The American College of Obstetricians and Gynecologists (ACOG) recommends risk-based screening for hepatitis C virus (HCV) infection during pregnancy.¹ However, the prevalence of HCV among pregnant women in the United States is on the rise. From 2009 to 2014, HCV infection present at delivery increased 89%.² In addition, the risk of an HCV-infected mother transmitting the infection to her baby is about 4% to 7% per pregnancy.³ Currently, the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases recommend universal HCV screening in pregnancy.⁴

Researchers at Tufts Medical Center in Boston, Massachusetts, a tertiary care center, presented survey findings on HCV screening among ObGyns at ACOG’s 2019 Annual Clinical and Scientific Meeting in Nashville, Tennessee.⁵ Katherine G. Koniares, MD, and colleagues sought to assess the opinions and clinical practices of ObGyns by emailing a 10-question electronic survey to providers. A total of 38 of 41 providers (93%) responded to the survey.

Survey results show lack of knowledge on risk factors

In response to the question, “Which pregnant patients do you believe should be screened for HCV,” 43.2% of providers stated “all pregnant women,” while 54.1% said “only pregnant women with risk factors for HCV.” A small percentage (2.7%) responded that they were not sure.

Providers also were asked which patients in their practice they screen for HCV. In response, 77.8% stated that they screen pregnant women for HCV based on risk factors, while 13.9% screen all pregnant patients for HCV; 8.3% do not screen for HCV.

When asked which risk factors providers use to screen patients for HCV, 42% to 85% said they screen for each indicated risk factor. Only 36% of providers, however, correctly identified all risk factors (for example, receiving blood products from donors who later tested positive for HCV; unexplained liver disease; and percutaneous/parenteral exposures in an unregulated setting, such as receiving tattoos outside a licensed parlor).

Further study needed on universal screening

The researchers assert that risk-based screening for HCV is not effective and that further research on universal HCV screening in pregnant patients is needed.

The American College of Obstetricians and Gynecologists (ACOG) recommends risk-based screening for hepatitis C virus (HCV) infection during pregnancy.¹ However, the prevalence of HCV among pregnant women in the United States is on the rise. From 2009 to 2014, HCV infection present at delivery increased 89%.² In addition, the risk of an HCV-infected mother transmitting the infection to her baby is about 4% to 7% per pregnancy.³ Currently, the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases recommend universal HCV screening in pregnancy.⁴

Researchers at Tufts Medical Center in Boston, Massachusetts, a tertiary care center, presented survey findings on HCV screening among ObGyns at ACOG’s 2019 Annual Clinical and Scientific Meeting in Nashville, Tennessee.⁵ Katherine G. Koniares, MD, and colleagues sought to assess the opinions and clinical practices of ObGyns by emailing a 10-question electronic survey to providers. A total of 38 of 41 providers (93%) responded to the survey.

Survey results show lack of knowledge on risk factors

In response to the question, “Which pregnant patients do you believe should be screened for HCV,” 43.2% of providers stated “all pregnant women,” while 54.1% said “only pregnant women with risk factors for HCV.” A small percentage (2.7%) responded that they were not sure.

Providers also were asked which patients in their practice they screen for HCV. In response, 77.8% stated that they screen pregnant women for HCV based on risk factors, while 13.9% screen all pregnant patients for HCV; 8.3% do not screen for HCV.

When asked which risk factors providers use to screen patients for HCV, 42% to 85% said they screen for each indicated risk factor. Only 36% of providers, however, correctly identified all risk factors (for example, receiving blood products from donors who later tested positive for HCV; unexplained liver disease; and percutaneous/parenteral exposures in an unregulated setting, such as receiving tattoos outside a licensed parlor).

Further study needed on universal screening

The researchers assert that risk-based screening for HCV is not effective and that further research on universal HCV screening in pregnant patients is needed.

The American College of Obstetricians and Gynecologists (ACOG) recommends risk-based screening for hepatitis C virus (HCV) infection during pregnancy.¹ However, the prevalence of HCV among pregnant women in the United States is on the rise. From 2009 to 2014, HCV infection present at delivery increased 89%.² In addition, the risk of an HCV-infected mother transmitting the infection to her baby is about 4% to 7% per pregnancy.³ Currently, the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases recommend universal HCV screening in pregnancy.⁴

Researchers at Tufts Medical Center in Boston, Massachusetts, a tertiary care center, presented survey findings on HCV screening among ObGyns at ACOG’s 2019 Annual Clinical and Scientific Meeting in Nashville, Tennessee.⁵ Katherine G. Koniares, MD, and colleagues sought to assess the opinions and clinical practices of ObGyns by emailing a 10-question electronic survey to providers. A total of 38 of 41 providers (93%) responded to the survey.

Survey results show lack of knowledge on risk factors

In response to the question, “Which pregnant patients do you believe should be screened for HCV,” 43.2% of providers stated “all pregnant women,” while 54.1% said “only pregnant women with risk factors for HCV.” A small percentage (2.7%) responded that they were not sure.

Providers also were asked which patients in their practice they screen for HCV. In response, 77.8% stated that they screen pregnant women for HCV based on risk factors, while 13.9% screen all pregnant patients for HCV; 8.3% do not screen for HCV.

When asked which risk factors providers use to screen patients for HCV, 42% to 85% said they screen for each indicated risk factor. Only 36% of providers, however, correctly identified all risk factors (for example, receiving blood products from donors who later tested positive for HCV; unexplained liver disease; and percutaneous/parenteral exposures in an unregulated setting, such as receiving tattoos outside a licensed parlor).

Further study needed on universal screening

The researchers assert that risk-based screening for HCV is not effective and that further research on universal HCV screening in pregnant patients is needed.

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.

As established last week, there has been a startling increase in sexually transmitted infections (STIs) among older adults in the United States. The burning question on everyone’s mind (certainly mine!) is: Why? Engaging in some “educated speculation” yields many factors possibly driving this trend. For example:

1. Provider Reluctance. Older Americans may not get regular screenings for STIs because their health care providers are often reluctant to raise the issue. That may be fueled by lack of awareness on the clinician’s part: More than 60% of individuals older than 60 have sex at least once a month, yet this population is rarely considered to be “at risk” for STIs.¹

2. Patient Embarrassment/awkwardness. For many older Americans, admitting that they are having sex makes them feel awkward or embarrassed. Reluctance to share intimate details means they may not seek evaluation and treatment for symptoms that seem related to their sexual health or activity.

3. Effects of Aging. There are 2 sides to this coin: actual physiologic changes that occur with age and assumptions that all changes are just part of aging. As people get older, their immune systems tend to deteriorate, making them more vulnerable to contracting any disease—including STIs. After menopause, women's vaginal tissues thin and natural lubrication declines, increasing their risk for microtears that can leave them susceptible to infectious organisms. And let’s be honest: Some STI symptoms, such as fatigue, weakness, and changes in memory, are nonspecific and may be mistaken by clinicians for the regular progression of age.²

4. Social Changes. The world has changed since most older adults last dove into the dating pool. We now have online dating services, some of which cater to a mature audience; as a result, people may be less familiar with their partner’s sexual history. Compounding that, many older adults just aren’t accustomed to thinking of themselves or a partner as being at high risk for STIs—and if you don’t even think about it, you definitely won’t ask. Widowed or divorced adults may date more than one person at a time, raising their risk for infection after a long period of monogamy. Seniors also may not be accustomed to using a condom or do not use one because they think the risk for STIs is minimal or nonexistent. Seniors may not consider oral or anal sex as a way of contracting or transmitting STIs.³

5. Medical Advances. Compared with previous generations, today’s seniors have an easier time having sex at an older age, thanks to the availability of medications such as sildenafil (Viagra) and tadalafil (Cialis) for men with erectile dysfunction. There has also been an increase in postmenopausal women requesting and receiving bioidentical hormone replacement. With increased libido and ability to perform come more sexual encounters among the older population—and as a result, more opportunities for STIs to spread. Are there other reasons for the increase in STIs in this population? Next week we’ll consider the unique societal influences of the Baby Boom generation. In the meantime, please share your insights with me at [email protected].

As established last week, there has been a startling increase in sexually transmitted infections (STIs) among older adults in the United States. The burning question on everyone’s mind (certainly mine!) is: Why? Engaging in some “educated speculation” yields many factors possibly driving this trend. For example:

1. Provider Reluctance. Older Americans may not get regular screenings for STIs because their health care providers are often reluctant to raise the issue. That may be fueled by lack of awareness on the clinician’s part: More than 60% of individuals older than 60 have sex at least once a month, yet this population is rarely considered to be “at risk” for STIs.¹

2. Patient Embarrassment/awkwardness. For many older Americans, admitting that they are having sex makes them feel awkward or embarrassed. Reluctance to share intimate details means they may not seek evaluation and treatment for symptoms that seem related to their sexual health or activity.

