differences between them in regard to either efficacy or safety.

“There is another product now in clinical trials, so perhaps we will have a fifth product in a year or so,” said Dr. Goldenberg, who noted that the competition has resulted in claims and counterclaims regarding such issues as speed of onset and durability.

For dermatologists new to providing botulinum toxin injections, Dr. Goldenberg suggested restricting initial procedures to the face, particularly glabellar lines for which all of the available products are indicated. The companies that make these products also should offer a broad array of resources for improving skills, he said.

Dr. Goldenberg reports no potential conflicts of interest with companies that make botulinum toxins.

NEW YORK – In patients receiving first-time botulinum toxin injections for cosmetic enhancements, it is prudent to use a relatively low dose, Gary Goldenberg, MD, advised at the American Academy of Dermatology summer meeting.

Ted Bosworth/MDedge News

Optimal dosing varies by individual, and undertreatment is easier to correct than is excess treatment. “This is a pearl. I always undercorrect, especially if I am injecting a patient for the first time,” said Dr. Goldenberg, an assistant clinical professor of dermatology and pathology at the Icahn School of Medicine at Mount Sinai, New York.

All patients are invited to return 2 weeks after their initial treatments, when the maximum effect is reached. Dr. Goldenberg does not charge for touch-ups administered at that time. “I want the patient to have the best possible experience,” he said.

The demand for botulinum toxin injections is skyrocketing, even among patients in their 20s. Also, men now represent a substantial proportion of those seeking cosmetic botulinum toxin injections.

Botulinum toxin injections are a source of high levels of patient satisfaction, according to Dr. Goldenberg. They are also a good way to get started in performing cosmetic procedures as skills in the injection of botulinum toxin are readily acquired, While some primary care physicians and gynecologists also are offering botulinum toxin injections for cosmetic purposes, dermatologists “are going to do a better job because we know the anatomy the best,” he said.

Dr. Goldenberg said botulinum toxin injections should be offered as a service in promotional efforts for one’s practice, but any mention to patients should be tactful. Patients should be informed that there are solutions for damaged or wrinkled skin, but the topic should be dropped if there is no apparent interest.

“I only suggest. I do not push,” he said. “I never talk about money. If they want to know how much (injections) will cost, they must speak to my office staff.”

With the recent approval of prabotulinumtoxinA (Jeuveau), there are four botulinum toxin injection products available in the United States. These include the original product, onabotulinumtoxinA (Botox), incobotulinumtoxinA (Xeomin), and abobotulinumtoxinA (Dysport). Dr. Goldenberg, who has administered them all, is not so far convinced there are important differences between them in regard to either efficacy or safety.

“There is another product now in clinical trials, so perhaps we will have a fifth product in a year or so,” said Dr. Goldenberg, who noted that the competition has resulted in claims and counterclaims regarding such issues as speed of onset and durability.

For dermatologists new to providing botulinum toxin injections, Dr. Goldenberg suggested restricting initial procedures to the face, particularly glabellar lines for which all of the available products are indicated. The companies that make these products also should offer a broad array of resources for improving skills, he said.

Dr. Goldenberg reports no potential conflicts of interest with companies that make botulinum toxins.

NEW YORK – In patients receiving first-time botulinum toxin injections for cosmetic enhancements, it is prudent to use a relatively low dose, Gary Goldenberg, MD, advised at the American Academy of Dermatology summer meeting.

Ted Bosworth/MDedge News

Optimal dosing varies by individual, and undertreatment is easier to correct than is excess treatment. “This is a pearl. I always undercorrect, especially if I am injecting a patient for the first time,” said Dr. Goldenberg, an assistant clinical professor of dermatology and pathology at the Icahn School of Medicine at Mount Sinai, New York.

All patients are invited to return 2 weeks after their initial treatments, when the maximum effect is reached. Dr. Goldenberg does not charge for touch-ups administered at that time. “I want the patient to have the best possible experience,” he said.

The demand for botulinum toxin injections is skyrocketing, even among patients in their 20s. Also, men now represent a substantial proportion of those seeking cosmetic botulinum toxin injections.

Botulinum toxin injections are a source of high levels of patient satisfaction, according to Dr. Goldenberg. They are also a good way to get started in performing cosmetic procedures as skills in the injection of botulinum toxin are readily acquired, While some primary care physicians and gynecologists also are offering botulinum toxin injections for cosmetic purposes, dermatologists “are going to do a better job because we know the anatomy the best,” he said.

Dr. Goldenberg said botulinum toxin injections should be offered as a service in promotional efforts for one’s practice, but any mention to patients should be tactful. Patients should be informed that there are solutions for damaged or wrinkled skin, but the topic should be dropped if there is no apparent interest.

“I only suggest. I do not push,” he said. “I never talk about money. If they want to know how much (injections) will cost, they must speak to my office staff.”

With the recent approval of prabotulinumtoxinA (Jeuveau), there are four botulinum toxin injection products available in the United States. These include the original product, onabotulinumtoxinA (Botox), incobotulinumtoxinA (Xeomin), and abobotulinumtoxinA (Dysport). Dr. Goldenberg, who has administered them all, is not so far convinced there are important differences between them in regard to either efficacy or safety.

“There is another product now in clinical trials, so perhaps we will have a fifth product in a year or so,” said Dr. Goldenberg, who noted that the competition has resulted in claims and counterclaims regarding such issues as speed of onset and durability.

For dermatologists new to providing botulinum toxin injections, Dr. Goldenberg suggested restricting initial procedures to the face, particularly glabellar lines for which all of the available products are indicated. The companies that make these products also should offer a broad array of resources for improving skills, he said.

Dr. Goldenberg reports no potential conflicts of interest with companies that make botulinum toxins.

ORLANDO – Clinicians at the primary care level should learn to distinguish the difference between severe and difficult-to-treat asthma to help facilitate referral to an asthma care specialist, according to a speaker at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.

Jeff Craven/MDedge News

Care providers are seeing patients with severe asthma at their primary care practice, whether they realize it or not, and should therefore learn to recognize and diagnose these patients even if they are not directly treating them for asthma, said Michelle R. Dickens, MSN, RN, FNP-C, AE-C, a nurse practitioner at Ferrell-Duncan Clinic department of allergy, asthma, and immunology in Springfield, Mo., said in her presentation.

“There’s still a lot we can do to get the ball rolling,” Ms. Dickens said. “While you may not be prescribing some of these newer biologics and some of the high-level, $30,000-a-year medications for your asthmatic, you still have a role in this in identifying them and helping us to get to where they need to be.”

Ms. Dickens noted that patients may not even disclose their asthma history with their primary care provider if it is not the reason for the office visit. “Because asthma can be such an episodic disease, it’s not right on the top of their radar,” she said. “They have bigger issues they want to talk about with you, and they forget to mention the asthma part.”

Under Global Initiative for Asthma (GINA) criteria, severe asthma is defined as poorly controlled asthma even after patients demonstrate adherence and good technique. However, before diagnosing a patient with severe asthma, clinicians should first rule out whether the patient has asthma that is difficult to treat, said Ms. Dickens. Difficult-to-treat asthma is characterized by inadequate dosing of medication, noncompliance with medication dose (“spreading out” the medication), poor technique when self-administering the medication, and comorbid conditions. It is also possible that difficult-to-treat asthma is not well controlled because the asthma was misdiagnosed and is actually another condition, she added.

If a patient has difficult-to-treat asthma, ensure they are adhering to the therapy, using proper technique, and that the medicine is being administered at the proper dose. Using Expert Panel Report 3 (EPR-3) and Global Initiative for Asthma (GINA) guidelines, clinicians should maximize the treatment for a patient with severe asthma based on the stepwise approach outlined in the guidelines, and referring out to an asthma specialist for add-on therapy or stepping up therapy when indicated.

Researchers are beginning to explore the genotypes, phenotypes, and endotypes of asthma to learn more about severe asthma and potentially identify asthma subtypes, said Ms. Dickens. “We’re not there yet, but we are learning a little bit about why certain patients have certain types of asthma,” she said.

The Severe Asthma Research Program has found three clusters of likely severe asthma candidates: those with classic childhood asthma onset, those who have asthma with chronic obstructive pulmonary disease (COPD), and patients with both obesity and asthma characterized by “high impairment but mildly abnormal lung function.” Clinicians can use spirometry, complete blood count with differential, total immunoglobulin E, body mass index, allergy testing, and exhaled nitric oxide with these data and biomarkers to gain a better idea of a patient’s asthma situation.

