Pulmonary Perspectives®

As of 2019, lung cancer remained the leading cause of cancer death in the United States. In March 2021, the USPSTF updated the guidelines for lung cancer screening, increasing the number of eligible patients in order to identify malignancies in the early stages when more treatment options exist. With the growth of lung cancer screening, increasingly smaller pulmonary nodules are being identified in more peripheral locations previously thought to be unreachable with bronchoscopy. While bronchoscopy has been utilized for over a century for therapeutic interventions, the development of the fiberoptic bronchoscope in 1967 ushered in an era of evolving diagnostic functions. From the initial endobronchial and transbronchial biopsy techniques, to the introduction of endobronchial ultrasound, and now the latest navigational and robotic modalities, these advances have opened a new realm of interventions available in our diagnostic approach to lung cancer.

Bronchoscopy has become essential in the diagnosis of thoracic malignancies, providing both diagnostic and staging information in one procedural setting. By first assessing the mediastinal and hilar lymph nodes with endobronchial ultrasound and transbronchial needle aspiration, involved lymph nodes can give both diagnosis and staging information required to guide treatment. This is particularly important in the case of non-small cell lung cancer, which utilizes the TNM staging system. Through the use of convex probe endobronchial ultrasound (CP-EBUS), combined with rapid on-site evaluation (ROSE) by pathologic condition, we can more accurately target the individual lymph nodes for biopsy without the need for any additional procedures that are often more complex and invasive, such as mediastinoscopy. It is important to note the role of CP-EBUS extends beyond the lymph node assessment and can also be utilized for the evaluation of other mediastinal lesions, such as central parenchymal masses. These would otherwise be difficult to access due to the lack of a clear airway to the lesion (Argento and Puchalski. Respir Med. 2016;116:55-8).

While EBUS has improved the sampling of lymph nodes, advanced imaging technologies and subsequent increases in lung cancer screening have increased the number of lung malignancies identified in earlier stages before extension to the lymph nodes occurs. This scenario requires a direct biopsy of the primary nodule or lung mass. While CP-EBUS can be utilized for some central parenchymal lesions, peripheral nodules pose a greater challenge to the bronchoscopist as they cannot be directly visualized with the conventional bronchoscope. These lesions are amenable to traditional sampling techniques such as bronchial brushings and washings in addition to transbronchial needle aspiration and transbronchial biopsy. However, the yield for peripheral lesions is less than that for central tumors and depends on lesion size, distance from hilum, spatial positioning from bronchus, and operator experience. To help localize peripheral lesions, a separate form of endobronchial ultrasound is available that can be used in combination with fluoroscopy to target a lesion. Radial probe endobronchial ultrasound (RP-EBUS) utilizes a rotating ultrasound transducer that can be advanced either through the working channel of the bronchoscope or through a guide sheath to extend to airways beyond what the conventional bronchoscope can reach. This assists the bronchoscopist with locating the correct airway and, therefore, increases the yield of sampling techniques. The use of RP-EBUS has reported diagnostic yields of almost 85% if the ultrasound is located within the lesion, but less than 50% if adjacent to the lesion (Chen et al. Ann Am Thorac Soc. 2014;11[4]:578-82). While this improves the yield beyond that achieved with conventional bronchoscopy alone, it continues to challenge the bronchoscopist to locate an accessible airway from a series of branching bronchi that are beyond the level of direct visualization.

Due to the historical difficulty in accurately reaching peripheral lesions, alternative technologies for sampling these lesions, such as image-guided biopsies or surgical resection, were employed. While CT scan-guided biopsies traditionally have high diagnostic yields, they also carry a higher rate of complications, including pneumothorax and bleeding. This has led to a significant increase over the past 2 decades in new bronchoscopic technologies targeting safer and more accurate sampling of increasingly smaller, peripheral lesions.

Traditionally, any new technologies created were intended to be used alongside flexible fiberoptic bronchoscopy. The more recently introduced technologies, however, aim to provide a safer, more accurate procedure through virtual bronchoscopy. By obtaining CT scan images prior to the procedure, a 3D visualization is constructed of the tracheobronchial tree, allowing for directed guidance of endobronchial accessories to more distal airways. Where the bronchoscopist was previously limited in navigating the bronchial tree to the subsegmental bronchi, virtual bronchoscopy can depict the airways up to the 7th order subdivision. This is a significant improvement in airway visualization – however, only when partnered with guidance technologies can the model be accurately navigated.

One modality that is often coupled with virtual bronchoscopy to accurately reach peripheral lesions is electromagnetic navigation bronchoscopy (ENB). Multiple ENB software systems have been created and continue to be highly utilized by bronchoscopists to target peripheral lesions, as it has often been likened to a GPS for the lungs. With the addition of specific hardware components, a magnetic field is created around the patient where the sensor position can be elicited to within 1-mm accuracy. When overlaid with the CT scan images, the bronchoscopist can have real-time positioning of the probe in all three planes and guide the necessary sampling tools to the lesion of interest. The reported yields for ENB vary but have been shown to increase in the presence of specific image findings such as a positive bronchus sign – an air-filled bronchus leading into the lesion. The presence of this finding can increase the yield up to almost 75% from just under 50% in the absence of a positive bronchus sign. (Ali et al. Ann Am Thorac Soc. 2018;15[8]:978-87). However, regardless of this finding, the overall diagnostic yields for ENB continue to fall below that seen with other image-guided biopsy techniques. The procedural complications, however, are significantly less and, therefore, many physicians continue to advocate for ENB as the initial procedure in attempt to decrease risk for the patient.