3. Effects of Aging. There are 2 sides to this coin: actual physiologic changes that occur with age and assumptions that all changes are just part of aging. As people get older, their immune systems tend to deteriorate, making them more vulnerable to contracting any disease—including STIs. After menopause, women's vaginal tissues thin and natural lubrication declines, increasing their risk for microtears that can leave them susceptible to infectious organisms. And let’s be honest: Some STI symptoms, such as fatigue, weakness, and changes in memory, are nonspecific and may be mistaken by clinicians for the regular progression of age.²

4. Social Changes. The world has changed since most older adults last dove into the dating pool. We now have online dating services, some of which cater to a mature audience; as a result, people may be less familiar with their partner’s sexual history. Compounding that, many older adults just aren’t accustomed to thinking of themselves or a partner as being at high risk for STIs—and if you don’t even think about it, you definitely won’t ask. Widowed or divorced adults may date more than one person at a time, raising their risk for infection after a long period of monogamy. Seniors also may not be accustomed to using a condom or do not use one because they think the risk for STIs is minimal or nonexistent. Seniors may not consider oral or anal sex as a way of contracting or transmitting STIs.³

5. Medical Advances. Compared with previous generations, today’s seniors have an easier time having sex at an older age, thanks to the availability of medications such as sildenafil (Viagra) and tadalafil (Cialis) for men with erectile dysfunction. There has also been an increase in postmenopausal women requesting and receiving bioidentical hormone replacement. With increased libido and ability to perform come more sexual encounters among the older population—and as a result, more opportunities for STIs to spread. Are there other reasons for the increase in STIs in this population? Next week we’ll consider the unique societal influences of the Baby Boom generation. In the meantime, please share your insights with me at [email protected].

As established last week, there has been a startling increase in sexually transmitted infections (STIs) among older adults in the United States. The burning question on everyone’s mind (certainly mine!) is: Why? Engaging in some “educated speculation” yields many factors possibly driving this trend. For example:

1. Provider Reluctance. Older Americans may not get regular screenings for STIs because their health care providers are often reluctant to raise the issue. That may be fueled by lack of awareness on the clinician’s part: More than 60% of individuals older than 60 have sex at least once a month, yet this population is rarely considered to be “at risk” for STIs.¹

2. Patient Embarrassment/awkwardness. For many older Americans, admitting that they are having sex makes them feel awkward or embarrassed. Reluctance to share intimate details means they may not seek evaluation and treatment for symptoms that seem related to their sexual health or activity.

3. Effects of Aging. There are 2 sides to this coin: actual physiologic changes that occur with age and assumptions that all changes are just part of aging. As people get older, their immune systems tend to deteriorate, making them more vulnerable to contracting any disease—including STIs. After menopause, women's vaginal tissues thin and natural lubrication declines, increasing their risk for microtears that can leave them susceptible to infectious organisms. And let’s be honest: Some STI symptoms, such as fatigue, weakness, and changes in memory, are nonspecific and may be mistaken by clinicians for the regular progression of age.²

4. Social Changes. The world has changed since most older adults last dove into the dating pool. We now have online dating services, some of which cater to a mature audience; as a result, people may be less familiar with their partner’s sexual history. Compounding that, many older adults just aren’t accustomed to thinking of themselves or a partner as being at high risk for STIs—and if you don’t even think about it, you definitely won’t ask. Widowed or divorced adults may date more than one person at a time, raising their risk for infection after a long period of monogamy. Seniors also may not be accustomed to using a condom or do not use one because they think the risk for STIs is minimal or nonexistent. Seniors may not consider oral or anal sex as a way of contracting or transmitting STIs.³

5. Medical Advances. Compared with previous generations, today’s seniors have an easier time having sex at an older age, thanks to the availability of medications such as sildenafil (Viagra) and tadalafil (Cialis) for men with erectile dysfunction. There has also been an increase in postmenopausal women requesting and receiving bioidentical hormone replacement. With increased libido and ability to perform come more sexual encounters among the older population—and as a result, more opportunities for STIs to spread. Are there other reasons for the increase in STIs in this population? Next week we’ll consider the unique societal influences of the Baby Boom generation. In the meantime, please share your insights with me at [email protected].

In states that mandate coverage for autism spectrum disorder (ASD) health services, families in high-deductible health plans (HDHPs) access ASD-related services without paying more out-of-pocket expenses than traditional plan enrollees, an analysis found.

copyright teekid/iStockphoto

Lead author Colleen L. Barry, PhD, of Johns Hopkins University, Baltimore, and colleagues examined insurance claims between 2008 and 2012 for children covered by three large U.S. insurers (United Healthcare, Aetna, and Humana) to compare the effects of ASD-related coverage mandates on health spending. At least 47 states and Washington, D.C., have enacted mandates that require insurers to cover ASD-related health services, such as diagnostic and assessment services and behavioral and functional therapies. The final study sample included 98,639 children aged 0-21 years with at least two ASD-related service claims on different days during the study period.

The investigators found that, among HDHP enrollees, coverage mandates were associated with marked increases in average monthly spending across all service categories, but not among traditional plan enrollees. Specifically for HDHP patients, ASD coverage mandates were linked to a $98 greater increase in average monthly spending for insurers on ASD-specific outpatient services, a $142 greater increase in average monthly insurer spending on all outpatient services, and a $142 greater increase in average monthly insurer spending on all health services, according to the study published in Pediatrics. Out-of-pocket spending by patients however, was not significantly different between HDHP and traditional plan enrollees in states that mandate ASD-related coverage, the study found.

Dr. Barry and associates concluded that patients in both HDHP and traditional insurance plans spend large sums on ASD-related care in coverage mandate states, but because costs likely exceed HDHP deductibles, insurers absorb any increases. They suggested that families with regularly high health care expenditures related to ASD services consider high-deductible plans in the context of mandate laws.

“Future research is needed to better understand how features of HDHPs, such as deductible size and health savings account structure, influence the ability of families to make wise choices in obtaining care, and to examine plan premiums and financial strain associated with these plans, particularly for families with children with ASD and high expenditures,” Dr. Barry and associates wrote.

The authors reported no relevant financial disclosures. The study was supported by a National Institute of Mental Health grant and funded by the National Institutes of Health.
 

[email protected]

SOURCE: Barry CL et al. Pediatrics. 2019 May 13. doi: 10.1542/peds.2018-2391.

In states that mandate coverage for autism spectrum disorder (ASD) health services, families in high-deductible health plans (HDHPs) access ASD-related services without paying more out-of-pocket expenses than traditional plan enrollees, an analysis found.

copyright teekid/iStockphoto

Lead author Colleen L. Barry, PhD, of Johns Hopkins University, Baltimore, and colleagues examined insurance claims between 2008 and 2012 for children covered by three large U.S. insurers (United Healthcare, Aetna, and Humana) to compare the effects of ASD-related coverage mandates on health spending. At least 47 states and Washington, D.C., have enacted mandates that require insurers to cover ASD-related health services, such as diagnostic and assessment services and behavioral and functional therapies. The final study sample included 98,639 children aged 0-21 years with at least two ASD-related service claims on different days during the study period.

The investigators found that, among HDHP enrollees, coverage mandates were associated with marked increases in average monthly spending across all service categories, but not among traditional plan enrollees. Specifically for HDHP patients, ASD coverage mandates were linked to a $98 greater increase in average monthly spending for insurers on ASD-specific outpatient services, a $142 greater increase in average monthly insurer spending on all outpatient services, and a $142 greater increase in average monthly insurer spending on all health services, according to the study published in Pediatrics. Out-of-pocket spending by patients however, was not significantly different between HDHP and traditional plan enrollees in states that mandate ASD-related coverage, the study found.

Dr. Barry and associates concluded that patients in both HDHP and traditional insurance plans spend large sums on ASD-related care in coverage mandate states, but because costs likely exceed HDHP deductibles, insurers absorb any increases. They suggested that families with regularly high health care expenditures related to ASD services consider high-deductible plans in the context of mandate laws.

“Future research is needed to better understand how features of HDHPs, such as deductible size and health savings account structure, influence the ability of families to make wise choices in obtaining care, and to examine plan premiums and financial strain associated with these plans, particularly for families with children with ASD and high expenditures,” Dr. Barry and associates wrote.

The authors reported no relevant financial disclosures. The study was supported by a National Institute of Mental Health grant and funded by the National Institutes of Health.
 

[email protected]

SOURCE: Barry CL et al. Pediatrics. 2019 May 13. doi: 10.1542/peds.2018-2391.

In states that mandate coverage for autism spectrum disorder (ASD) health services, families in high-deductible health plans (HDHPs) access ASD-related services without paying more out-of-pocket expenses than traditional plan enrollees, an analysis found.

copyright teekid/iStockphoto

Lead author Colleen L. Barry, PhD, of Johns Hopkins University, Baltimore, and colleagues examined insurance claims between 2008 and 2012 for children covered by three large U.S. insurers (United Healthcare, Aetna, and Humana) to compare the effects of ASD-related coverage mandates on health spending. At least 47 states and Washington, D.C., have enacted mandates that require insurers to cover ASD-related health services, such as diagnostic and assessment services and behavioral and functional therapies. The final study sample included 98,639 children aged 0-21 years with at least two ASD-related service claims on different days during the study period.