Referrals to an asthma specialist should be considered if a patient experiences a life-threatening exacerbation, is not responding to therapy, has an unusual presentation of asthma symptoms, has comorbid conditions, or needs additional testing or additional education. Patients who are at step 2 or higher in EPR-3 guidelines and ready to move to step 3 and are under 4 years of age, and patients who are 5 years or older at step 4 of therapy or higher should be referred to an asthma specialist. “I think the younger the patient and the more severe the [symptoms], the more likely you should be referring to a specialist,” said Ms. Dickens.

Ms. Dickens reports no relevant financial disclosures. Global Academy for Medical Education and this news organization are owned by the same parent company.

ORLANDO – Clinicians at the primary care level should learn to distinguish the difference between severe and difficult-to-treat asthma to help facilitate referral to an asthma care specialist, according to a speaker at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.

Jeff Craven/MDedge News

Care providers are seeing patients with severe asthma at their primary care practice, whether they realize it or not, and should therefore learn to recognize and diagnose these patients even if they are not directly treating them for asthma, said Michelle R. Dickens, MSN, RN, FNP-C, AE-C, a nurse practitioner at Ferrell-Duncan Clinic department of allergy, asthma, and immunology in Springfield, Mo., said in her presentation.

“There’s still a lot we can do to get the ball rolling,” Ms. Dickens said. “While you may not be prescribing some of these newer biologics and some of the high-level, $30,000-a-year medications for your asthmatic, you still have a role in this in identifying them and helping us to get to where they need to be.”

Ms. Dickens noted that patients may not even disclose their asthma history with their primary care provider if it is not the reason for the office visit. “Because asthma can be such an episodic disease, it’s not right on the top of their radar,” she said. “They have bigger issues they want to talk about with you, and they forget to mention the asthma part.”

Under Global Initiative for Asthma (GINA) criteria, severe asthma is defined as poorly controlled asthma even after patients demonstrate adherence and good technique. However, before diagnosing a patient with severe asthma, clinicians should first rule out whether the patient has asthma that is difficult to treat, said Ms. Dickens. Difficult-to-treat asthma is characterized by inadequate dosing of medication, noncompliance with medication dose (“spreading out” the medication), poor technique when self-administering the medication, and comorbid conditions. It is also possible that difficult-to-treat asthma is not well controlled because the asthma was misdiagnosed and is actually another condition, she added.

If a patient has difficult-to-treat asthma, ensure they are adhering to the therapy, using proper technique, and that the medicine is being administered at the proper dose. Using Expert Panel Report 3 (EPR-3) and Global Initiative for Asthma (GINA) guidelines, clinicians should maximize the treatment for a patient with severe asthma based on the stepwise approach outlined in the guidelines, and referring out to an asthma specialist for add-on therapy or stepping up therapy when indicated.

Researchers are beginning to explore the genotypes, phenotypes, and endotypes of asthma to learn more about severe asthma and potentially identify asthma subtypes, said Ms. Dickens. “We’re not there yet, but we are learning a little bit about why certain patients have certain types of asthma,” she said.

The Severe Asthma Research Program has found three clusters of likely severe asthma candidates: those with classic childhood asthma onset, those who have asthma with chronic obstructive pulmonary disease (COPD), and patients with both obesity and asthma characterized by “high impairment but mildly abnormal lung function.” Clinicians can use spirometry, complete blood count with differential, total immunoglobulin E, body mass index, allergy testing, and exhaled nitric oxide with these data and biomarkers to gain a better idea of a patient’s asthma situation.

Referrals to an asthma specialist should be considered if a patient experiences a life-threatening exacerbation, is not responding to therapy, has an unusual presentation of asthma symptoms, has comorbid conditions, or needs additional testing or additional education. Patients who are at step 2 or higher in EPR-3 guidelines and ready to move to step 3 and are under 4 years of age, and patients who are 5 years or older at step 4 of therapy or higher should be referred to an asthma specialist. “I think the younger the patient and the more severe the [symptoms], the more likely you should be referring to a specialist,” said Ms. Dickens.

Ms. Dickens reports no relevant financial disclosures. Global Academy for Medical Education and this news organization are owned by the same parent company.

ORLANDO – Clinicians at the primary care level should learn to distinguish the difference between severe and difficult-to-treat asthma to help facilitate referral to an asthma care specialist, according to a speaker at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.

Jeff Craven/MDedge News

Care providers are seeing patients with severe asthma at their primary care practice, whether they realize it or not, and should therefore learn to recognize and diagnose these patients even if they are not directly treating them for asthma, said Michelle R. Dickens, MSN, RN, FNP-C, AE-C, a nurse practitioner at Ferrell-Duncan Clinic department of allergy, asthma, and immunology in Springfield, Mo., said in her presentation.

“There’s still a lot we can do to get the ball rolling,” Ms. Dickens said. “While you may not be prescribing some of these newer biologics and some of the high-level, $30,000-a-year medications for your asthmatic, you still have a role in this in identifying them and helping us to get to where they need to be.”

Ms. Dickens noted that patients may not even disclose their asthma history with their primary care provider if it is not the reason for the office visit. “Because asthma can be such an episodic disease, it’s not right on the top of their radar,” she said. “They have bigger issues they want to talk about with you, and they forget to mention the asthma part.”

Under Global Initiative for Asthma (GINA) criteria, severe asthma is defined as poorly controlled asthma even after patients demonstrate adherence and good technique. However, before diagnosing a patient with severe asthma, clinicians should first rule out whether the patient has asthma that is difficult to treat, said Ms. Dickens. Difficult-to-treat asthma is characterized by inadequate dosing of medication, noncompliance with medication dose (“spreading out” the medication), poor technique when self-administering the medication, and comorbid conditions. It is also possible that difficult-to-treat asthma is not well controlled because the asthma was misdiagnosed and is actually another condition, she added.

If a patient has difficult-to-treat asthma, ensure they are adhering to the therapy, using proper technique, and that the medicine is being administered at the proper dose. Using Expert Panel Report 3 (EPR-3) and Global Initiative for Asthma (GINA) guidelines, clinicians should maximize the treatment for a patient with severe asthma based on the stepwise approach outlined in the guidelines, and referring out to an asthma specialist for add-on therapy or stepping up therapy when indicated.

Researchers are beginning to explore the genotypes, phenotypes, and endotypes of asthma to learn more about severe asthma and potentially identify asthma subtypes, said Ms. Dickens. “We’re not there yet, but we are learning a little bit about why certain patients have certain types of asthma,” she said.

The Severe Asthma Research Program has found three clusters of likely severe asthma candidates: those with classic childhood asthma onset, those who have asthma with chronic obstructive pulmonary disease (COPD), and patients with both obesity and asthma characterized by “high impairment but mildly abnormal lung function.” Clinicians can use spirometry, complete blood count with differential, total immunoglobulin E, body mass index, allergy testing, and exhaled nitric oxide with these data and biomarkers to gain a better idea of a patient’s asthma situation.

Referrals to an asthma specialist should be considered if a patient experiences a life-threatening exacerbation, is not responding to therapy, has an unusual presentation of asthma symptoms, has comorbid conditions, or needs additional testing or additional education. Patients who are at step 2 or higher in EPR-3 guidelines and ready to move to step 3 and are under 4 years of age, and patients who are 5 years or older at step 4 of therapy or higher should be referred to an asthma specialist. “I think the younger the patient and the more severe the [symptoms], the more likely you should be referring to a specialist,” said Ms. Dickens.

Ms. Dickens reports no relevant financial disclosures. Global Academy for Medical Education and this news organization are owned by the same parent company.

It goes without saying that as a physician, it’s essential to keep your knowledge and skills current. But too many private practitioners overlook the similar needs of their employees.

Continuing education is as important for your staff as for you. Like you, staff members provide better care to patients when they know the latest findings and techniques. They also provide better information: When patients ask questions of your staff, either in the office or over the phone (which happens more often than you probably think), you certainly want their answers to be accurate and up to date.

But there are lots of other good reasons to invest in ongoing staff training. It’s a win-win strategy for you, your staff, and for your practice.