The newest technology to be introduced to target peripheral lung lesions and to improve upon the shortcomings of other techniques is robotic-assisted bronchoscopy. While surgical specialties have seen success with robotic techniques over many years, the first robotic bronchoscopy system was not introduced until 2018. At present, there are two systems available: the Monarch^® system by Auris Health and the Ion Endoluminal^® System by Intuitive Surgical. These systems allow for increased bronchoscope stability, improved visualization, adjustable angulation of biopsy tools, and an improved ability to make even subtle turns in the airways. Early studies on both systems were cadaver based, but an increasing number of patient trials are now being reported or actively enrolling. Both systems have shown high rates of lesion localization, greater than 85%, with varying diagnostic yields from 69-79%. Some cadaver studies that utilized artificial tumors reported higher diagnostic yields – over 90% – but this was not seen in initial patient-based studies. (Agrawal et al. J Thorac Dis. 2020;12[6]:3279-86) More data related to the robotic-assisted bronchoscopy systems can be expected in the future as more experience is gained, but initial results are promising in the system’s ability to diagnose early lung cancers safely and accurately.

With increasing technologies and equipment available, bronchoscopy has quickly become an essential step in the diagnosis of lung cancer. While other techniques exist beyond those described here, these are some of the more widely used options currently available. It is not possible at this time to define one technology as the best tool for the diagnosis of lung cancer, as patient factors will always have to be taken into consideration to ensure safety and accuracy. However, with constantly changing technologies, the bronchoscopist now has a variety of tools available to help target previously “unreachable” lesions as we aim to decrease the historically high mortality rates of lung cancer.

Dr. Jewani and Dr. Johnson are from Loyola University Medical Center, Department of Pulmonary and Critical Care Medicine, Maywood, Illinois.


1. Agrawal, Abhinav et al. “Robotic bronchoscopy for pulmonary lesions: a review of existing technologies and clinical data.” Journal of thoracic disease vol. 12,6 (2020): 3279-3286. doi:10.21037/jtd.2020.03.35

2. Ali MS, Sethi J, Taneja A, Musani A, Maldonado F. Computed Tomography Bronchus Sign and the Diagnostic Yield of Guided Bronchoscopy for Peripheral Pulmonary Lesions. A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. 2018 Aug;15(8):978-987. doi: 10.1513/AnnalsATS.201711-856OC. PMID: 29877715.

3. Argento AC, Puchalski J. Convex probe EBUS for centrally located parenchymal lesions without a bronchus sign. Respir Med. 2016 Jul;116:55-8. doi: 10.1016/j.rmed.2016.04.012. Epub 2016 Apr 29. PMID: 27296821.

4. Chen A, Chenna P, Loiselle A, Massoni J, Mayse M, Misselhorn D. Radial probe endobronchial ultrasound for peripheral pulmonary lesions. A 5-year institutional experience. Ann Am Thorac Soc. 2014 May;11(4):578-82. doi: 10.1513/AnnalsATS.201311-384OC. PMID: 24635641.
 

As of 2019, lung cancer remained the leading cause of cancer death in the United States. In March 2021, the USPSTF updated the guidelines for lung cancer screening, increasing the number of eligible patients in order to identify malignancies in the early stages when more treatment options exist. With the growth of lung cancer screening, increasingly smaller pulmonary nodules are being identified in more peripheral locations previously thought to be unreachable with bronchoscopy. While bronchoscopy has been utilized for over a century for therapeutic interventions, the development of the fiberoptic bronchoscope in 1967 ushered in an era of evolving diagnostic functions. From the initial endobronchial and transbronchial biopsy techniques, to the introduction of endobronchial ultrasound, and now the latest navigational and robotic modalities, these advances have opened a new realm of interventions available in our diagnostic approach to lung cancer.

Bronchoscopy has become essential in the diagnosis of thoracic malignancies, providing both diagnostic and staging information in one procedural setting. By first assessing the mediastinal and hilar lymph nodes with endobronchial ultrasound and transbronchial needle aspiration, involved lymph nodes can give both diagnosis and staging information required to guide treatment. This is particularly important in the case of non-small cell lung cancer, which utilizes the TNM staging system. Through the use of convex probe endobronchial ultrasound (CP-EBUS), combined with rapid on-site evaluation (ROSE) by pathologic condition, we can more accurately target the individual lymph nodes for biopsy without the need for any additional procedures that are often more complex and invasive, such as mediastinoscopy. It is important to note the role of CP-EBUS extends beyond the lymph node assessment and can also be utilized for the evaluation of other mediastinal lesions, such as central parenchymal masses. These would otherwise be difficult to access due to the lack of a clear airway to the lesion (Argento and Puchalski. Respir Med. 2016;116:55-8).