The investigators found that, among HDHP enrollees, coverage mandates were associated with marked increases in average monthly spending across all service categories, but not among traditional plan enrollees. Specifically for HDHP patients, ASD coverage mandates were linked to a $98 greater increase in average monthly spending for insurers on ASD-specific outpatient services, a $142 greater increase in average monthly insurer spending on all outpatient services, and a $142 greater increase in average monthly insurer spending on all health services, according to the study published in Pediatrics. Out-of-pocket spending by patients however, was not significantly different between HDHP and traditional plan enrollees in states that mandate ASD-related coverage, the study found.

Dr. Barry and associates concluded that patients in both HDHP and traditional insurance plans spend large sums on ASD-related care in coverage mandate states, but because costs likely exceed HDHP deductibles, insurers absorb any increases. They suggested that families with regularly high health care expenditures related to ASD services consider high-deductible plans in the context of mandate laws.

“Future research is needed to better understand how features of HDHPs, such as deductible size and health savings account structure, influence the ability of families to make wise choices in obtaining care, and to examine plan premiums and financial strain associated with these plans, particularly for families with children with ASD and high expenditures,” Dr. Barry and associates wrote.

The authors reported no relevant financial disclosures. The study was supported by a National Institute of Mental Health grant and funded by the National Institutes of Health.
 

[email protected]

SOURCE: Barry CL et al. Pediatrics. 2019 May 13. doi: 10.1542/peds.2018-2391.

SILVER SPRING, MD. – Daiichi Sankyo failed to make the case for approval of its investigational tyrosine kinase inhibitor quizartinib for patients with acute myeloid leukemia bearing the FLT3 internal tandem duplication (ITD) mutation.

Members of the Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted 8-3 not to recommend approval of the drug at this time, despite the prevailing sentiment among oncologists on the panel that, as one stated, “I need this drug. I want this drug.”

The prevailing majority of committee members agreed that the drug may have a place in the treatment of patients with FLT3-mutated AML, but that more robust data were needed to prove it.

Currently, only one agent, gilteritinib (Xospata) is approved by the FDA for the treatment of patients with relapsed or refractory FLT3-mutated AML.

QuANTUM-R

Daiichi Sankyo sought approval for quizartinib based on results of the phase 3 randomized QuANTUM-R trial. In this trial, single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – of patients with relapsed/refractory FLT3-ITD positive AML.

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177).

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to hematopoietic stem cell transplant (HSCT).

Principal investigator Jorge Cortes, MD, from the University of Texas MD Anderson Cancer Center in Houston, speaking in support of the application, said that combined with the phase 2 study results, “these data support a clear and clinically meaningful benefit of quizartinib in this patient population.”

Mark Levis, MD. PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, also spoke in support of the FLT3 inhibitor.

“I have studied both in the lab and in the clinic most FLT3 inhibitors that have been developed, including lestaurtinib, midostaurin, sorafenib and gilteritinib. Quizartinib is the most highly potent and selective FLT3 inhibitor I have ever worked with,” Dr. Levis said.

FDA: Data not up to snuff

But as FDA staff member Kunthel By, PhD, a statistical reviewer in the Office of Biostatistics, pointed out, the upper limit of the hazard ratio favoring quizartinib over chemotherapy was 0.99, and the difference in median overall survival was just 6.5 weeks.

Additionally, the trial data lacked internal consistency, showing no benefits for the drug in either event-free survival (EFS) or in complete response rates.

There were also imbalances in the number of patients with subsequent HSCT between the arms, with more patients on quizartinib undergoing HSCT despite not having a complete remission, than in the chemotherapy group. Also, there were differences in the number of patients who were randomized but not treated and in those censored early. And statistical stress tests indicated “a lack of robustness in the estimated treatment effect,” he said.

Safety issues raised in QuANTUM-R included slow potassium channel (IKs) blockade and related cardiac toxicitites, as well as the differentiation syndrome, acute febrile neutrophilic dermatosis, and cytopenias, said Aviva Krauss, MD, a clinical reviewer in the FDA’s Office of Hematology and Oncology Products.

“Quizartinib therapy is associated with significant and unique safety concerns in the [proposed population], including the risk of fatal cardiac events that cannot be predicted with certainty using routine QTc measurements,” she said.

She noted that the events occurred in QuANTUM-R despite dose modifications and concomitant medications guidelines in the study protocol.

Reviewers recommended that should the drug receive approval, the package labeling should include contraindication for use with other QT-prolonging agents, and a recommendation for prophylactic beta blockage, although the panelists in general felt that the latter recommendation was not necessary.

‘I believe in this drug’

The ODAC meeting was convened to answer questions about whether the overall survival results were credible based on a single clinical trial and outweighed the risks of treatment with quizartinib, and to assess risk strategies for reducing risks of potentially fatal cardiac toxicities, primarily prolongation of the QT interval.

A. Michael Lincoff, MD, a cardiologist at Case Western Reserve University and the Cleveland Clinic, both in Cleveland, Ohio, voted in favor of approval.

“I’m less concerned about the risk and I do think on the balance there is benefit,” he said.

But most committee members echoed the comments of Anthony D. Sung, MD, from the division of hematologic malignancies and cellular therapy at Duke University in Durham, N.C.

“My vote is based purely on the data I’m shown, and my vote is no,” he said. “But I want the FDA to know that I believe in this drug, and I think it should get approved, and I want to use it.”

The trial was sponsored by Daiichi Sankyo. Dr. Cortes reported research funding from Daiichi Sankyo, Pfizer, Arog, Astellas Pharma and Novartis, and consulting activities for all of the same companies except Arog. Dr. Levis is a paid consultant for Daiichi Sankyo. He and Dr. Cortes stated that they had no financial interests in the outcome of the ODAC meeting.

SILVER SPRING, MD. – Daiichi Sankyo failed to make the case for approval of its investigational tyrosine kinase inhibitor quizartinib for patients with acute myeloid leukemia bearing the FLT3 internal tandem duplication (ITD) mutation.

Members of the Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted 8-3 not to recommend approval of the drug at this time, despite the prevailing sentiment among oncologists on the panel that, as one stated, “I need this drug. I want this drug.”

The prevailing majority of committee members agreed that the drug may have a place in the treatment of patients with FLT3-mutated AML, but that more robust data were needed to prove it.

Currently, only one agent, gilteritinib (Xospata) is approved by the FDA for the treatment of patients with relapsed or refractory FLT3-mutated AML.

QuANTUM-R

Daiichi Sankyo sought approval for quizartinib based on results of the phase 3 randomized QuANTUM-R trial. In this trial, single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – of patients with relapsed/refractory FLT3-ITD positive AML.

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177).

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to hematopoietic stem cell transplant (HSCT).

Principal investigator Jorge Cortes, MD, from the University of Texas MD Anderson Cancer Center in Houston, speaking in support of the application, said that combined with the phase 2 study results, “these data support a clear and clinically meaningful benefit of quizartinib in this patient population.”

Mark Levis, MD. PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, also spoke in support of the FLT3 inhibitor.

“I have studied both in the lab and in the clinic most FLT3 inhibitors that have been developed, including lestaurtinib, midostaurin, sorafenib and gilteritinib. Quizartinib is the most highly potent and selective FLT3 inhibitor I have ever worked with,” Dr. Levis said.

FDA: Data not up to snuff

But as FDA staff member Kunthel By, PhD, a statistical reviewer in the Office of Biostatistics, pointed out, the upper limit of the hazard ratio favoring quizartinib over chemotherapy was 0.99, and the difference in median overall survival was just 6.5 weeks.

Additionally, the trial data lacked internal consistency, showing no benefits for the drug in either event-free survival (EFS) or in complete response rates.

There were also imbalances in the number of patients with subsequent HSCT between the arms, with more patients on quizartinib undergoing HSCT despite not having a complete remission, than in the chemotherapy group. Also, there were differences in the number of patients who were randomized but not treated and in those censored early. And statistical stress tests indicated “a lack of robustness in the estimated treatment effect,” he said.

Safety issues raised in QuANTUM-R included slow potassium channel (IKs) blockade and related cardiac toxicitites, as well as the differentiation syndrome, acute febrile neutrophilic dermatosis, and cytopenias, said Aviva Krauss, MD, a clinical reviewer in the FDA’s Office of Hematology and Oncology Products.

“Quizartinib therapy is associated with significant and unique safety concerns in the [proposed population], including the risk of fatal cardiac events that cannot be predicted with certainty using routine QTc measurements,” she said.

She noted that the events occurred in QuANTUM-R despite dose modifications and concomitant medications guidelines in the study protocol.

Reviewers recommended that should the drug receive approval, the package labeling should include contraindication for use with other QT-prolonging agents, and a recommendation for prophylactic beta blockage, although the panelists in general felt that the latter recommendation was not necessary.

‘I believe in this drug’

The ODAC meeting was convened to answer questions about whether the overall survival results were credible based on a single clinical trial and outweighed the risks of treatment with quizartinib, and to assess risk strategies for reducing risks of potentially fatal cardiac toxicities, primarily prolongation of the QT interval.