The more your employees know, the more productive they will be. Not only will they complete everyday duties more efficiently, they will be stimulated to learn new tasks and accept more responsibility.

Staffers who have learned new skills are more willing to take on new challenges. And the better their skills and the greater their confidence, the less supervision they need from you, and the more they become involved in their work.

They will also be happier in their jobs. Investing in your employees’ competence makes them feel valued and appreciated. This leads to reduced turnover – which, alone, often pays for the training.

You probably already do some ongoing education: You do your yearly OSHA training because the law requires it, you run HIPAA updates as necessary, and you have everyone recertified periodically in basic or advanced CPR (I hope). But I’m talking about going beyond the basic stuff, which may satisfy legal requirements, but does not motivate your people to loftier goals.

An obvious example is sending your insurance people annually to coding and insurance processing courses – or at the very least, online refreshers – so they are always current on the latest third-party changes. The use of outdated or obsolete codes can cost you thousands of dollars every month. Other opportunities include keyboarding and computer courses for staff who work with your computers, and Excel and QuickBooks updates for your bookkeepers.

Continuing education does not have to be costly, and in some cases it can be free. For example, pharmaceutical representatives will be happy to run an in-service for your staff on a new medication or procedure or instrument, or refresh their memories on an established one. Be sure to make clear to the rep that the presentation must be as objective and impartial as possible, given the obvious potential conflict of interest involved.

Your office manager should join the Association of Dermatology Administrators and Managers. It holds annual meetings at the same time and in the same city as the American Academy of Dermatology winter meetings, with a good selection of refresher courses and lots of opportunities for networking with other managers, both personally or virtually.

Many other venues are available for employee education, in the cloud and in conventional classrooms. Courses are offered in many relevant subjects; a quick Google search turns up an eclectic mix, including medical terminology, record keeping and accounting, laboratory skills, diagnostic tests and procedures, pharmacology and medication administration, patient relations, medical law and ethics, and many others.

By far the most common question I receive on this issue is, “What if I pay for all that training, and then the employees leave?”

My reply: “What if you don’t, and they stay?”

Well-trained employees are vastly preferable to untrained ones. I suppose there is some risk of an occasional staffer accepting training and then moving on; but in 38 years, it has never happened in my office. In my experience, well-trained employees will stay. Education fosters loyalty. Employees who know you care enough about them to advance their skills will sense that they have a stake in the practice, and thus will be less likely to want to leave. Furthermore, continuing education will always be cheaper than training new employees from scratch.

In any case, everyone will benefit from a well-trained staff – you, your employees, your practice, and most importantly your patients.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

It goes without saying that as a physician, it’s essential to keep your knowledge and skills current. But too many private practitioners overlook the similar needs of their employees.

Continuing education is as important for your staff as for you. Like you, staff members provide better care to patients when they know the latest findings and techniques. They also provide better information: When patients ask questions of your staff, either in the office or over the phone (which happens more often than you probably think), you certainly want their answers to be accurate and up to date.

But there are lots of other good reasons to invest in ongoing staff training. It’s a win-win strategy for you, your staff, and for your practice.

The more your employees know, the more productive they will be. Not only will they complete everyday duties more efficiently, they will be stimulated to learn new tasks and accept more responsibility.

Staffers who have learned new skills are more willing to take on new challenges. And the better their skills and the greater their confidence, the less supervision they need from you, and the more they become involved in their work.

They will also be happier in their jobs. Investing in your employees’ competence makes them feel valued and appreciated. This leads to reduced turnover – which, alone, often pays for the training.

You probably already do some ongoing education: You do your yearly OSHA training because the law requires it, you run HIPAA updates as necessary, and you have everyone recertified periodically in basic or advanced CPR (I hope). But I’m talking about going beyond the basic stuff, which may satisfy legal requirements, but does not motivate your people to loftier goals.

An obvious example is sending your insurance people annually to coding and insurance processing courses – or at the very least, online refreshers – so they are always current on the latest third-party changes. The use of outdated or obsolete codes can cost you thousands of dollars every month. Other opportunities include keyboarding and computer courses for staff who work with your computers, and Excel and QuickBooks updates for your bookkeepers.

Continuing education does not have to be costly, and in some cases it can be free. For example, pharmaceutical representatives will be happy to run an in-service for your staff on a new medication or procedure or instrument, or refresh their memories on an established one. Be sure to make clear to the rep that the presentation must be as objective and impartial as possible, given the obvious potential conflict of interest involved.

Your office manager should join the Association of Dermatology Administrators and Managers. It holds annual meetings at the same time and in the same city as the American Academy of Dermatology winter meetings, with a good selection of refresher courses and lots of opportunities for networking with other managers, both personally or virtually.

Many other venues are available for employee education, in the cloud and in conventional classrooms. Courses are offered in many relevant subjects; a quick Google search turns up an eclectic mix, including medical terminology, record keeping and accounting, laboratory skills, diagnostic tests and procedures, pharmacology and medication administration, patient relations, medical law and ethics, and many others.

By far the most common question I receive on this issue is, “What if I pay for all that training, and then the employees leave?”

My reply: “What if you don’t, and they stay?”

Well-trained employees are vastly preferable to untrained ones. I suppose there is some risk of an occasional staffer accepting training and then moving on; but in 38 years, it has never happened in my office. In my experience, well-trained employees will stay. Education fosters loyalty. Employees who know you care enough about them to advance their skills will sense that they have a stake in the practice, and thus will be less likely to want to leave. Furthermore, continuing education will always be cheaper than training new employees from scratch.

In any case, everyone will benefit from a well-trained staff – you, your employees, your practice, and most importantly your patients.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

It goes without saying that as a physician, it’s essential to keep your knowledge and skills current. But too many private practitioners overlook the similar needs of their employees.

Continuing education is as important for your staff as for you. Like you, staff members provide better care to patients when they know the latest findings and techniques. They also provide better information: When patients ask questions of your staff, either in the office or over the phone (which happens more often than you probably think), you certainly want their answers to be accurate and up to date.

But there are lots of other good reasons to invest in ongoing staff training. It’s a win-win strategy for you, your staff, and for your practice.

The more your employees know, the more productive they will be. Not only will they complete everyday duties more efficiently, they will be stimulated to learn new tasks and accept more responsibility.

Staffers who have learned new skills are more willing to take on new challenges. And the better their skills and the greater their confidence, the less supervision they need from you, and the more they become involved in their work.

They will also be happier in their jobs. Investing in your employees’ competence makes them feel valued and appreciated. This leads to reduced turnover – which, alone, often pays for the training.

You probably already do some ongoing education: You do your yearly OSHA training because the law requires it, you run HIPAA updates as necessary, and you have everyone recertified periodically in basic or advanced CPR (I hope). But I’m talking about going beyond the basic stuff, which may satisfy legal requirements, but does not motivate your people to loftier goals.

An obvious example is sending your insurance people annually to coding and insurance processing courses – or at the very least, online refreshers – so they are always current on the latest third-party changes. The use of outdated or obsolete codes can cost you thousands of dollars every month. Other opportunities include keyboarding and computer courses for staff who work with your computers, and Excel and QuickBooks updates for your bookkeepers.

Continuing education does not have to be costly, and in some cases it can be free. For example, pharmaceutical representatives will be happy to run an in-service for your staff on a new medication or procedure or instrument, or refresh their memories on an established one. Be sure to make clear to the rep that the presentation must be as objective and impartial as possible, given the obvious potential conflict of interest involved.

Your office manager should join the Association of Dermatology Administrators and Managers. It holds annual meetings at the same time and in the same city as the American Academy of Dermatology winter meetings, with a good selection of refresher courses and lots of opportunities for networking with other managers, both personally or virtually.

Many other venues are available for employee education, in the cloud and in conventional classrooms. Courses are offered in many relevant subjects; a quick Google search turns up an eclectic mix, including medical terminology, record keeping and accounting, laboratory skills, diagnostic tests and procedures, pharmacology and medication administration, patient relations, medical law and ethics, and many others.

By far the most common question I receive on this issue is, “What if I pay for all that training, and then the employees leave?”

My reply: “What if you don’t, and they stay?”