While EBUS has improved the sampling of lymph nodes, advanced imaging technologies and subsequent increases in lung cancer screening have increased the number of lung malignancies identified in earlier stages before extension to the lymph nodes occurs. This scenario requires a direct biopsy of the primary nodule or lung mass. While CP-EBUS can be utilized for some central parenchymal lesions, peripheral nodules pose a greater challenge to the bronchoscopist as they cannot be directly visualized with the conventional bronchoscope. These lesions are amenable to traditional sampling techniques such as bronchial brushings and washings in addition to transbronchial needle aspiration and transbronchial biopsy. However, the yield for peripheral lesions is less than that for central tumors and depends on lesion size, distance from hilum, spatial positioning from bronchus, and operator experience. To help localize peripheral lesions, a separate form of endobronchial ultrasound is available that can be used in combination with fluoroscopy to target a lesion. Radial probe endobronchial ultrasound (RP-EBUS) utilizes a rotating ultrasound transducer that can be advanced either through the working channel of the bronchoscope or through a guide sheath to extend to airways beyond what the conventional bronchoscope can reach. This assists the bronchoscopist with locating the correct airway and, therefore, increases the yield of sampling techniques. The use of RP-EBUS has reported diagnostic yields of almost 85% if the ultrasound is located within the lesion, but less than 50% if adjacent to the lesion (Chen et al. Ann Am Thorac Soc. 2014;11[4]:578-82). While this improves the yield beyond that achieved with conventional bronchoscopy alone, it continues to challenge the bronchoscopist to locate an accessible airway from a series of branching bronchi that are beyond the level of direct visualization.

Due to the historical difficulty in accurately reaching peripheral lesions, alternative technologies for sampling these lesions, such as image-guided biopsies or surgical resection, were employed. While CT scan-guided biopsies traditionally have high diagnostic yields, they also carry a higher rate of complications, including pneumothorax and bleeding. This has led to a significant increase over the past 2 decades in new bronchoscopic technologies targeting safer and more accurate sampling of increasingly smaller, peripheral lesions.

Traditionally, any new technologies created were intended to be used alongside flexible fiberoptic bronchoscopy. The more recently introduced technologies, however, aim to provide a safer, more accurate procedure through virtual bronchoscopy. By obtaining CT scan images prior to the procedure, a 3D visualization is constructed of the tracheobronchial tree, allowing for directed guidance of endobronchial accessories to more distal airways. Where the bronchoscopist was previously limited in navigating the bronchial tree to the subsegmental bronchi, virtual bronchoscopy can depict the airways up to the 7th order subdivision. This is a significant improvement in airway visualization – however, only when partnered with guidance technologies can the model be accurately navigated.

One modality that is often coupled with virtual bronchoscopy to accurately reach peripheral lesions is electromagnetic navigation bronchoscopy (ENB). Multiple ENB software systems have been created and continue to be highly utilized by bronchoscopists to target peripheral lesions, as it has often been likened to a GPS for the lungs. With the addition of specific hardware components, a magnetic field is created around the patient where the sensor position can be elicited to within 1-mm accuracy. When overlaid with the CT scan images, the bronchoscopist can have real-time positioning of the probe in all three planes and guide the necessary sampling tools to the lesion of interest. The reported yields for ENB vary but have been shown to increase in the presence of specific image findings such as a positive bronchus sign – an air-filled bronchus leading into the lesion. The presence of this finding can increase the yield up to almost 75% from just under 50% in the absence of a positive bronchus sign. (Ali et al. Ann Am Thorac Soc. 2018;15[8]:978-87). However, regardless of this finding, the overall diagnostic yields for ENB continue to fall below that seen with other image-guided biopsy techniques. The procedural complications, however, are significantly less and, therefore, many physicians continue to advocate for ENB as the initial procedure in attempt to decrease risk for the patient.

The newest technology to be introduced to target peripheral lung lesions and to improve upon the shortcomings of other techniques is robotic-assisted bronchoscopy. While surgical specialties have seen success with robotic techniques over many years, the first robotic bronchoscopy system was not introduced until 2018. At present, there are two systems available: the Monarch^® system by Auris Health and the Ion Endoluminal^® System by Intuitive Surgical. These systems allow for increased bronchoscope stability, improved visualization, adjustable angulation of biopsy tools, and an improved ability to make even subtle turns in the airways. Early studies on both systems were cadaver based, but an increasing number of patient trials are now being reported or actively enrolling. Both systems have shown high rates of lesion localization, greater than 85%, with varying diagnostic yields from 69-79%. Some cadaver studies that utilized artificial tumors reported higher diagnostic yields – over 90% – but this was not seen in initial patient-based studies. (Agrawal et al. J Thorac Dis. 2020;12[6]:3279-86) More data related to the robotic-assisted bronchoscopy systems can be expected in the future as more experience is gained, but initial results are promising in the system’s ability to diagnose early lung cancers safely and accurately.