A. Michael Lincoff, MD, a cardiologist at Case Western Reserve University and the Cleveland Clinic, both in Cleveland, Ohio, voted in favor of approval.

“I’m less concerned about the risk and I do think on the balance there is benefit,” he said.

But most committee members echoed the comments of Anthony D. Sung, MD, from the division of hematologic malignancies and cellular therapy at Duke University in Durham, N.C.

“My vote is based purely on the data I’m shown, and my vote is no,” he said. “But I want the FDA to know that I believe in this drug, and I think it should get approved, and I want to use it.”

The trial was sponsored by Daiichi Sankyo. Dr. Cortes reported research funding from Daiichi Sankyo, Pfizer, Arog, Astellas Pharma and Novartis, and consulting activities for all of the same companies except Arog. Dr. Levis is a paid consultant for Daiichi Sankyo. He and Dr. Cortes stated that they had no financial interests in the outcome of the ODAC meeting.

SILVER SPRING, MD. – Daiichi Sankyo failed to make the case for approval of its investigational tyrosine kinase inhibitor quizartinib for patients with acute myeloid leukemia bearing the FLT3 internal tandem duplication (ITD) mutation.

Members of the Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted 8-3 not to recommend approval of the drug at this time, despite the prevailing sentiment among oncologists on the panel that, as one stated, “I need this drug. I want this drug.”

The prevailing majority of committee members agreed that the drug may have a place in the treatment of patients with FLT3-mutated AML, but that more robust data were needed to prove it.

Currently, only one agent, gilteritinib (Xospata) is approved by the FDA for the treatment of patients with relapsed or refractory FLT3-mutated AML.

QuANTUM-R

Daiichi Sankyo sought approval for quizartinib based on results of the phase 3 randomized QuANTUM-R trial. In this trial, single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – of patients with relapsed/refractory FLT3-ITD positive AML.

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177).

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to hematopoietic stem cell transplant (HSCT).

Principal investigator Jorge Cortes, MD, from the University of Texas MD Anderson Cancer Center in Houston, speaking in support of the application, said that combined with the phase 2 study results, “these data support a clear and clinically meaningful benefit of quizartinib in this patient population.”

Mark Levis, MD. PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, also spoke in support of the FLT3 inhibitor.

“I have studied both in the lab and in the clinic most FLT3 inhibitors that have been developed, including lestaurtinib, midostaurin, sorafenib and gilteritinib. Quizartinib is the most highly potent and selective FLT3 inhibitor I have ever worked with,” Dr. Levis said.

FDA: Data not up to snuff

But as FDA staff member Kunthel By, PhD, a statistical reviewer in the Office of Biostatistics, pointed out, the upper limit of the hazard ratio favoring quizartinib over chemotherapy was 0.99, and the difference in median overall survival was just 6.5 weeks.

Additionally, the trial data lacked internal consistency, showing no benefits for the drug in either event-free survival (EFS) or in complete response rates.

There were also imbalances in the number of patients with subsequent HSCT between the arms, with more patients on quizartinib undergoing HSCT despite not having a complete remission, than in the chemotherapy group. Also, there were differences in the number of patients who were randomized but not treated and in those censored early. And statistical stress tests indicated “a lack of robustness in the estimated treatment effect,” he said.

Safety issues raised in QuANTUM-R included slow potassium channel (IKs) blockade and related cardiac toxicitites, as well as the differentiation syndrome, acute febrile neutrophilic dermatosis, and cytopenias, said Aviva Krauss, MD, a clinical reviewer in the FDA’s Office of Hematology and Oncology Products.

“Quizartinib therapy is associated with significant and unique safety concerns in the [proposed population], including the risk of fatal cardiac events that cannot be predicted with certainty using routine QTc measurements,” she said.

She noted that the events occurred in QuANTUM-R despite dose modifications and concomitant medications guidelines in the study protocol.

Reviewers recommended that should the drug receive approval, the package labeling should include contraindication for use with other QT-prolonging agents, and a recommendation for prophylactic beta blockage, although the panelists in general felt that the latter recommendation was not necessary.

‘I believe in this drug’

The ODAC meeting was convened to answer questions about whether the overall survival results were credible based on a single clinical trial and outweighed the risks of treatment with quizartinib, and to assess risk strategies for reducing risks of potentially fatal cardiac toxicities, primarily prolongation of the QT interval.

A. Michael Lincoff, MD, a cardiologist at Case Western Reserve University and the Cleveland Clinic, both in Cleveland, Ohio, voted in favor of approval.

“I’m less concerned about the risk and I do think on the balance there is benefit,” he said.

But most committee members echoed the comments of Anthony D. Sung, MD, from the division of hematologic malignancies and cellular therapy at Duke University in Durham, N.C.

“My vote is based purely on the data I’m shown, and my vote is no,” he said. “But I want the FDA to know that I believe in this drug, and I think it should get approved, and I want to use it.”

The trial was sponsored by Daiichi Sankyo. Dr. Cortes reported research funding from Daiichi Sankyo, Pfizer, Arog, Astellas Pharma and Novartis, and consulting activities for all of the same companies except Arog. Dr. Levis is a paid consultant for Daiichi Sankyo. He and Dr. Cortes stated that they had no financial interests in the outcome of the ODAC meeting.

MADISON, WISC. – Only half of United States veterans with inflammatory arthritis received disease-modifying medication within 90 days of diagnosis if they received care within the Veterans Health Administration, according to a study presented at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Over the study period, 58.2% of all inflammatory arthritis patients began a disease-modifying antirheumatic drug (DMARD) within 12 months of diagnosis. Rates of DMARD initiation were similar for patients with rheumatoid arthritis (RA, 57.7%) and psoriatic arthritis (PsA, 64.3%), said the first author of the poster presentation, Sogol S. Amjadi, DO, a resident physician at Bingham Memorial Hospital, Blackfoot, Idaho.

However, at 12 months after diagnosis, only 29.6% of ankylosing spondylitis (AS) patients had not been started on a DMARD. “The ankylosing spondylitis group really had the lowest DMARD initiation over time,” said Dr. Amjadi in an interview.

The study used diagnosis codes and natural language processing to look for incident cases of the three inflammatory arthritides (IAs) among patients receiving care within the Veterans Health Administration from 2007 through 2015.

In all, 12,118 patients with incident IA were identified. Of these, 9,711 had RA, 1,472 had PsA, and 935 had AS. Patients were mostly (91.3%) male, with a mean age of 63.7 years.

Over the study period, 41.2% of IA patients were dispensed a DMARD within 30 days of diagnosis, and 50% received a DMARD within 90 days of diagnosis. Patients with PsA or RA had similar rates of DMARD prescription within 30 days of diagnosis (about 42% and 43%, respectively).

The investigators discovered in their analysis that another factor in prompt treatment was access to specialty care.“Timely access to a rheumatology provider is likely important for early DMARD treatment,” wrote Dr. Amjadi and her coauthors in the poster accompanying the presentation. Of patients who did receive a DMARD, 82.7% had received rheumatology specialty care before nonbiologic DMARD dispensing, as had 90.0% of patients receiving biologic DMARDs. Over the entire study period, about 10% of all IA patients had biologic DMARD exposure.

There was a trend over time for increased DMARD dispensing, said the investigators. “The percentage of IA patients with DMARD exposure during the 12-month follow-up period increased from 48.8% in 2008 to 66.4% in 2015.”

For AS patients, early DMARD prescribing rates rose from about 20% in 2007 to nearly 30% in 2015. “DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in patients with AS,” wrote the investigators. “Delays in treatment for inflammatory arthritis are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability.”

The authors reported no conflicts of interest and no outside sources of funding.

[email protected]

MADISON, WISC. – Only half of United States veterans with inflammatory arthritis received disease-modifying medication within 90 days of diagnosis if they received care within the Veterans Health Administration, according to a study presented at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Over the study period, 58.2% of all inflammatory arthritis patients began a disease-modifying antirheumatic drug (DMARD) within 12 months of diagnosis. Rates of DMARD initiation were similar for patients with rheumatoid arthritis (RA, 57.7%) and psoriatic arthritis (PsA, 64.3%), said the first author of the poster presentation, Sogol S. Amjadi, DO, a resident physician at Bingham Memorial Hospital, Blackfoot, Idaho.

However, at 12 months after diagnosis, only 29.6% of ankylosing spondylitis (AS) patients had not been started on a DMARD. “The ankylosing spondylitis group really had the lowest DMARD initiation over time,” said Dr. Amjadi in an interview.

The study used diagnosis codes and natural language processing to look for incident cases of the three inflammatory arthritides (IAs) among patients receiving care within the Veterans Health Administration from 2007 through 2015.

In all, 12,118 patients with incident IA were identified. Of these, 9,711 had RA, 1,472 had PsA, and 935 had AS. Patients were mostly (91.3%) male, with a mean age of 63.7 years.