Well-trained employees are vastly preferable to untrained ones. I suppose there is some risk of an occasional staffer accepting training and then moving on; but in 38 years, it has never happened in my office. In my experience, well-trained employees will stay. Education fosters loyalty. Employees who know you care enough about them to advance their skills will sense that they have a stake in the practice, and thus will be less likely to want to leave. Furthermore, continuing education will always be cheaper than training new employees from scratch.

In any case, everyone will benefit from a well-trained staff – you, your employees, your practice, and most importantly your patients.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Cardiac biomarkers were used to predict the likelihood of cardiovascular events at day 1 and day 30 in patients with community-acquired pneumonia, in a recently conducted study.

Thomas Northcut/Thinkstock

These biomarkers were also used to predict late cardiovascular events at day 30 of community-acquired pneumonia (CAP) in patients who did not have a history of cardiovascular disease, according to Rosario Menéndez, MD, from the Hospital Universitario y Politécnico La Fe and Instituto de Investigación Sanitaria La Fe in Valencia, Spain, and colleagues.

“Some patients have still high levels of inflammatory and cardiac biomarkers at 30 days, when they are usually referred to primary care without receiving any specific additional recommendations,” Dr. Menéndez and colleagues wrote in CHEST. “Our results suggest that a change in usual practice is needed to reduce current and further cardiovascular CAP complications.”

Dr. Menéndez and colleagues prospectively followed 730 patients for 1 year who were hospitalized for CAP, measuring the cardiac biomarkers proadrenomedullin (proADM), pro b-type natriuretic peptide (proBNP), proendothelin-1, and troponin T, and the inflammatory biomarkers interleukin 6 (IL-6), C-reactive protein (CRP), and procalcitonin (PCT). The researchers also collected data on age, gender, smoking status, and vaccination history, as well as whether patients had any cardiac, renal, pulmonary, neurological or diabetes-related comorbidities.

Overall, 95 patients experienced early cardiovascular events, 67 patients had long-term cardiovascular events, and 20 patients experienced both early and late events. In hospital, the mortality rate was 4.7%; the 30-day mortality rate was 5.3%, and the 1-year mortality rate was 9.9%.

With regard to biomarkers, patients who experienced both early and late cardiovascular events had significantly higher initial levels of proADM, proendothelin-1, troponin, proBNP, and IL-6. Patients who experienced later events had consistent levels of these biomarkers until day 30, except for a decrease at day 4 or day 5.

After adjustment for age, sepsis, previous cardiac disease, and a partial pressure of oxygen in the alveoli to fractional inspired oxygen ratio (PaO₂/FiO₂) of less than 250mm Hg, cardiac biomarkers proendothelin-1 (odds ratio, 2.25; 95% confidence interval, 1.34-3.79), proADM (OR, 2.53; 95% CI, 1.53-4.20), proBNP (OR, 2.67; 95% CI, 1.59-4.49), and troponin T (OR, 2.70; 95% CI, 1.62-4.49) significantly predicted early cardiovascular events, while proendothelin-1 (OR, 3.13; 95% CI, 1.41-7.80), proADM (2.29; 95% CI, 1.01-5.19) and proBNP (OR, 2.34; 95% CI, 1.01-5.56) significantly predicted late cardiovascular events. For day 30 results, when researchers added IL-6 levels to proendothelin-1, the odds ratio for late events increased to 3.53, and when they added IL-6 levels to proADM, the odds ratio increased to 2.80.

Researchers noted the limitations of the study included that they did not analyze cardiac biomarkers to predict specific cardiovascular events, did not identify the cause for mortality at 1 year in most patients, and did not include a control group.

This study was supported in part by funding from Instituto de Salud Carlos III, Sociedad Española de Neumología y Cirugía Torácica, and the Center for Biomedical Research Network in Respiratory Diseases. The authors reported no relevant conflicts of interest.
 

SOURCE: Menéndez R et al. Chest. 2019 Aug 2. doi: 10.1016/j.chest.2019.06.040.

Cardiac biomarkers were used to predict the likelihood of cardiovascular events at day 1 and day 30 in patients with community-acquired pneumonia, in a recently conducted study.

Thomas Northcut/Thinkstock

These biomarkers were also used to predict late cardiovascular events at day 30 of community-acquired pneumonia (CAP) in patients who did not have a history of cardiovascular disease, according to Rosario Menéndez, MD, from the Hospital Universitario y Politécnico La Fe and Instituto de Investigación Sanitaria La Fe in Valencia, Spain, and colleagues.

“Some patients have still high levels of inflammatory and cardiac biomarkers at 30 days, when they are usually referred to primary care without receiving any specific additional recommendations,” Dr. Menéndez and colleagues wrote in CHEST. “Our results suggest that a change in usual practice is needed to reduce current and further cardiovascular CAP complications.”

Dr. Menéndez and colleagues prospectively followed 730 patients for 1 year who were hospitalized for CAP, measuring the cardiac biomarkers proadrenomedullin (proADM), pro b-type natriuretic peptide (proBNP), proendothelin-1, and troponin T, and the inflammatory biomarkers interleukin 6 (IL-6), C-reactive protein (CRP), and procalcitonin (PCT). The researchers also collected data on age, gender, smoking status, and vaccination history, as well as whether patients had any cardiac, renal, pulmonary, neurological or diabetes-related comorbidities.

Overall, 95 patients experienced early cardiovascular events, 67 patients had long-term cardiovascular events, and 20 patients experienced both early and late events. In hospital, the mortality rate was 4.7%; the 30-day mortality rate was 5.3%, and the 1-year mortality rate was 9.9%.

With regard to biomarkers, patients who experienced both early and late cardiovascular events had significantly higher initial levels of proADM, proendothelin-1, troponin, proBNP, and IL-6. Patients who experienced later events had consistent levels of these biomarkers until day 30, except for a decrease at day 4 or day 5.

After adjustment for age, sepsis, previous cardiac disease, and a partial pressure of oxygen in the alveoli to fractional inspired oxygen ratio (PaO₂/FiO₂) of less than 250mm Hg, cardiac biomarkers proendothelin-1 (odds ratio, 2.25; 95% confidence interval, 1.34-3.79), proADM (OR, 2.53; 95% CI, 1.53-4.20), proBNP (OR, 2.67; 95% CI, 1.59-4.49), and troponin T (OR, 2.70; 95% CI, 1.62-4.49) significantly predicted early cardiovascular events, while proendothelin-1 (OR, 3.13; 95% CI, 1.41-7.80), proADM (2.29; 95% CI, 1.01-5.19) and proBNP (OR, 2.34; 95% CI, 1.01-5.56) significantly predicted late cardiovascular events. For day 30 results, when researchers added IL-6 levels to proendothelin-1, the odds ratio for late events increased to 3.53, and when they added IL-6 levels to proADM, the odds ratio increased to 2.80.

Researchers noted the limitations of the study included that they did not analyze cardiac biomarkers to predict specific cardiovascular events, did not identify the cause for mortality at 1 year in most patients, and did not include a control group.

This study was supported in part by funding from Instituto de Salud Carlos III, Sociedad Española de Neumología y Cirugía Torácica, and the Center for Biomedical Research Network in Respiratory Diseases. The authors reported no relevant conflicts of interest.
 

SOURCE: Menéndez R et al. Chest. 2019 Aug 2. doi: 10.1016/j.chest.2019.06.040.

Cardiac biomarkers were used to predict the likelihood of cardiovascular events at day 1 and day 30 in patients with community-acquired pneumonia, in a recently conducted study.

Thomas Northcut/Thinkstock

These biomarkers were also used to predict late cardiovascular events at day 30 of community-acquired pneumonia (CAP) in patients who did not have a history of cardiovascular disease, according to Rosario Menéndez, MD, from the Hospital Universitario y Politécnico La Fe and Instituto de Investigación Sanitaria La Fe in Valencia, Spain, and colleagues.

“Some patients have still high levels of inflammatory and cardiac biomarkers at 30 days, when they are usually referred to primary care without receiving any specific additional recommendations,” Dr. Menéndez and colleagues wrote in CHEST. “Our results suggest that a change in usual practice is needed to reduce current and further cardiovascular CAP complications.”