With increasing technologies and equipment available, bronchoscopy has quickly become an essential step in the diagnosis of lung cancer. While other techniques exist beyond those described here, these are some of the more widely used options currently available. It is not possible at this time to define one technology as the best tool for the diagnosis of lung cancer, as patient factors will always have to be taken into consideration to ensure safety and accuracy. However, with constantly changing technologies, the bronchoscopist now has a variety of tools available to help target previously “unreachable” lesions as we aim to decrease the historically high mortality rates of lung cancer.

Dr. Jewani and Dr. Johnson are from Loyola University Medical Center, Department of Pulmonary and Critical Care Medicine, Maywood, Illinois.


1. Agrawal, Abhinav et al. “Robotic bronchoscopy for pulmonary lesions: a review of existing technologies and clinical data.” Journal of thoracic disease vol. 12,6 (2020): 3279-3286. doi:10.21037/jtd.2020.03.35

2. Ali MS, Sethi J, Taneja A, Musani A, Maldonado F. Computed Tomography Bronchus Sign and the Diagnostic Yield of Guided Bronchoscopy for Peripheral Pulmonary Lesions. A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. 2018 Aug;15(8):978-987. doi: 10.1513/AnnalsATS.201711-856OC. PMID: 29877715.

3. Argento AC, Puchalski J. Convex probe EBUS for centrally located parenchymal lesions without a bronchus sign. Respir Med. 2016 Jul;116:55-8. doi: 10.1016/j.rmed.2016.04.012. Epub 2016 Apr 29. PMID: 27296821.

4. Chen A, Chenna P, Loiselle A, Massoni J, Mayse M, Misselhorn D. Radial probe endobronchial ultrasound for peripheral pulmonary lesions. A 5-year institutional experience. Ann Am Thorac Soc. 2014 May;11(4):578-82. doi: 10.1513/AnnalsATS.201311-384OC. PMID: 24635641.
 

As of 2019, lung cancer remained the leading cause of cancer death in the United States. In March 2021, the USPSTF updated the guidelines for lung cancer screening, increasing the number of eligible patients in order to identify malignancies in the early stages when more treatment options exist. With the growth of lung cancer screening, increasingly smaller pulmonary nodules are being identified in more peripheral locations previously thought to be unreachable with bronchoscopy. While bronchoscopy has been utilized for over a century for therapeutic interventions, the development of the fiberoptic bronchoscope in 1967 ushered in an era of evolving diagnostic functions. From the initial endobronchial and transbronchial biopsy techniques, to the introduction of endobronchial ultrasound, and now the latest navigational and robotic modalities, these advances have opened a new realm of interventions available in our diagnostic approach to lung cancer.

Bronchoscopy has become essential in the diagnosis of thoracic malignancies, providing both diagnostic and staging information in one procedural setting. By first assessing the mediastinal and hilar lymph nodes with endobronchial ultrasound and transbronchial needle aspiration, involved lymph nodes can give both diagnosis and staging information required to guide treatment. This is particularly important in the case of non-small cell lung cancer, which utilizes the TNM staging system. Through the use of convex probe endobronchial ultrasound (CP-EBUS), combined with rapid on-site evaluation (ROSE) by pathologic condition, we can more accurately target the individual lymph nodes for biopsy without the need for any additional procedures that are often more complex and invasive, such as mediastinoscopy. It is important to note the role of CP-EBUS extends beyond the lymph node assessment and can also be utilized for the evaluation of other mediastinal lesions, such as central parenchymal masses. These would otherwise be difficult to access due to the lack of a clear airway to the lesion (Argento and Puchalski. Respir Med. 2016;116:55-8).

While EBUS has improved the sampling of lymph nodes, advanced imaging technologies and subsequent increases in lung cancer screening have increased the number of lung malignancies identified in earlier stages before extension to the lymph nodes occurs. This scenario requires a direct biopsy of the primary nodule or lung mass. While CP-EBUS can be utilized for some central parenchymal lesions, peripheral nodules pose a greater challenge to the bronchoscopist as they cannot be directly visualized with the conventional bronchoscope. These lesions are amenable to traditional sampling techniques such as bronchial brushings and washings in addition to transbronchial needle aspiration and transbronchial biopsy. However, the yield for peripheral lesions is less than that for central tumors and depends on lesion size, distance from hilum, spatial positioning from bronchus, and operator experience. To help localize peripheral lesions, a separate form of endobronchial ultrasound is available that can be used in combination with fluoroscopy to target a lesion. Radial probe endobronchial ultrasound (RP-EBUS) utilizes a rotating ultrasound transducer that can be advanced either through the working channel of the bronchoscope or through a guide sheath to extend to airways beyond what the conventional bronchoscope can reach. This assists the bronchoscopist with locating the correct airway and, therefore, increases the yield of sampling techniques. The use of RP-EBUS has reported diagnostic yields of almost 85% if the ultrasound is located within the lesion, but less than 50% if adjacent to the lesion (Chen et al. Ann Am Thorac Soc. 2014;11[4]:578-82). While this improves the yield beyond that achieved with conventional bronchoscopy alone, it continues to challenge the bronchoscopist to locate an accessible airway from a series of branching bronchi that are beyond the level of direct visualization.