Over the study period, 41.2% of IA patients were dispensed a DMARD within 30 days of diagnosis, and 50% received a DMARD within 90 days of diagnosis. Patients with PsA or RA had similar rates of DMARD prescription within 30 days of diagnosis (about 42% and 43%, respectively).

The investigators discovered in their analysis that another factor in prompt treatment was access to specialty care.“Timely access to a rheumatology provider is likely important for early DMARD treatment,” wrote Dr. Amjadi and her coauthors in the poster accompanying the presentation. Of patients who did receive a DMARD, 82.7% had received rheumatology specialty care before nonbiologic DMARD dispensing, as had 90.0% of patients receiving biologic DMARDs. Over the entire study period, about 10% of all IA patients had biologic DMARD exposure.

There was a trend over time for increased DMARD dispensing, said the investigators. “The percentage of IA patients with DMARD exposure during the 12-month follow-up period increased from 48.8% in 2008 to 66.4% in 2015.”

For AS patients, early DMARD prescribing rates rose from about 20% in 2007 to nearly 30% in 2015. “DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in patients with AS,” wrote the investigators. “Delays in treatment for inflammatory arthritis are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability.”

The authors reported no conflicts of interest and no outside sources of funding.

[email protected]

MADISON, WISC. – Only half of United States veterans with inflammatory arthritis received disease-modifying medication within 90 days of diagnosis if they received care within the Veterans Health Administration, according to a study presented at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Over the study period, 58.2% of all inflammatory arthritis patients began a disease-modifying antirheumatic drug (DMARD) within 12 months of diagnosis. Rates of DMARD initiation were similar for patients with rheumatoid arthritis (RA, 57.7%) and psoriatic arthritis (PsA, 64.3%), said the first author of the poster presentation, Sogol S. Amjadi, DO, a resident physician at Bingham Memorial Hospital, Blackfoot, Idaho.

However, at 12 months after diagnosis, only 29.6% of ankylosing spondylitis (AS) patients had not been started on a DMARD. “The ankylosing spondylitis group really had the lowest DMARD initiation over time,” said Dr. Amjadi in an interview.

The study used diagnosis codes and natural language processing to look for incident cases of the three inflammatory arthritides (IAs) among patients receiving care within the Veterans Health Administration from 2007 through 2015.

In all, 12,118 patients with incident IA were identified. Of these, 9,711 had RA, 1,472 had PsA, and 935 had AS. Patients were mostly (91.3%) male, with a mean age of 63.7 years.

Over the study period, 41.2% of IA patients were dispensed a DMARD within 30 days of diagnosis, and 50% received a DMARD within 90 days of diagnosis. Patients with PsA or RA had similar rates of DMARD prescription within 30 days of diagnosis (about 42% and 43%, respectively).

The investigators discovered in their analysis that another factor in prompt treatment was access to specialty care.“Timely access to a rheumatology provider is likely important for early DMARD treatment,” wrote Dr. Amjadi and her coauthors in the poster accompanying the presentation. Of patients who did receive a DMARD, 82.7% had received rheumatology specialty care before nonbiologic DMARD dispensing, as had 90.0% of patients receiving biologic DMARDs. Over the entire study period, about 10% of all IA patients had biologic DMARD exposure.

There was a trend over time for increased DMARD dispensing, said the investigators. “The percentage of IA patients with DMARD exposure during the 12-month follow-up period increased from 48.8% in 2008 to 66.4% in 2015.”

For AS patients, early DMARD prescribing rates rose from about 20% in 2007 to nearly 30% in 2015. “DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in patients with AS,” wrote the investigators. “Delays in treatment for inflammatory arthritis are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability.”

The authors reported no conflicts of interest and no outside sources of funding.

[email protected]

Novartis has recalled three lots of 12.5-mg eltrombopag (Promacta) for oral suspension following discovery of possible contamination with peanut flour at a third-party manufacturing site.

Tablets at doses of 12.5 mg, 25 mg, 50 mg, and 75 mg are unaffected by this recall because they are not manufactured in the same facility. The recalled lots of medication were distributed between January and April 2019, but so far, Novartis has not received any reports of adverse events related to the recall.

Oral suspension of eltrombopag is indicated for certain patients with chronic immune thrombocytopenia, hepatitis C–associated thrombocytopenia, and severe aplastic anemia.

More information on the recalled lots and instructions on how to return the product can be found in the full announcement, which is also available through the Food and Drug Administration website.

[email protected]

Novartis has recalled three lots of 12.5-mg eltrombopag (Promacta) for oral suspension following discovery of possible contamination with peanut flour at a third-party manufacturing site.

Tablets at doses of 12.5 mg, 25 mg, 50 mg, and 75 mg are unaffected by this recall because they are not manufactured in the same facility. The recalled lots of medication were distributed between January and April 2019, but so far, Novartis has not received any reports of adverse events related to the recall.

Oral suspension of eltrombopag is indicated for certain patients with chronic immune thrombocytopenia, hepatitis C–associated thrombocytopenia, and severe aplastic anemia.

More information on the recalled lots and instructions on how to return the product can be found in the full announcement, which is also available through the Food and Drug Administration website.

[email protected]

Novartis has recalled three lots of 12.5-mg eltrombopag (Promacta) for oral suspension following discovery of possible contamination with peanut flour at a third-party manufacturing site.

Tablets at doses of 12.5 mg, 25 mg, 50 mg, and 75 mg are unaffected by this recall because they are not manufactured in the same facility. The recalled lots of medication were distributed between January and April 2019, but so far, Novartis has not received any reports of adverse events related to the recall.

Oral suspension of eltrombopag is indicated for certain patients with chronic immune thrombocytopenia, hepatitis C–associated thrombocytopenia, and severe aplastic anemia.

More information on the recalled lots and instructions on how to return the product can be found in the full announcement, which is also available through the Food and Drug Administration website.

[email protected]

LOS ANGELES – In the opinion of Felicia Cosman, MD, the current state of osteoporosis treatment is fraught with clinical challenges.

First, most patients at highest risk for future fractures are not being treated. “In fact, fewer than 25% of patients with new clinical fractures are treated for their underlying disease,” Dr. Cosman, professor of medicine at Columbia University, New York, said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“One of the reasons doctors are not treating these patients is that many of them do not have a T-score in the osteoporosis range. There’s a misunderstanding here. A fracture that occurs in people with low bone mass in the setting of minimal trauma – such as a fall from standing height – meets the criteria for the clinical diagnosis of osteoporosis and qualifies a person for being at high risk of more fractures. This is likely because bone weakness or fragility is related not just to quantitative aspects, but also to structural and qualitative aspects that cannot be measured as easily.”

Another problem is that some of the highest-risk patients are those with a vertebral fracture. “However, vertebral fractures are particularly difficult to find and treat because they’re often asymptomatic and we’re not [identifying] these patients,” she said. “Targeted screening [with] spine imaging to find vertebral fractures is probably as important as BMD [bone mineral density] testing.”

To complicate matters, Dr. Cosman said that clinicians and patients “misunderstand the balance between benefits and risks of osteoporosis medications and they don’t consider the risk of not treating the underlying disease. Lastly, there’s little evidence to help guide long-term strategies. Guidelines across medical specialties are incredibly inconsistent. With the exception of guidelines from AACE, the one thing that they’re very consistent about is underrecognizing the value of anabolic therapy for people with severe osteoporosis.”

It is well known that previous bone fracture is the most important risk factor for a future fracture, but the recency of the fracture is also important. In a recent study, researchers followed 377,561 female Medicare beneficiaries with a first fracture for up to 5 years (Osteoporos Int. 2019;30[1]:79-92). They found that at 1 year, the risk of another fracture was 10%. The fracture risk rose to 18% at 2 years, and to 31% at 5 years. “I like to think of this as the osteoporosis emergency,” said Dr. Cosman, co–editor-in-chief of Osteoporosis International. “We need to treat these people right away to prevent more fractures and related disability, morbidity, and mortality.”

According to data from pivotal trials, the anabolic agents teriparatide, abaloparatide, and romosozumab appear to produce more rapid and larger effects against all fractures, compared with even the best antiresorptive agents. “However, comparing across studies can be problematic, because the different populations have varying baseline characteristics and different underlying risk,” Dr. Cosman said. “The protocols and the outcome definitions might be different. It’s better to compare anabolic agents with antiresorptive agents in head-to-head trials, and we now have a few of these.”

Two trials are older studies in which fracture outcomes were not the primary endpoints. One study evaluated a population of patients with glucocorticoid-induced osteoporosis and found that over 18 months, teriparatide reduced vertebral fractures by 90%, compared with alendronate (N Engl J Med. 2007;357[20]:2028-39). The other trial focused on a population of patients with acute, painful vertebral fractures. It found that over 1 year, teriparatide reduced vertebral fractures by 50%, compared with risedronate (Osteoporos Int. 2012;23[8]:2141-50). Two more recent studies compared anabolic and antiresorptive therapies on fracture outcomes as primary endpoints in patients with prevalent fractures. The VERO trial compared teriparatide with risedronate (Lancet. 2018;391[10117]:230-40), and ARCH compared romosozumab with alendronate (N Engl J Med. 2017;377[15]:1417-27).