Dr. Menéndez and colleagues prospectively followed 730 patients for 1 year who were hospitalized for CAP, measuring the cardiac biomarkers proadrenomedullin (proADM), pro b-type natriuretic peptide (proBNP), proendothelin-1, and troponin T, and the inflammatory biomarkers interleukin 6 (IL-6), C-reactive protein (CRP), and procalcitonin (PCT). The researchers also collected data on age, gender, smoking status, and vaccination history, as well as whether patients had any cardiac, renal, pulmonary, neurological or diabetes-related comorbidities.

Overall, 95 patients experienced early cardiovascular events, 67 patients had long-term cardiovascular events, and 20 patients experienced both early and late events. In hospital, the mortality rate was 4.7%; the 30-day mortality rate was 5.3%, and the 1-year mortality rate was 9.9%.

With regard to biomarkers, patients who experienced both early and late cardiovascular events had significantly higher initial levels of proADM, proendothelin-1, troponin, proBNP, and IL-6. Patients who experienced later events had consistent levels of these biomarkers until day 30, except for a decrease at day 4 or day 5.

After adjustment for age, sepsis, previous cardiac disease, and a partial pressure of oxygen in the alveoli to fractional inspired oxygen ratio (PaO₂/FiO₂) of less than 250mm Hg, cardiac biomarkers proendothelin-1 (odds ratio, 2.25; 95% confidence interval, 1.34-3.79), proADM (OR, 2.53; 95% CI, 1.53-4.20), proBNP (OR, 2.67; 95% CI, 1.59-4.49), and troponin T (OR, 2.70; 95% CI, 1.62-4.49) significantly predicted early cardiovascular events, while proendothelin-1 (OR, 3.13; 95% CI, 1.41-7.80), proADM (2.29; 95% CI, 1.01-5.19) and proBNP (OR, 2.34; 95% CI, 1.01-5.56) significantly predicted late cardiovascular events. For day 30 results, when researchers added IL-6 levels to proendothelin-1, the odds ratio for late events increased to 3.53, and when they added IL-6 levels to proADM, the odds ratio increased to 2.80.

Researchers noted the limitations of the study included that they did not analyze cardiac biomarkers to predict specific cardiovascular events, did not identify the cause for mortality at 1 year in most patients, and did not include a control group.

This study was supported in part by funding from Instituto de Salud Carlos III, Sociedad Española de Neumología y Cirugía Torácica, and the Center for Biomedical Research Network in Respiratory Diseases. The authors reported no relevant conflicts of interest.
 

SOURCE: Menéndez R et al. Chest. 2019 Aug 2. doi: 10.1016/j.chest.2019.06.040.

Philadelphia – At 1.5 hours after dosing, lasmiditan is associated with impaired simulated driving, according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.

Eli Lilly

Lasmiditan, a 5-HT_1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
 

Two studies in healthy participants

Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.

In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.

During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
 

Participants reported that they could drive safely

In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.

Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.

Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.

Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
 

Questions for further study

Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.

Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.

[email protected]

SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.

Philadelphia – At 1.5 hours after dosing, lasmiditan is associated with impaired simulated driving, according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.

Eli Lilly

Lasmiditan, a 5-HT_1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
 

Two studies in healthy participants

Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.

In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.

During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
 

Participants reported that they could drive safely

In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.

Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.

Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.

Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
 

Questions for further study

Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.

Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.

[email protected]

SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.

Philadelphia – At 1.5 hours after dosing, lasmiditan is associated with impaired simulated driving, according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.

Eli Lilly

Lasmiditan, a 5-HT_1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
 

Two studies in healthy participants

Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.

In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.

During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
 

Participants reported that they could drive safely

In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.

Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.

Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.

Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
 

Questions for further study

Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.

Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.

[email protected]

SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.

Physicians are praising the decision by officials at the Centers for Medicare & Medicaid Services to provide coverage of chimeric antigen receptor T-cell therapy, though they say the planned payment structure will still leave hospitals in the red when treatment is administered.

On Aug. 7, 2019, the agency issued a national coverage determination that outlines Medicare coverage of chimeric antigen receptor (CAR) T-cell therapies when they are provided in health care facilities enrolled in the Food and Drug Administration’s Risk Evaluation and Mitigation Strategies program. Medicare will cover treatments for both FDA-approved indications and off-label uses that are recommended in CMS-approved compendia.

“What you’ve seen in both the [Medicare Inpatient Prospective Payment System] rule, as well as this coverage determination, is recognition by CMS that, with CAR T cells, we are dealing with something different and something extraordinary,” Joseph Alvarnas, MD, vice president of government affairs at City of Hope, Duarte, Calif., said in an interview. “For a lot of patients who suffer with non-Hodgkin’s lymphoma, the consequences of being refractory to standard therapies mean that many patients have few great prospects for moving forward with curative treatments. CAR T cells represent a really innovative set of treatments for patients.”

A proposed national coverage determination, issued in February 2019, would have put in place a coverage with evidence development (CED) requirement for CAR T-cell therapy, covering treatment nationwide if it was offered through CMS-approved registries or clinical studies in which patients were monitored for 2 or more years following treatment.

Physicians applauded the decision not to restrict access by imposing the CED requirement.

Courtesy Russell Lee

“I think what CMS has put out is a good thing,” said Navneet Majhail, MD, director of the Cleveland Clinic’s blood and marrow transplant program, and president of the American Society for Transplantation and Cellular Therapy.

“Both at the Cleveland Clinic level and the society level, we have been asking CMS for something similar and we are really glad and excited that CMS did do this. The concern was that CMS might do this in the context of some other regulatory requirements like CED that they sometimes do. I am glad that CMS decided not to put that mechanism into place for the CAR T-cell therapies,” Dr. Majhail said.

Dr. Alvarnas, who also serves as chair of the American Society of Hematology Committee on Practice, agreed. “I see good. I don’t see bad. I have read through this and it strikes me as being written with fairly great clarity.”

Dr. Alvarnas added that he had been worried about potential restrictions, such as CED. “Once you put something under that whole rubric of coverage with evidence development, then what you do is you create a bottleneck around access to therapy because you have to have an accruing clinical trial for patients to, in fact, be able to participate in that form of therapy.”

By not imposing a CED requirement, it opens the door to better understanding the role CAR T cells play in treatment, Dr. Alvarnas noted.

“Over time, the number of patients for whom these therapeutics work, based upon real medical evidence, will escalate and grow at a pace that can far exceed the restrictions placed under a CED model,” he said, adding that the national coverage determination “gives us the license to deliver therapeutics to the right patients based upon medical evidence as it evolves, provided that these things get listed as part of the compendia. I think that is a fantastic recognition that new roles for drugs, agents, therapeutics ... are going to evolve at a pace far faster than what CMS can write rules about.”

While Medicare’s coverage determination garnered positive reviews, the agency’s Inpatient Prospective Payment System final rule – which outlines reimbursement for CAR T-cell therapy and other new technologies – got a more tepid response.

In the final rule, CMS raised the payment it makes to hospitals for administering CAR T-cell therapies through its new technology add-on payment. Payments will rise from 50% of the technology to 65%, an increase from $186,500 to $242,450 for CAR T-cell therapies, beginning on Oct. 1, 2019.

But even the bump up to 65% may not be enough.

“I see the move to 65% as a new technology add-on payment as an incremental step in the correct direction, but what we’ve done to some extent is that we’ve delayed getting to some sort of more wholly conceived system,” Dr. Alvarnas said, noting that a new system will be needed as the new technology add-on payment goes away in 2021.

Abhinav Deol, MD, of the Karmanos Cancer Institute in Detroit said it’s a challenge to cover costs for the treatment. “If you just look at the simple math, it is still going to be an economic challenge. The cells that are approved for lymphoma patients that will probably fall into the Medicare category, the list price of those cells is $373,000. Even with the 65% coverage, it’s about $235,000-$240,000 in reimbursement,” he said. “For a facility to be able to provide the care for patients, you have that delta that is still not covered. It is still going to be an economic challenge for many of the facilities to provide this care.”

Thomas LeBlanc, MD, an associate professor of medicine at Duke University, Durham, N.C., said that, while the coverage determination is a positive step, it’s not clear that it will provide meaningful access to CAR T-cell therapy because of the cost.

“These products are incredibly expensive, and the total cost of providing them is woefully underestimated in only focusing on the sticker price of the product,” he said. “Doing so ignores the significant hospital care, sometimes even critical care, as well as specialized knowledge and high touch supportive care, all of which is required to safely get patients through this revolutionary yet often risky treatment. So when CMS offers to pay just 65% of the sticker price, I suspect that many institutions will still lose six figures for each patient treated.”