Due to the historical difficulty in accurately reaching peripheral lesions, alternative technologies for sampling these lesions, such as image-guided biopsies or surgical resection, were employed. While CT scan-guided biopsies traditionally have high diagnostic yields, they also carry a higher rate of complications, including pneumothorax and bleeding. This has led to a significant increase over the past 2 decades in new bronchoscopic technologies targeting safer and more accurate sampling of increasingly smaller, peripheral lesions.

Traditionally, any new technologies created were intended to be used alongside flexible fiberoptic bronchoscopy. The more recently introduced technologies, however, aim to provide a safer, more accurate procedure through virtual bronchoscopy. By obtaining CT scan images prior to the procedure, a 3D visualization is constructed of the tracheobronchial tree, allowing for directed guidance of endobronchial accessories to more distal airways. Where the bronchoscopist was previously limited in navigating the bronchial tree to the subsegmental bronchi, virtual bronchoscopy can depict the airways up to the 7th order subdivision. This is a significant improvement in airway visualization – however, only when partnered with guidance technologies can the model be accurately navigated.

One modality that is often coupled with virtual bronchoscopy to accurately reach peripheral lesions is electromagnetic navigation bronchoscopy (ENB). Multiple ENB software systems have been created and continue to be highly utilized by bronchoscopists to target peripheral lesions, as it has often been likened to a GPS for the lungs. With the addition of specific hardware components, a magnetic field is created around the patient where the sensor position can be elicited to within 1-mm accuracy. When overlaid with the CT scan images, the bronchoscopist can have real-time positioning of the probe in all three planes and guide the necessary sampling tools to the lesion of interest. The reported yields for ENB vary but have been shown to increase in the presence of specific image findings such as a positive bronchus sign – an air-filled bronchus leading into the lesion. The presence of this finding can increase the yield up to almost 75% from just under 50% in the absence of a positive bronchus sign. (Ali et al. Ann Am Thorac Soc. 2018;15[8]:978-87). However, regardless of this finding, the overall diagnostic yields for ENB continue to fall below that seen with other image-guided biopsy techniques. The procedural complications, however, are significantly less and, therefore, many physicians continue to advocate for ENB as the initial procedure in attempt to decrease risk for the patient.

The newest technology to be introduced to target peripheral lung lesions and to improve upon the shortcomings of other techniques is robotic-assisted bronchoscopy. While surgical specialties have seen success with robotic techniques over many years, the first robotic bronchoscopy system was not introduced until 2018. At present, there are two systems available: the Monarch^® system by Auris Health and the Ion Endoluminal^® System by Intuitive Surgical. These systems allow for increased bronchoscope stability, improved visualization, adjustable angulation of biopsy tools, and an improved ability to make even subtle turns in the airways. Early studies on both systems were cadaver based, but an increasing number of patient trials are now being reported or actively enrolling. Both systems have shown high rates of lesion localization, greater than 85%, with varying diagnostic yields from 69-79%. Some cadaver studies that utilized artificial tumors reported higher diagnostic yields – over 90% – but this was not seen in initial patient-based studies. (Agrawal et al. J Thorac Dis. 2020;12[6]:3279-86) More data related to the robotic-assisted bronchoscopy systems can be expected in the future as more experience is gained, but initial results are promising in the system’s ability to diagnose early lung cancers safely and accurately.

With increasing technologies and equipment available, bronchoscopy has quickly become an essential step in the diagnosis of lung cancer. While other techniques exist beyond those described here, these are some of the more widely used options currently available. It is not possible at this time to define one technology as the best tool for the diagnosis of lung cancer, as patient factors will always have to be taken into consideration to ensure safety and accuracy. However, with constantly changing technologies, the bronchoscopist now has a variety of tools available to help target previously “unreachable” lesions as we aim to decrease the historically high mortality rates of lung cancer.

Dr. Jewani and Dr. Johnson are from Loyola University Medical Center, Department of Pulmonary and Critical Care Medicine, Maywood, Illinois.


1. Agrawal, Abhinav et al. “Robotic bronchoscopy for pulmonary lesions: a review of existing technologies and clinical data.” Journal of thoracic disease vol. 12,6 (2020): 3279-3286. doi:10.21037/jtd.2020.03.35

2. Ali MS, Sethi J, Taneja A, Musani A, Maldonado F. Computed Tomography Bronchus Sign and the Diagnostic Yield of Guided Bronchoscopy for Peripheral Pulmonary Lesions. A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. 2018 Aug;15(8):978-987. doi: 10.1513/AnnalsATS.201711-856OC. PMID: 29877715.

3. Argento AC, Puchalski J. Convex probe EBUS for centrally located parenchymal lesions without a bronchus sign. Respir Med. 2016 Jul;116:55-8. doi: 10.1016/j.rmed.2016.04.012. Epub 2016 Apr 29. PMID: 27296821.