In VERO, 1,360 patients with a prevalent vertebral fracture were randomized to receive teriparatide or risedronate for 2 years. At 12 months, the proportion of patients with a new vertebral fracture was 3.1% and 6% in the teriparatide and risedronate groups, respectively, a pattern that held true at 24 months (6.4% vs. 12%). The study also showed that the number of nonvertebral fractures was significantly lower in teriparatide-treated patients, compared with those on risedronate. In ARCH, 4,093 postmenopausal women at high risk of fracture were randomized to receive romosozumab or alendronate for 1 year and then followed for a median period of 33 months. At 12 months, the proportion of patients with a new vertebral fracture was 4% and 6.3% in the romosozumab and alendronate groups, respectively, a pattern that held true at 24 months (6.2% vs. 11.9%).

“These trials showed that the antifracture effects are faster and larger with anabolic agents, compared with antiresorptive agents,” Dr. Cosman said. “They also showed that antifracture effects are sustained after transition to antiresorptive therapy.” In ARCH, both nonvertebral and hip fracture incidences were lower in the romosozumab group, compared with the alendronate group.

The trials demonstrated that improving total hip BMD is associated with improved bone strength and resistance to fracture, yet treatment sequence matters. “The greatest BMD gains of the hip are seen when anabolic agents are used first-line, followed by a potent antiresorptive agent,” she said.

Dr. Cosman offered a strategy for patients on potent antiresorptive agents who need anabolic medication. In patients on bisphosphonates, especially with an incident hip fracture or very low hip BMD, consider combination therapy with initiation of teriparatide or abaloparatide, along with an antiresorptive agent. “There are very little data addressing patients on denosumab, but I would suggest perhaps adding teriparatide or abaloparatide in this population, and continuing denosumab,” she said. “That could lead to BMD gain. Switching to romosozumab might also be an option. But, if possible, use an anabolic agent first. The role of anabolic medication for osteoporosis is evolving as evidence continues to suggest superior benefit of anabolic-first regimens for high-risk patients.”

Dr. Cosman disclosed that she has received advising, consulting, and speaking fees from Amgen and Radius. She has received consulting fees from Tarsa and research grants and medication from Amgen.

[email protected]

LOS ANGELES – In the opinion of Felicia Cosman, MD, the current state of osteoporosis treatment is fraught with clinical challenges.

First, most patients at highest risk for future fractures are not being treated. “In fact, fewer than 25% of patients with new clinical fractures are treated for their underlying disease,” Dr. Cosman, professor of medicine at Columbia University, New York, said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“One of the reasons doctors are not treating these patients is that many of them do not have a T-score in the osteoporosis range. There’s a misunderstanding here. A fracture that occurs in people with low bone mass in the setting of minimal trauma – such as a fall from standing height – meets the criteria for the clinical diagnosis of osteoporosis and qualifies a person for being at high risk of more fractures. This is likely because bone weakness or fragility is related not just to quantitative aspects, but also to structural and qualitative aspects that cannot be measured as easily.”

Another problem is that some of the highest-risk patients are those with a vertebral fracture. “However, vertebral fractures are particularly difficult to find and treat because they’re often asymptomatic and we’re not [identifying] these patients,” she said. “Targeted screening [with] spine imaging to find vertebral fractures is probably as important as BMD [bone mineral density] testing.”

To complicate matters, Dr. Cosman said that clinicians and patients “misunderstand the balance between benefits and risks of osteoporosis medications and they don’t consider the risk of not treating the underlying disease. Lastly, there’s little evidence to help guide long-term strategies. Guidelines across medical specialties are incredibly inconsistent. With the exception of guidelines from AACE, the one thing that they’re very consistent about is underrecognizing the value of anabolic therapy for people with severe osteoporosis.”

It is well known that previous bone fracture is the most important risk factor for a future fracture, but the recency of the fracture is also important. In a recent study, researchers followed 377,561 female Medicare beneficiaries with a first fracture for up to 5 years (Osteoporos Int. 2019;30[1]:79-92). They found that at 1 year, the risk of another fracture was 10%. The fracture risk rose to 18% at 2 years, and to 31% at 5 years. “I like to think of this as the osteoporosis emergency,” said Dr. Cosman, co–editor-in-chief of Osteoporosis International. “We need to treat these people right away to prevent more fractures and related disability, morbidity, and mortality.”

According to data from pivotal trials, the anabolic agents teriparatide, abaloparatide, and romosozumab appear to produce more rapid and larger effects against all fractures, compared with even the best antiresorptive agents. “However, comparing across studies can be problematic, because the different populations have varying baseline characteristics and different underlying risk,” Dr. Cosman said. “The protocols and the outcome definitions might be different. It’s better to compare anabolic agents with antiresorptive agents in head-to-head trials, and we now have a few of these.”

Two trials are older studies in which fracture outcomes were not the primary endpoints. One study evaluated a population of patients with glucocorticoid-induced osteoporosis and found that over 18 months, teriparatide reduced vertebral fractures by 90%, compared with alendronate (N Engl J Med. 2007;357[20]:2028-39). The other trial focused on a population of patients with acute, painful vertebral fractures. It found that over 1 year, teriparatide reduced vertebral fractures by 50%, compared with risedronate (Osteoporos Int. 2012;23[8]:2141-50). Two more recent studies compared anabolic and antiresorptive therapies on fracture outcomes as primary endpoints in patients with prevalent fractures. The VERO trial compared teriparatide with risedronate (Lancet. 2018;391[10117]:230-40), and ARCH compared romosozumab with alendronate (N Engl J Med. 2017;377[15]:1417-27).

In VERO, 1,360 patients with a prevalent vertebral fracture were randomized to receive teriparatide or risedronate for 2 years. At 12 months, the proportion of patients with a new vertebral fracture was 3.1% and 6% in the teriparatide and risedronate groups, respectively, a pattern that held true at 24 months (6.4% vs. 12%). The study also showed that the number of nonvertebral fractures was significantly lower in teriparatide-treated patients, compared with those on risedronate. In ARCH, 4,093 postmenopausal women at high risk of fracture were randomized to receive romosozumab or alendronate for 1 year and then followed for a median period of 33 months. At 12 months, the proportion of patients with a new vertebral fracture was 4% and 6.3% in the romosozumab and alendronate groups, respectively, a pattern that held true at 24 months (6.2% vs. 11.9%).

“These trials showed that the antifracture effects are faster and larger with anabolic agents, compared with antiresorptive agents,” Dr. Cosman said. “They also showed that antifracture effects are sustained after transition to antiresorptive therapy.” In ARCH, both nonvertebral and hip fracture incidences were lower in the romosozumab group, compared with the alendronate group.

The trials demonstrated that improving total hip BMD is associated with improved bone strength and resistance to fracture, yet treatment sequence matters. “The greatest BMD gains of the hip are seen when anabolic agents are used first-line, followed by a potent antiresorptive agent,” she said.

Dr. Cosman offered a strategy for patients on potent antiresorptive agents who need anabolic medication. In patients on bisphosphonates, especially with an incident hip fracture or very low hip BMD, consider combination therapy with initiation of teriparatide or abaloparatide, along with an antiresorptive agent. “There are very little data addressing patients on denosumab, but I would suggest perhaps adding teriparatide or abaloparatide in this population, and continuing denosumab,” she said. “That could lead to BMD gain. Switching to romosozumab might also be an option. But, if possible, use an anabolic agent first. The role of anabolic medication for osteoporosis is evolving as evidence continues to suggest superior benefit of anabolic-first regimens for high-risk patients.”

Dr. Cosman disclosed that she has received advising, consulting, and speaking fees from Amgen and Radius. She has received consulting fees from Tarsa and research grants and medication from Amgen.

[email protected]

LOS ANGELES – In the opinion of Felicia Cosman, MD, the current state of osteoporosis treatment is fraught with clinical challenges.

First, most patients at highest risk for future fractures are not being treated. “In fact, fewer than 25% of patients with new clinical fractures are treated for their underlying disease,” Dr. Cosman, professor of medicine at Columbia University, New York, said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“One of the reasons doctors are not treating these patients is that many of them do not have a T-score in the osteoporosis range. There’s a misunderstanding here. A fracture that occurs in people with low bone mass in the setting of minimal trauma – such as a fall from standing height – meets the criteria for the clinical diagnosis of osteoporosis and qualifies a person for being at high risk of more fractures. This is likely because bone weakness or fragility is related not just to quantitative aspects, but also to structural and qualitative aspects that cannot be measured as easily.”

Another problem is that some of the highest-risk patients are those with a vertebral fracture. “However, vertebral fractures are particularly difficult to find and treat because they’re often asymptomatic and we’re not [identifying] these patients,” she said. “Targeted screening [with] spine imaging to find vertebral fractures is probably as important as BMD [bone mineral density] testing.”