Dr. LeBlanc predicted that many centers will decline to provide CAR T-cell therapy despite the increase in the new technology add-on payment, though he added that “I’d love to be wrong about this.”

Dr. Majhail agreed, noting that, even with the bump in the add-on payment, hospitals “won’t be whole in terms of providing care for these patients.”

“The reimbursement piece continues to be a challenge,” he said. “It is better than what it was, but there is still more work to be done. That is something we will have to keep working with the agency on.”

[email protected]

Physicians are praising the decision by officials at the Centers for Medicare & Medicaid Services to provide coverage of chimeric antigen receptor T-cell therapy, though they say the planned payment structure will still leave hospitals in the red when treatment is administered.

On Aug. 7, 2019, the agency issued a national coverage determination that outlines Medicare coverage of chimeric antigen receptor (CAR) T-cell therapies when they are provided in health care facilities enrolled in the Food and Drug Administration’s Risk Evaluation and Mitigation Strategies program. Medicare will cover treatments for both FDA-approved indications and off-label uses that are recommended in CMS-approved compendia.

“What you’ve seen in both the [Medicare Inpatient Prospective Payment System] rule, as well as this coverage determination, is recognition by CMS that, with CAR T cells, we are dealing with something different and something extraordinary,” Joseph Alvarnas, MD, vice president of government affairs at City of Hope, Duarte, Calif., said in an interview. “For a lot of patients who suffer with non-Hodgkin’s lymphoma, the consequences of being refractory to standard therapies mean that many patients have few great prospects for moving forward with curative treatments. CAR T cells represent a really innovative set of treatments for patients.”

A proposed national coverage determination, issued in February 2019, would have put in place a coverage with evidence development (CED) requirement for CAR T-cell therapy, covering treatment nationwide if it was offered through CMS-approved registries or clinical studies in which patients were monitored for 2 or more years following treatment.

Physicians applauded the decision not to restrict access by imposing the CED requirement.

Courtesy Russell Lee

“I think what CMS has put out is a good thing,” said Navneet Majhail, MD, director of the Cleveland Clinic’s blood and marrow transplant program, and president of the American Society for Transplantation and Cellular Therapy.

“Both at the Cleveland Clinic level and the society level, we have been asking CMS for something similar and we are really glad and excited that CMS did do this. The concern was that CMS might do this in the context of some other regulatory requirements like CED that they sometimes do. I am glad that CMS decided not to put that mechanism into place for the CAR T-cell therapies,” Dr. Majhail said.

Dr. Alvarnas, who also serves as chair of the American Society of Hematology Committee on Practice, agreed. “I see good. I don’t see bad. I have read through this and it strikes me as being written with fairly great clarity.”

Dr. Alvarnas added that he had been worried about potential restrictions, such as CED. “Once you put something under that whole rubric of coverage with evidence development, then what you do is you create a bottleneck around access to therapy because you have to have an accruing clinical trial for patients to, in fact, be able to participate in that form of therapy.”

By not imposing a CED requirement, it opens the door to better understanding the role CAR T cells play in treatment, Dr. Alvarnas noted.

“Over time, the number of patients for whom these therapeutics work, based upon real medical evidence, will escalate and grow at a pace that can far exceed the restrictions placed under a CED model,” he said, adding that the national coverage determination “gives us the license to deliver therapeutics to the right patients based upon medical evidence as it evolves, provided that these things get listed as part of the compendia. I think that is a fantastic recognition that new roles for drugs, agents, therapeutics ... are going to evolve at a pace far faster than what CMS can write rules about.”

While Medicare’s coverage determination garnered positive reviews, the agency’s Inpatient Prospective Payment System final rule – which outlines reimbursement for CAR T-cell therapy and other new technologies – got a more tepid response.

In the final rule, CMS raised the payment it makes to hospitals for administering CAR T-cell therapies through its new technology add-on payment. Payments will rise from 50% of the technology to 65%, an increase from $186,500 to $242,450 for CAR T-cell therapies, beginning on Oct. 1, 2019.

But even the bump up to 65% may not be enough.

“I see the move to 65% as a new technology add-on payment as an incremental step in the correct direction, but what we’ve done to some extent is that we’ve delayed getting to some sort of more wholly conceived system,” Dr. Alvarnas said, noting that a new system will be needed as the new technology add-on payment goes away in 2021.

Abhinav Deol, MD, of the Karmanos Cancer Institute in Detroit said it’s a challenge to cover costs for the treatment. “If you just look at the simple math, it is still going to be an economic challenge. The cells that are approved for lymphoma patients that will probably fall into the Medicare category, the list price of those cells is $373,000. Even with the 65% coverage, it’s about $235,000-$240,000 in reimbursement,” he said. “For a facility to be able to provide the care for patients, you have that delta that is still not covered. It is still going to be an economic challenge for many of the facilities to provide this care.”

Thomas LeBlanc, MD, an associate professor of medicine at Duke University, Durham, N.C., said that, while the coverage determination is a positive step, it’s not clear that it will provide meaningful access to CAR T-cell therapy because of the cost.

“These products are incredibly expensive, and the total cost of providing them is woefully underestimated in only focusing on the sticker price of the product,” he said. “Doing so ignores the significant hospital care, sometimes even critical care, as well as specialized knowledge and high touch supportive care, all of which is required to safely get patients through this revolutionary yet often risky treatment. So when CMS offers to pay just 65% of the sticker price, I suspect that many institutions will still lose six figures for each patient treated.”

Dr. LeBlanc predicted that many centers will decline to provide CAR T-cell therapy despite the increase in the new technology add-on payment, though he added that “I’d love to be wrong about this.”

Dr. Majhail agreed, noting that, even with the bump in the add-on payment, hospitals “won’t be whole in terms of providing care for these patients.”

“The reimbursement piece continues to be a challenge,” he said. “It is better than what it was, but there is still more work to be done. That is something we will have to keep working with the agency on.”

[email protected]

Physicians are praising the decision by officials at the Centers for Medicare & Medicaid Services to provide coverage of chimeric antigen receptor T-cell therapy, though they say the planned payment structure will still leave hospitals in the red when treatment is administered.

On Aug. 7, 2019, the agency issued a national coverage determination that outlines Medicare coverage of chimeric antigen receptor (CAR) T-cell therapies when they are provided in health care facilities enrolled in the Food and Drug Administration’s Risk Evaluation and Mitigation Strategies program. Medicare will cover treatments for both FDA-approved indications and off-label uses that are recommended in CMS-approved compendia.

“What you’ve seen in both the [Medicare Inpatient Prospective Payment System] rule, as well as this coverage determination, is recognition by CMS that, with CAR T cells, we are dealing with something different and something extraordinary,” Joseph Alvarnas, MD, vice president of government affairs at City of Hope, Duarte, Calif., said in an interview. “For a lot of patients who suffer with non-Hodgkin’s lymphoma, the consequences of being refractory to standard therapies mean that many patients have few great prospects for moving forward with curative treatments. CAR T cells represent a really innovative set of treatments for patients.”

A proposed national coverage determination, issued in February 2019, would have put in place a coverage with evidence development (CED) requirement for CAR T-cell therapy, covering treatment nationwide if it was offered through CMS-approved registries or clinical studies in which patients were monitored for 2 or more years following treatment.

Physicians applauded the decision not to restrict access by imposing the CED requirement.

Courtesy Russell Lee

“I think what CMS has put out is a good thing,” said Navneet Majhail, MD, director of the Cleveland Clinic’s blood and marrow transplant program, and president of the American Society for Transplantation and Cellular Therapy.

“Both at the Cleveland Clinic level and the society level, we have been asking CMS for something similar and we are really glad and excited that CMS did do this. The concern was that CMS might do this in the context of some other regulatory requirements like CED that they sometimes do. I am glad that CMS decided not to put that mechanism into place for the CAR T-cell therapies,” Dr. Majhail said.

Dr. Alvarnas, who also serves as chair of the American Society of Hematology Committee on Practice, agreed. “I see good. I don’t see bad. I have read through this and it strikes me as being written with fairly great clarity.”