4. Chen A, Chenna P, Loiselle A, Massoni J, Mayse M, Misselhorn D. Radial probe endobronchial ultrasound for peripheral pulmonary lesions. A 5-year institutional experience. Ann Am Thorac Soc. 2014 May;11(4):578-82. doi: 10.1513/AnnalsATS.201311-384OC. PMID: 24635641.
 

Lung cancer is the second-most common cancer and one of the leading causes of mortality in the United States among both men and women. It accounts for almost 25% of all cancer deaths, and every year more people die of lung cancer than colon, breast, and prostate cancers combined. The American Cancer Society estimates about 235,760 new lung cancer cases and about 131,880 deaths from lung cancer in 2021.

Smoking and increasing age are the two most important risk factors for lung cancer. Lung cancer has a higher incidence among Black men than White men, and among White women compared with Black women. These differences are likely related to smoking exposure. Early diagnosis of lung cancer can improve survival, and hence screening for lung cancer in high-risk populations is desired. Among the available cancer screening tests, radiology is primarily involved in breast and lung cancer screening (LCS). In 2011, the National Lung Screening Trial (NLST) showed a benefit of annual low- dose chest CT for LCS, with about 20% reduction in lung cancer-related mortality in high-risk participants compared with chest radiographs (Aberle DR, et al. N Engl J Med. 2011 Aug 4;365[5]:395-409).

Dr. Stowell and Dr. Sonavane are with the Mayo Clinic in Jacksonville, Fla.

Lung cancer is the second-most common cancer and one of the leading causes of mortality in the United States among both men and women. It accounts for almost 25% of all cancer deaths, and every year more people die of lung cancer than colon, breast, and prostate cancers combined. The American Cancer Society estimates about 235,760 new lung cancer cases and about 131,880 deaths from lung cancer in 2021.

Smoking and increasing age are the two most important risk factors for lung cancer. Lung cancer has a higher incidence among Black men than White men, and among White women compared with Black women. These differences are likely related to smoking exposure. Early diagnosis of lung cancer can improve survival, and hence screening for lung cancer in high-risk populations is desired. Among the available cancer screening tests, radiology is primarily involved in breast and lung cancer screening (LCS). In 2011, the National Lung Screening Trial (NLST) showed a benefit of annual low- dose chest CT for LCS, with about 20% reduction in lung cancer-related mortality in high-risk participants compared with chest radiographs (Aberle DR, et al. N Engl J Med. 2011 Aug 4;365[5]:395-409).

Dr. Stowell and Dr. Sonavane are with the Mayo Clinic in Jacksonville, Fla.

Lung cancer is the second-most common cancer and one of the leading causes of mortality in the United States among both men and women. It accounts for almost 25% of all cancer deaths, and every year more people die of lung cancer than colon, breast, and prostate cancers combined. The American Cancer Society estimates about 235,760 new lung cancer cases and about 131,880 deaths from lung cancer in 2021.

Smoking and increasing age are the two most important risk factors for lung cancer. Lung cancer has a higher incidence among Black men than White men, and among White women compared with Black women. These differences are likely related to smoking exposure. Early diagnosis of lung cancer can improve survival, and hence screening for lung cancer in high-risk populations is desired. Among the available cancer screening tests, radiology is primarily involved in breast and lung cancer screening (LCS). In 2011, the National Lung Screening Trial (NLST) showed a benefit of annual low- dose chest CT for LCS, with about 20% reduction in lung cancer-related mortality in high-risk participants compared with chest radiographs (Aberle DR, et al. N Engl J Med. 2011 Aug 4;365[5]:395-409).

Dr. Stowell and Dr. Sonavane are with the Mayo Clinic in Jacksonville, Fla.

National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.¹

FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.²

Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.

The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.^3,4

LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.⁵ LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.

For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.

Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.⁶ All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.

This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.^7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
 

References

1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.

2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.

3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.

4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.

5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.

6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.

7. Global strategy for asthma management and prevention. 2020.

8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.

National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.¹

FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.²

Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.

The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.^3,4

LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.⁵ LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.

For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.

Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.⁶ All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.

This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.^7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
 

References

1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.

2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.

3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.

4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.

5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.

6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.

7. Global strategy for asthma management and prevention. 2020.

8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.

National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.¹

FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.²

Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.

The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.^3,4

LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.⁵ LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.

For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.

Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.⁶ All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.

This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.^7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
 

References

1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.

2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.

3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.

4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.

5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.

6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.

7. Global strategy for asthma management and prevention. 2020.

8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.

What’s in a name?

Bronchiolitis, a group of diseases also referred to as “small airways diseases,” is characterized by inflammation and/or fibrosis in airways less than 2 mm in diameter. In pediatric patients, it is most commonly related to acute viral infections, while in adults, it is often associated with chronic diseases. Bronchiolitis is a well-recognized complication in a significant number of patients who have undergone lung or stem cell transplantation. Common associations also include connective tissue diseases, environmental or occupational inhalation exposures, aspiration, drug toxicity, and infections. Diagnosing bronchiolitis can be challenging for clinicians, and few treatment options exist apart from treating identifiable underlying etiologies. More research is needed into noninvasive diagnostic techniques and treatment modalities.