To complicate matters, Dr. Cosman said that clinicians and patients “misunderstand the balance between benefits and risks of osteoporosis medications and they don’t consider the risk of not treating the underlying disease. Lastly, there’s little evidence to help guide long-term strategies. Guidelines across medical specialties are incredibly inconsistent. With the exception of guidelines from AACE, the one thing that they’re very consistent about is underrecognizing the value of anabolic therapy for people with severe osteoporosis.”

It is well known that previous bone fracture is the most important risk factor for a future fracture, but the recency of the fracture is also important. In a recent study, researchers followed 377,561 female Medicare beneficiaries with a first fracture for up to 5 years (Osteoporos Int. 2019;30[1]:79-92). They found that at 1 year, the risk of another fracture was 10%. The fracture risk rose to 18% at 2 years, and to 31% at 5 years. “I like to think of this as the osteoporosis emergency,” said Dr. Cosman, co–editor-in-chief of Osteoporosis International. “We need to treat these people right away to prevent more fractures and related disability, morbidity, and mortality.”

According to data from pivotal trials, the anabolic agents teriparatide, abaloparatide, and romosozumab appear to produce more rapid and larger effects against all fractures, compared with even the best antiresorptive agents. “However, comparing across studies can be problematic, because the different populations have varying baseline characteristics and different underlying risk,” Dr. Cosman said. “The protocols and the outcome definitions might be different. It’s better to compare anabolic agents with antiresorptive agents in head-to-head trials, and we now have a few of these.”

Two trials are older studies in which fracture outcomes were not the primary endpoints. One study evaluated a population of patients with glucocorticoid-induced osteoporosis and found that over 18 months, teriparatide reduced vertebral fractures by 90%, compared with alendronate (N Engl J Med. 2007;357[20]:2028-39). The other trial focused on a population of patients with acute, painful vertebral fractures. It found that over 1 year, teriparatide reduced vertebral fractures by 50%, compared with risedronate (Osteoporos Int. 2012;23[8]:2141-50). Two more recent studies compared anabolic and antiresorptive therapies on fracture outcomes as primary endpoints in patients with prevalent fractures. The VERO trial compared teriparatide with risedronate (Lancet. 2018;391[10117]:230-40), and ARCH compared romosozumab with alendronate (N Engl J Med. 2017;377[15]:1417-27).

In VERO, 1,360 patients with a prevalent vertebral fracture were randomized to receive teriparatide or risedronate for 2 years. At 12 months, the proportion of patients with a new vertebral fracture was 3.1% and 6% in the teriparatide and risedronate groups, respectively, a pattern that held true at 24 months (6.4% vs. 12%). The study also showed that the number of nonvertebral fractures was significantly lower in teriparatide-treated patients, compared with those on risedronate. In ARCH, 4,093 postmenopausal women at high risk of fracture were randomized to receive romosozumab or alendronate for 1 year and then followed for a median period of 33 months. At 12 months, the proportion of patients with a new vertebral fracture was 4% and 6.3% in the romosozumab and alendronate groups, respectively, a pattern that held true at 24 months (6.2% vs. 11.9%).

“These trials showed that the antifracture effects are faster and larger with anabolic agents, compared with antiresorptive agents,” Dr. Cosman said. “They also showed that antifracture effects are sustained after transition to antiresorptive therapy.” In ARCH, both nonvertebral and hip fracture incidences were lower in the romosozumab group, compared with the alendronate group.

The trials demonstrated that improving total hip BMD is associated with improved bone strength and resistance to fracture, yet treatment sequence matters. “The greatest BMD gains of the hip are seen when anabolic agents are used first-line, followed by a potent antiresorptive agent,” she said.

Dr. Cosman offered a strategy for patients on potent antiresorptive agents who need anabolic medication. In patients on bisphosphonates, especially with an incident hip fracture or very low hip BMD, consider combination therapy with initiation of teriparatide or abaloparatide, along with an antiresorptive agent. “There are very little data addressing patients on denosumab, but I would suggest perhaps adding teriparatide or abaloparatide in this population, and continuing denosumab,” she said. “That could lead to BMD gain. Switching to romosozumab might also be an option. But, if possible, use an anabolic agent first. The role of anabolic medication for osteoporosis is evolving as evidence continues to suggest superior benefit of anabolic-first regimens for high-risk patients.”

Dr. Cosman disclosed that she has received advising, consulting, and speaking fees from Amgen and Radius. She has received consulting fees from Tarsa and research grants and medication from Amgen.

[email protected]

BALTIMORE – A study that examined the quality of data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBASQIP) registry found inconsistencies that may undermine the quality of the registry, which could be misleading for clinicians and investigators who used the data, according to an analysis presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons. The researchers recommended ways to improve data-gathering techniques to better identify the nature of these inconsistencies.

“Our original enthusiasm about the availability of data from MBASQIP turned into a cautious optimism about potential usefulness of these data,” Katia Noyes, PhD, of the State University of New York at Buffalo, said in presenting the study. She noted her research team’s analysis of 168,093 cases in the 2015 MBASQIP Participant Use Data File found that 20% of the cases (n = 33,868) had missing or unusable information for at least one key variable, such as age, race, ethnicity, body mass index (BMI) before and after surgery, and American Society of Anesthesiologists classification. Specifically, preoperative and postoperative BMI data were missing or zero in 6.7% of cases (n = 11,211).

The researchers developed a single flat file for patient-level outcomes evaluation using five files (main, BMI, readmission, intervention, and reoperation). They used logic and validity tests that included individual profiles of patient BMI changes over time, individual patient care pathways (chronologic record of patient admission, discharge and procedure history), and correlation tests between pairs of variables associated with the same clinical encounters (emergency intervention vs. procedure type; related admission with intervention vs. planned intervention).

“Weight reduction at the first postoperative visit ranged from –71% to a gain of 132% of preoperative weight,” she said. “We also found inconsistency in the sequence of events. Seven percent of readmissions and 12.5% of postoperative interventions were categorized as planned, which is not a problem, but when you look at the reported reasons for planned procedures, they could not all have been possibly planned before discharge.”

Based on 2015 MBASQIP data, “planned” readmissions and postoperative procedures included admissions for nonspecific abdominal pain, band erosion, slippage or prolapse, bleeding, gastrogastric fistula, incisional hernia, infection and/or fever, pneumonia, and wound infection, among other reasons.

“Our analysis found inconsistent quality of data for key parameters, missing and miscoded values and lack of clarity for coding and definitions,” Dr. Noyes said.

The study made four recommendations to improve the quality of data submitted to MASQIP.

• Use health IT applications to provide automated data checks to validate completeness of submitted data – by utilizing a no-skip pattern for core variables – and accuracy of data– by flagging values outside predefined acceptable ranges.
• Perform data audits for consistency, using multiple variables to conduct logic checks, such as by not allowing “readmission” before discharge for the index admission.
• Give data auditors specific recommendations for definitions of registry variables, standardization of algorithms for abstracting values based on commonly used clinical data systems, such as Allscripts and Epic, and standardized use of diagnostic and procedure codes to link with payers’ reimbursement schedules.
• Provide ongoing education to stakeholders such as researchers and hospital administrators on best data management practices and how to best use the data for quality improvement.

Dr. Noyes had no financial relationships to disclose. Coauthor Steven Schwaitzberg, MD, disclosed consulting arrangements with New View Surgical, AcuityBio, Activ Surgical, Human Extensions, Levita Magnetics, and Arch Therapeutics. Aaron Hoffman, MD, disclosed a consulting arrangement with Ethicon.

SOURCE: Noyes K et al. SAGES 2019, Abstract 21

BALTIMORE – A study that examined the quality of data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBASQIP) registry found inconsistencies that may undermine the quality of the registry, which could be misleading for clinicians and investigators who used the data, according to an analysis presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons. The researchers recommended ways to improve data-gathering techniques to better identify the nature of these inconsistencies.

“Our original enthusiasm about the availability of data from MBASQIP turned into a cautious optimism about potential usefulness of these data,” Katia Noyes, PhD, of the State University of New York at Buffalo, said in presenting the study. She noted her research team’s analysis of 168,093 cases in the 2015 MBASQIP Participant Use Data File found that 20% of the cases (n = 33,868) had missing or unusable information for at least one key variable, such as age, race, ethnicity, body mass index (BMI) before and after surgery, and American Society of Anesthesiologists classification. Specifically, preoperative and postoperative BMI data were missing or zero in 6.7% of cases (n = 11,211).

The researchers developed a single flat file for patient-level outcomes evaluation using five files (main, BMI, readmission, intervention, and reoperation). They used logic and validity tests that included individual profiles of patient BMI changes over time, individual patient care pathways (chronologic record of patient admission, discharge and procedure history), and correlation tests between pairs of variables associated with the same clinical encounters (emergency intervention vs. procedure type; related admission with intervention vs. planned intervention).

“Weight reduction at the first postoperative visit ranged from –71% to a gain of 132% of preoperative weight,” she said. “We also found inconsistency in the sequence of events. Seven percent of readmissions and 12.5% of postoperative interventions were categorized as planned, which is not a problem, but when you look at the reported reasons for planned procedures, they could not all have been possibly planned before discharge.”