Dr. Alvarnas added that he had been worried about potential restrictions, such as CED. “Once you put something under that whole rubric of coverage with evidence development, then what you do is you create a bottleneck around access to therapy because you have to have an accruing clinical trial for patients to, in fact, be able to participate in that form of therapy.”

By not imposing a CED requirement, it opens the door to better understanding the role CAR T cells play in treatment, Dr. Alvarnas noted.

“Over time, the number of patients for whom these therapeutics work, based upon real medical evidence, will escalate and grow at a pace that can far exceed the restrictions placed under a CED model,” he said, adding that the national coverage determination “gives us the license to deliver therapeutics to the right patients based upon medical evidence as it evolves, provided that these things get listed as part of the compendia. I think that is a fantastic recognition that new roles for drugs, agents, therapeutics ... are going to evolve at a pace far faster than what CMS can write rules about.”

While Medicare’s coverage determination garnered positive reviews, the agency’s Inpatient Prospective Payment System final rule – which outlines reimbursement for CAR T-cell therapy and other new technologies – got a more tepid response.

In the final rule, CMS raised the payment it makes to hospitals for administering CAR T-cell therapies through its new technology add-on payment. Payments will rise from 50% of the technology to 65%, an increase from $186,500 to $242,450 for CAR T-cell therapies, beginning on Oct. 1, 2019.

But even the bump up to 65% may not be enough.

“I see the move to 65% as a new technology add-on payment as an incremental step in the correct direction, but what we’ve done to some extent is that we’ve delayed getting to some sort of more wholly conceived system,” Dr. Alvarnas said, noting that a new system will be needed as the new technology add-on payment goes away in 2021.

Abhinav Deol, MD, of the Karmanos Cancer Institute in Detroit said it’s a challenge to cover costs for the treatment. “If you just look at the simple math, it is still going to be an economic challenge. The cells that are approved for lymphoma patients that will probably fall into the Medicare category, the list price of those cells is $373,000. Even with the 65% coverage, it’s about $235,000-$240,000 in reimbursement,” he said. “For a facility to be able to provide the care for patients, you have that delta that is still not covered. It is still going to be an economic challenge for many of the facilities to provide this care.”

Thomas LeBlanc, MD, an associate professor of medicine at Duke University, Durham, N.C., said that, while the coverage determination is a positive step, it’s not clear that it will provide meaningful access to CAR T-cell therapy because of the cost.

“These products are incredibly expensive, and the total cost of providing them is woefully underestimated in only focusing on the sticker price of the product,” he said. “Doing so ignores the significant hospital care, sometimes even critical care, as well as specialized knowledge and high touch supportive care, all of which is required to safely get patients through this revolutionary yet often risky treatment. So when CMS offers to pay just 65% of the sticker price, I suspect that many institutions will still lose six figures for each patient treated.”

Dr. LeBlanc predicted that many centers will decline to provide CAR T-cell therapy despite the increase in the new technology add-on payment, though he added that “I’d love to be wrong about this.”

Dr. Majhail agreed, noting that, even with the bump in the add-on payment, hospitals “won’t be whole in terms of providing care for these patients.”

“The reimbursement piece continues to be a challenge,” he said. “It is better than what it was, but there is still more work to be done. That is something we will have to keep working with the agency on.”

[email protected]

PHILADELPHIA – Among patients with episodic cluster headache, the use of acute medications is high, but the use of preventive medications is low, according to an analysis presented at the annual meeting of the American Headache Society.

Although consensus treatment guidelines do not exist for episodic cluster headache, treatment of this disorder did not follow many established recommendations that call for the use of preventive medications (e.g., MacGregor et al., 2010; Sarchielli et al., 2012; and May et al., 2006). Additional preventive medication options may be needed.

Patients with episodic cluster headache have several unilateral headache attacks per day. Little information is available to guide the selection of treatments for this population, and little is known about how available treatments are used in routine practice.
 

Analyzing cross-sectional survey data

To address this paucity of evidence, Jeffrey Scott Andrews, PharmD, a senior research scientist at Eli Lilly in Indianapolis, and colleagues examined data from the Adelphi 2017 Cluster Headache Disease Specific Programme, a large, international, cross-sectional survey. Physicians and patients in Germany, the United Kingdom, and the United States responded to the survey. Eligible physicians consulted with at least four patients with cluster headache per month, and eligible patients had a diagnosis of episodic cluster headache that was consistent with ICHD-3 beta criteria. Additional data were collected from all participants through questionnaires.

The analysis included 309 patients in Germany, 328 in the United Kingdom, and 375 in the United States. The average age of the patients was 40 years, and most of the patients were male. Less than 70% of patients reported working full time, which may indicate “the impact of this condition on work status,” said Dr. Andrews. Patients’ average number of attacks per day within an active period was 2.4. The two most commonly reported comorbidities were anxiety and depression. About 40% of cases of depression were reported to have occurred after the receipt of a diagnosis of cluster headache.
 

Use of inhaled oxygen was low

Most patients received acute treatments. The proportion of patients who received acute therapy only was 53% in Germany, 48% in the United Kingdom, and 43% in the United States. Approximately 34% of patients in Germany received a combination of acute and preventive therapy, compared with 37% in the United Kingdom and 42% in the United States. The proportion of patients who received preventive therapy only was 10% in Germany, 8% in the United Kingdom, and 12% in the United States.

The most commonly prescribed acute treatment, regardless of formulation, was sumatriptan. About 60% of patients received this medication. Less than one-third of patients used inhaled oxygen. Oxygen was prescribed more often in Germany (45%) and the United Kingdom (33%), compared with the United States (19%). U.S. patients face well-known obstacles in getting access to, and reimbursement for, oxygen, said Dr. Andrews. “That’s an area that deserves increased attention.” Zolmitriptan was the third most commonly prescribed acute medication.

Among prescriptions for sumatriptan, oral and injectable formulations were approximately equally common. Recommendations, however, indicate formulations with potentially fast onset of action. “The average duration of one of these attacks is between 15 and 180 minutes, so that certainly suggests that a formulation that gives you a faster onset of action might improve outcomes,” said Dr. Andrews. The use of injectable sumatriptan was lowest in the United States and highest in the United Kingdom.

“The most common decision regarding preventive treatment was [to give] no preventive treatment,” said Dr. Andrews. Verapamil was the most commonly prescribed preventive therapy (34% in Germany, 29% in the United States, and 25% in the United Kingdom), followed by topiramate, lithium, and valproate.
 

Nonadherence and noncompliance was common

Fewer U.K. patients (32%) reported taking their preventive therapy as advised, compared with German patients (60%) and U.S. patients (80%). Common reasons for noncompliance, regardless of location, were forgetfulness, the belief that a dose was not needed, and side effects. Most patients in the United Kingdom (60%) and the United States (54%) reported the need to take an extra dose of their acute medication to relieve pain symptoms, compared with 30% in Germany. Furthermore, 13% of U.S. patients indicated that they took extra doses all the time or nearly all the time, compared with 2% in Germany and 7% in the United Kingdom. Among patients who had discontinued a preventive treatment in the past, the most common reasons for discontinuation were lack of efficacy and problems with tolerability.

One limitation of the study was that the survey was not designed to represent the general cluster headache or treating physician populations fully. The data may reflect selection bias in favor of physicians who treat high volumes of patients and in favor of patients who frequently seek health care. In addition, the data were based on self-reports.

“Increased awareness and educational efforts that aim at promoting the need and benefit of the preventive treatment for these patients is warranted,” Dr. Andrews concluded.

Dr. Andrews is an employee of Eli Lilly, which funded the study.

[email protected]

SOURCE: Nichols R et al. AHS 2019. Abstract OR04.

PHILADELPHIA – Among patients with episodic cluster headache, the use of acute medications is high, but the use of preventive medications is low, according to an analysis presented at the annual meeting of the American Headache Society.

Although consensus treatment guidelines do not exist for episodic cluster headache, treatment of this disorder did not follow many established recommendations that call for the use of preventive medications (e.g., MacGregor et al., 2010; Sarchielli et al., 2012; and May et al., 2006). Additional preventive medication options may be needed.

Patients with episodic cluster headache have several unilateral headache attacks per day. Little information is available to guide the selection of treatments for this population, and little is known about how available treatments are used in routine practice.
 