The terminology used to describe bronchiolitis has evolved over time. Bronchiolitis is now used to describe conditions where the primary pathologic condition is damage to the bronchiolar epithelium not attributable to a larger parenchymal disease (such as hypersensitivity pneumonitis). This change in nomenclature explains why the condition formerly known as “bronchiolitis obliterans organizing pneumonia” (BOOP) is now simply recognized as “organizing pneumonia.” Despite several proposed classification schemes focusing on histopathology, there is no consensus regarding the different subtypes of bronchiolitis, leading to confusion in some cases. Recently, authors have attempted to distinguish cases based on three main histologic patterns (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

• Obliterative/constrictive bronchiolitis (OB) – the terms “obliterative” and “constrictive” are used interchangeably throughout pulmonary literature. It is characterized by fibroblast-rich tissue accumulation in the sub-epithelium of bronchioles leading to progressive narrowing of the lumen. In addition to the transplant setting, it is often seen in patients with rheumatoid arthritis or other connective tissue diseases, inhalational exposures, or acute respiratory infections. More recently, clinicians have recognized diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) as a rare condition causing OB with potentially effective treatment.
• Follicular bronchiolitis (FB) – features peribronchiolar inflammation with subepithelial lymphoid deposits leading to luminal obstruction. FB is chiefly associated with conditions of impaired immunity or chronic airway infection, such as autoimmune connective tissues diseases (especially rheumatoid arthritis and Sjogren’s), severe combined immunodeficiency, HIV, cystic fibrosis, and primary ciliary dyskinesia. 
• Diffuse panbronchiolitis (DBP) – features bilateral bronchiolar lesions with lymphocytic inflammation of the bronchiolar wall, as well as peribronchiolar inflammation and accumulation of interstitial foamy macrophages. Patients afflicted with DBP may suffer repeated bacterial colonization or infection. There is a higher prevalence of DBP in Asia where it was first identified in the 1960s, potentially due to several HLA alleles that are more common in Asia. 

In addition to the above terminology, the transplant-setting diagnosis “bronchiolitis obliterans syndrome” (BOS) is used to denote progressive obstructive lung disease for which there is not another cause aside from chronic graft rejection. For these patients, clinicians assume the underlying disease entity is OB, but they often lack histopathologic confirmation. 
 

Diagnosis is challenging

Symptoms of bronchiolitis are typically dyspnea and cough, and patients may often be diagnosed with asthma or COPD initially. Pulmonary function testing may show signs of obstruction, restriction, or mixed disease with or without a reduction in Dlco. Chest radiography often appears normal, but high-resolution CT may show expiratory air trapping and centrilobular nodules. Advanced imaging modalities may augment or replace CT imaging in diagnosing bronchiolitis: investigators are evaluating pulmonary MRI and fluoroscopy with computerized ventilation analysis in clinical trials (NCT04080232).

Currently, open or thoracoscopic lung biopsy is typically required to make a definitive diagnosis. Because bronchiolitis is a patchy and heterogeneous process, transbronchial biopsy may provide insufficient yield, with a sensitivity of 29% to 70% reported in lung transplant literature (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

Recent studies have demonstrated transbronchial cryobiopsy to be a promising alternative to surgical biopsy, owing to larger tissue samples than conventional transbronchial lung biopsies. For example, in a recent case series four patients underwent transbronchial cryobiopsy. The procedure yielded adequate tissue for diagnosis of a chronic bronchiolitis in each case (Yamakawa H, et al. Internal Med Advance Publication. doi: 10.2169/internalmedicine.6028-20.
 

Treatment options are growing

Evidence for treatment of bronchiolitis remains limited. Options are extrapolated from lung transplant patients, where incidence of BOS ranges from 50% at 5 years to 76% at 10 years post transplant. Guidelines recommend a 3-month minimum trial of azithromycin, which has been shown to slow or reverse decline of lung function in some patients. Modification of immunosuppression is also recommended. In patients who have continued lung function decline, a systematic review concluded that extracorporeal photopheresis had the most robust evidence for efficacy with stabilized lung function and improved overall survival (Benden C, et al. J Heart Lung Transplant. 2017;36[9]:921). Other salvage therapies that have lower-quality evidence of benefit include total lymphoid irradiation, montelukast, and aerosolized cyclosporine.

In patients who have undergone hematopoietic stem cell transplant, steroids are typically the first line treatment for OB as it is thought to be a form of chronic graft-vs-host disease (GVHD). Ruxolitinib, a selective JAK1/2 inhibitor, demonstrated significant improvement overall in patients with steroid-refractory acute GVHD in a recent randomized clinical trial, although the trial did not examine its effect on pulmonary manifestations (Zeiser R, et al. N Engl J Med. 2020;382[19]:1800). To date, retrospective observational studies of ruxolitinib in patients with lung GVHD have shown conflicting results regarding benefit. Investigators are currently studying ruxolitinib in a phase II trial for patients with BOS following stem cell transplant (NCT03674047).