Based on 2015 MBASQIP data, “planned” readmissions and postoperative procedures included admissions for nonspecific abdominal pain, band erosion, slippage or prolapse, bleeding, gastrogastric fistula, incisional hernia, infection and/or fever, pneumonia, and wound infection, among other reasons.

“Our analysis found inconsistent quality of data for key parameters, missing and miscoded values and lack of clarity for coding and definitions,” Dr. Noyes said.

The study made four recommendations to improve the quality of data submitted to MASQIP.

• Use health IT applications to provide automated data checks to validate completeness of submitted data – by utilizing a no-skip pattern for core variables – and accuracy of data– by flagging values outside predefined acceptable ranges.
• Perform data audits for consistency, using multiple variables to conduct logic checks, such as by not allowing “readmission” before discharge for the index admission.
• Give data auditors specific recommendations for definitions of registry variables, standardization of algorithms for abstracting values based on commonly used clinical data systems, such as Allscripts and Epic, and standardized use of diagnostic and procedure codes to link with payers’ reimbursement schedules.
• Provide ongoing education to stakeholders such as researchers and hospital administrators on best data management practices and how to best use the data for quality improvement.

Dr. Noyes had no financial relationships to disclose. Coauthor Steven Schwaitzberg, MD, disclosed consulting arrangements with New View Surgical, AcuityBio, Activ Surgical, Human Extensions, Levita Magnetics, and Arch Therapeutics. Aaron Hoffman, MD, disclosed a consulting arrangement with Ethicon.

SOURCE: Noyes K et al. SAGES 2019, Abstract 21

BALTIMORE – A study that examined the quality of data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBASQIP) registry found inconsistencies that may undermine the quality of the registry, which could be misleading for clinicians and investigators who used the data, according to an analysis presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons. The researchers recommended ways to improve data-gathering techniques to better identify the nature of these inconsistencies.

“Our original enthusiasm about the availability of data from MBASQIP turned into a cautious optimism about potential usefulness of these data,” Katia Noyes, PhD, of the State University of New York at Buffalo, said in presenting the study. She noted her research team’s analysis of 168,093 cases in the 2015 MBASQIP Participant Use Data File found that 20% of the cases (n = 33,868) had missing or unusable information for at least one key variable, such as age, race, ethnicity, body mass index (BMI) before and after surgery, and American Society of Anesthesiologists classification. Specifically, preoperative and postoperative BMI data were missing or zero in 6.7% of cases (n = 11,211).

The researchers developed a single flat file for patient-level outcomes evaluation using five files (main, BMI, readmission, intervention, and reoperation). They used logic and validity tests that included individual profiles of patient BMI changes over time, individual patient care pathways (chronologic record of patient admission, discharge and procedure history), and correlation tests between pairs of variables associated with the same clinical encounters (emergency intervention vs. procedure type; related admission with intervention vs. planned intervention).

“Weight reduction at the first postoperative visit ranged from –71% to a gain of 132% of preoperative weight,” she said. “We also found inconsistency in the sequence of events. Seven percent of readmissions and 12.5% of postoperative interventions were categorized as planned, which is not a problem, but when you look at the reported reasons for planned procedures, they could not all have been possibly planned before discharge.”

Based on 2015 MBASQIP data, “planned” readmissions and postoperative procedures included admissions for nonspecific abdominal pain, band erosion, slippage or prolapse, bleeding, gastrogastric fistula, incisional hernia, infection and/or fever, pneumonia, and wound infection, among other reasons.

“Our analysis found inconsistent quality of data for key parameters, missing and miscoded values and lack of clarity for coding and definitions,” Dr. Noyes said.

The study made four recommendations to improve the quality of data submitted to MASQIP.

• Use health IT applications to provide automated data checks to validate completeness of submitted data – by utilizing a no-skip pattern for core variables – and accuracy of data– by flagging values outside predefined acceptable ranges.
• Perform data audits for consistency, using multiple variables to conduct logic checks, such as by not allowing “readmission” before discharge for the index admission.
• Give data auditors specific recommendations for definitions of registry variables, standardization of algorithms for abstracting values based on commonly used clinical data systems, such as Allscripts and Epic, and standardized use of diagnostic and procedure codes to link with payers’ reimbursement schedules.
• Provide ongoing education to stakeholders such as researchers and hospital administrators on best data management practices and how to best use the data for quality improvement.

Dr. Noyes had no financial relationships to disclose. Coauthor Steven Schwaitzberg, MD, disclosed consulting arrangements with New View Surgical, AcuityBio, Activ Surgical, Human Extensions, Levita Magnetics, and Arch Therapeutics. Aaron Hoffman, MD, disclosed a consulting arrangement with Ethicon.

SOURCE: Noyes K et al. SAGES 2019, Abstract 21

Comorbid depression significantly increased hospitalization costs, length of stay, and mortality among pediatric patients, according to a study in the Journal of Affective Disorders.

©drpnncpp/thinkstockphotos.com

The investigators led by Mayowa Olusunmade, MD, MPH, of New Jersey Medical School, Newark, found that, compared with those among nondepressed pediatric patients, hospitalization costs were $2,961 higher (P less than .001), length of stay was 0.89 days longer (P less than .001), and odds of death as an outcome while hospitalized was 1.77 times higher (P = .013) among depressed pediatric patients. On the other hand, depressed patients had 0.3 fewer procedures (P less than .001) than nondepressed patients.

This analysis is based on 17,073 pairs of patients with and without depression that were created through one-to-one propensity score matching. The investigators drew these pairs from an estimated 937,971 patients in the Kids’ Inpatient Database for 2012 who were identified as being aged 6 years and older and having any of the 10 of the most common diagnoses other than affective disorders. The investigators then determined which children among those identified had comorbid depression (2.9%) and which did not (97.1%) to create the propensity score–matched pairs.

One limitation in this study is that the mean age was 17.5 years because depression diagnosis is more atypical among younger patients such that adolescents were disproportionately represented.

The study did not receive funding, and the authors declared there are no conflicts of interest.

[email protected]

SOURCE: Olusunmade M et al. J Affect Disord. 2019 Mar 27. doi: 10.1016/j.jad.2019.03.073.

Comorbid depression significantly increased hospitalization costs, length of stay, and mortality among pediatric patients, according to a study in the Journal of Affective Disorders.

©drpnncpp/thinkstockphotos.com

The investigators led by Mayowa Olusunmade, MD, MPH, of New Jersey Medical School, Newark, found that, compared with those among nondepressed pediatric patients, hospitalization costs were $2,961 higher (P less than .001), length of stay was 0.89 days longer (P less than .001), and odds of death as an outcome while hospitalized was 1.77 times higher (P = .013) among depressed pediatric patients. On the other hand, depressed patients had 0.3 fewer procedures (P less than .001) than nondepressed patients.

This analysis is based on 17,073 pairs of patients with and without depression that were created through one-to-one propensity score matching. The investigators drew these pairs from an estimated 937,971 patients in the Kids’ Inpatient Database for 2012 who were identified as being aged 6 years and older and having any of the 10 of the most common diagnoses other than affective disorders. The investigators then determined which children among those identified had comorbid depression (2.9%) and which did not (97.1%) to create the propensity score–matched pairs.

One limitation in this study is that the mean age was 17.5 years because depression diagnosis is more atypical among younger patients such that adolescents were disproportionately represented.

The study did not receive funding, and the authors declared there are no conflicts of interest.

[email protected]

SOURCE: Olusunmade M et al. J Affect Disord. 2019 Mar 27. doi: 10.1016/j.jad.2019.03.073.

Comorbid depression significantly increased hospitalization costs, length of stay, and mortality among pediatric patients, according to a study in the Journal of Affective Disorders.

©drpnncpp/thinkstockphotos.com

The investigators led by Mayowa Olusunmade, MD, MPH, of New Jersey Medical School, Newark, found that, compared with those among nondepressed pediatric patients, hospitalization costs were $2,961 higher (P less than .001), length of stay was 0.89 days longer (P less than .001), and odds of death as an outcome while hospitalized was 1.77 times higher (P = .013) among depressed pediatric patients. On the other hand, depressed patients had 0.3 fewer procedures (P less than .001) than nondepressed patients.

This analysis is based on 17,073 pairs of patients with and without depression that were created through one-to-one propensity score matching. The investigators drew these pairs from an estimated 937,971 patients in the Kids’ Inpatient Database for 2012 who were identified as being aged 6 years and older and having any of the 10 of the most common diagnoses other than affective disorders. The investigators then determined which children among those identified had comorbid depression (2.9%) and which did not (97.1%) to create the propensity score–matched pairs.

One limitation in this study is that the mean age was 17.5 years because depression diagnosis is more atypical among younger patients such that adolescents were disproportionately represented.

The study did not receive funding, and the authors declared there are no conflicts of interest.

[email protected]

SOURCE: Olusunmade M et al. J Affect Disord. 2019 Mar 27. doi: 10.1016/j.jad.2019.03.073.