Analyzing cross-sectional survey data

To address this paucity of evidence, Jeffrey Scott Andrews, PharmD, a senior research scientist at Eli Lilly in Indianapolis, and colleagues examined data from the Adelphi 2017 Cluster Headache Disease Specific Programme, a large, international, cross-sectional survey. Physicians and patients in Germany, the United Kingdom, and the United States responded to the survey. Eligible physicians consulted with at least four patients with cluster headache per month, and eligible patients had a diagnosis of episodic cluster headache that was consistent with ICHD-3 beta criteria. Additional data were collected from all participants through questionnaires.

The analysis included 309 patients in Germany, 328 in the United Kingdom, and 375 in the United States. The average age of the patients was 40 years, and most of the patients were male. Less than 70% of patients reported working full time, which may indicate “the impact of this condition on work status,” said Dr. Andrews. Patients’ average number of attacks per day within an active period was 2.4. The two most commonly reported comorbidities were anxiety and depression. About 40% of cases of depression were reported to have occurred after the receipt of a diagnosis of cluster headache.
 

Use of inhaled oxygen was low

Most patients received acute treatments. The proportion of patients who received acute therapy only was 53% in Germany, 48% in the United Kingdom, and 43% in the United States. Approximately 34% of patients in Germany received a combination of acute and preventive therapy, compared with 37% in the United Kingdom and 42% in the United States. The proportion of patients who received preventive therapy only was 10% in Germany, 8% in the United Kingdom, and 12% in the United States.

The most commonly prescribed acute treatment, regardless of formulation, was sumatriptan. About 60% of patients received this medication. Less than one-third of patients used inhaled oxygen. Oxygen was prescribed more often in Germany (45%) and the United Kingdom (33%), compared with the United States (19%). U.S. patients face well-known obstacles in getting access to, and reimbursement for, oxygen, said Dr. Andrews. “That’s an area that deserves increased attention.” Zolmitriptan was the third most commonly prescribed acute medication.

Among prescriptions for sumatriptan, oral and injectable formulations were approximately equally common. Recommendations, however, indicate formulations with potentially fast onset of action. “The average duration of one of these attacks is between 15 and 180 minutes, so that certainly suggests that a formulation that gives you a faster onset of action might improve outcomes,” said Dr. Andrews. The use of injectable sumatriptan was lowest in the United States and highest in the United Kingdom.

“The most common decision regarding preventive treatment was [to give] no preventive treatment,” said Dr. Andrews. Verapamil was the most commonly prescribed preventive therapy (34% in Germany, 29% in the United States, and 25% in the United Kingdom), followed by topiramate, lithium, and valproate.
 

Nonadherence and noncompliance was common

Fewer U.K. patients (32%) reported taking their preventive therapy as advised, compared with German patients (60%) and U.S. patients (80%). Common reasons for noncompliance, regardless of location, were forgetfulness, the belief that a dose was not needed, and side effects. Most patients in the United Kingdom (60%) and the United States (54%) reported the need to take an extra dose of their acute medication to relieve pain symptoms, compared with 30% in Germany. Furthermore, 13% of U.S. patients indicated that they took extra doses all the time or nearly all the time, compared with 2% in Germany and 7% in the United Kingdom. Among patients who had discontinued a preventive treatment in the past, the most common reasons for discontinuation were lack of efficacy and problems with tolerability.

One limitation of the study was that the survey was not designed to represent the general cluster headache or treating physician populations fully. The data may reflect selection bias in favor of physicians who treat high volumes of patients and in favor of patients who frequently seek health care. In addition, the data were based on self-reports.

“Increased awareness and educational efforts that aim at promoting the need and benefit of the preventive treatment for these patients is warranted,” Dr. Andrews concluded.

Dr. Andrews is an employee of Eli Lilly, which funded the study.

[email protected]

SOURCE: Nichols R et al. AHS 2019. Abstract OR04.

PHILADELPHIA – Among patients with episodic cluster headache, the use of acute medications is high, but the use of preventive medications is low, according to an analysis presented at the annual meeting of the American Headache Society.

Although consensus treatment guidelines do not exist for episodic cluster headache, treatment of this disorder did not follow many established recommendations that call for the use of preventive medications (e.g., MacGregor et al., 2010; Sarchielli et al., 2012; and May et al., 2006). Additional preventive medication options may be needed.

Patients with episodic cluster headache have several unilateral headache attacks per day. Little information is available to guide the selection of treatments for this population, and little is known about how available treatments are used in routine practice.
 

Analyzing cross-sectional survey data

To address this paucity of evidence, Jeffrey Scott Andrews, PharmD, a senior research scientist at Eli Lilly in Indianapolis, and colleagues examined data from the Adelphi 2017 Cluster Headache Disease Specific Programme, a large, international, cross-sectional survey. Physicians and patients in Germany, the United Kingdom, and the United States responded to the survey. Eligible physicians consulted with at least four patients with cluster headache per month, and eligible patients had a diagnosis of episodic cluster headache that was consistent with ICHD-3 beta criteria. Additional data were collected from all participants through questionnaires.

The analysis included 309 patients in Germany, 328 in the United Kingdom, and 375 in the United States. The average age of the patients was 40 years, and most of the patients were male. Less than 70% of patients reported working full time, which may indicate “the impact of this condition on work status,” said Dr. Andrews. Patients’ average number of attacks per day within an active period was 2.4. The two most commonly reported comorbidities were anxiety and depression. About 40% of cases of depression were reported to have occurred after the receipt of a diagnosis of cluster headache.
 

Use of inhaled oxygen was low

Most patients received acute treatments. The proportion of patients who received acute therapy only was 53% in Germany, 48% in the United Kingdom, and 43% in the United States. Approximately 34% of patients in Germany received a combination of acute and preventive therapy, compared with 37% in the United Kingdom and 42% in the United States. The proportion of patients who received preventive therapy only was 10% in Germany, 8% in the United Kingdom, and 12% in the United States.

The most commonly prescribed acute treatment, regardless of formulation, was sumatriptan. About 60% of patients received this medication. Less than one-third of patients used inhaled oxygen. Oxygen was prescribed more often in Germany (45%) and the United Kingdom (33%), compared with the United States (19%). U.S. patients face well-known obstacles in getting access to, and reimbursement for, oxygen, said Dr. Andrews. “That’s an area that deserves increased attention.” Zolmitriptan was the third most commonly prescribed acute medication.

Among prescriptions for sumatriptan, oral and injectable formulations were approximately equally common. Recommendations, however, indicate formulations with potentially fast onset of action. “The average duration of one of these attacks is between 15 and 180 minutes, so that certainly suggests that a formulation that gives you a faster onset of action might improve outcomes,” said Dr. Andrews. The use of injectable sumatriptan was lowest in the United States and highest in the United Kingdom.

“The most common decision regarding preventive treatment was [to give] no preventive treatment,” said Dr. Andrews. Verapamil was the most commonly prescribed preventive therapy (34% in Germany, 29% in the United States, and 25% in the United Kingdom), followed by topiramate, lithium, and valproate.
 

Nonadherence and noncompliance was common

Fewer U.K. patients (32%) reported taking their preventive therapy as advised, compared with German patients (60%) and U.S. patients (80%). Common reasons for noncompliance, regardless of location, were forgetfulness, the belief that a dose was not needed, and side effects. Most patients in the United Kingdom (60%) and the United States (54%) reported the need to take an extra dose of their acute medication to relieve pain symptoms, compared with 30% in Germany. Furthermore, 13% of U.S. patients indicated that they took extra doses all the time or nearly all the time, compared with 2% in Germany and 7% in the United Kingdom. Among patients who had discontinued a preventive treatment in the past, the most common reasons for discontinuation were lack of efficacy and problems with tolerability.

One limitation of the study was that the survey was not designed to represent the general cluster headache or treating physician populations fully. The data may reflect selection bias in favor of physicians who treat high volumes of patients and in favor of patients who frequently seek health care. In addition, the data were based on self-reports.

“Increased awareness and educational efforts that aim at promoting the need and benefit of the preventive treatment for these patients is warranted,” Dr. Andrews concluded.

Dr. Andrews is an employee of Eli Lilly, which funded the study.

[email protected]

SOURCE: Nichols R et al. AHS 2019. Abstract OR04.