DIPNECH is unique from other bronchiolitis entities, as small airways dysfunction develops as a result of neuroendocrine cell proliferation in the airway mucosa, ultimately leading to bronchial narrowing. It most commonly presents in middle-aged nonsmoking women with years of chronic cough and dyspnea. While it has an indolent course in many patients, some patients develop progressive symptoms and obstructive lung disease. DIPNECH is considered a precursor to other pulmonary neuroendocrine tumors. The lesions demonstrate somatostatin receptor expression in many cases, prompting the use of somatostatin analogues as treatment. In the largest published case series, 42 patients from three different institutions were identified who were treated with somatostatin analogues for a mean of 38.8 months at the time of review. Symptomatic improvement was seen in 33 of the 42 (79%), and of the 15 with posttreatment PFT data, 14 (93%) showed improvement in PFTs (Al-Toubah, T, et al. Chest. 2020;158[1]:401). Other small studies have demonstrated varying results with symptomatic improvement in 29% to 76% of patients and improvement or stability of PFTs in 50% to 100% of patients (Samhouri BF, et al. ERJ Open Res. 2020;6[4]:527).

For patients who have not undergone lung transplant, and who do not have an identifiable exposure or underlying rheumatologic condition, a similar 3-month minimum trial of macrolide antibiotics is reasonable. Macrolides have been shown to double long-term survival rates to over 90% in patients with DPB. Evidence in this patient population is quite limited, and further research is needed to determine effective therapies for patients.
 

What’s next for bronchiolitis

While clinicians currently have few tools for diagnosing and treating these uncommon diseases, in the coming years, we should learn whether novel imaging modalities or less invasive procedures can aid in the diagnosis. Physicians hope these advances will preclude the need for invasive biopsies in more patients going forward. We should also learn whether newer, targeted agents like ruxolitinib are effective for BOS in patients with stem cell transplant. If so, this finding may open it and similar agents to investigation in other forms of bronchiolitis.
 

Dr. Poole and Dr. Callahan are with University of Utah Health, Salt Lake City, Utah.

What’s in a name?

Bronchiolitis, a group of diseases also referred to as “small airways diseases,” is characterized by inflammation and/or fibrosis in airways less than 2 mm in diameter. In pediatric patients, it is most commonly related to acute viral infections, while in adults, it is often associated with chronic diseases. Bronchiolitis is a well-recognized complication in a significant number of patients who have undergone lung or stem cell transplantation. Common associations also include connective tissue diseases, environmental or occupational inhalation exposures, aspiration, drug toxicity, and infections. Diagnosing bronchiolitis can be challenging for clinicians, and few treatment options exist apart from treating identifiable underlying etiologies. More research is needed into noninvasive diagnostic techniques and treatment modalities.

The terminology used to describe bronchiolitis has evolved over time. Bronchiolitis is now used to describe conditions where the primary pathologic condition is damage to the bronchiolar epithelium not attributable to a larger parenchymal disease (such as hypersensitivity pneumonitis). This change in nomenclature explains why the condition formerly known as “bronchiolitis obliterans organizing pneumonia” (BOOP) is now simply recognized as “organizing pneumonia.” Despite several proposed classification schemes focusing on histopathology, there is no consensus regarding the different subtypes of bronchiolitis, leading to confusion in some cases. Recently, authors have attempted to distinguish cases based on three main histologic patterns (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

• Obliterative/constrictive bronchiolitis (OB) – the terms “obliterative” and “constrictive” are used interchangeably throughout pulmonary literature. It is characterized by fibroblast-rich tissue accumulation in the sub-epithelium of bronchioles leading to progressive narrowing of the lumen. In addition to the transplant setting, it is often seen in patients with rheumatoid arthritis or other connective tissue diseases, inhalational exposures, or acute respiratory infections. More recently, clinicians have recognized diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) as a rare condition causing OB with potentially effective treatment.
• Follicular bronchiolitis (FB) – features peribronchiolar inflammation with subepithelial lymphoid deposits leading to luminal obstruction. FB is chiefly associated with conditions of impaired immunity or chronic airway infection, such as autoimmune connective tissues diseases (especially rheumatoid arthritis and Sjogren’s), severe combined immunodeficiency, HIV, cystic fibrosis, and primary ciliary dyskinesia. 
• Diffuse panbronchiolitis (DBP) – features bilateral bronchiolar lesions with lymphocytic inflammation of the bronchiolar wall, as well as peribronchiolar inflammation and accumulation of interstitial foamy macrophages. Patients afflicted with DBP may suffer repeated bacterial colonization or infection. There is a higher prevalence of DBP in Asia where it was first identified in the 1960s, potentially due to several HLA alleles that are more common in Asia. 

In addition to the above terminology, the transplant-setting diagnosis “bronchiolitis obliterans syndrome” (BOS) is used to denote progressive obstructive lung disease for which there is not another cause aside from chronic graft rejection. For these patients, clinicians assume the underlying disease entity is OB, but they often lack histopathologic confirmation. 
 

Diagnosis is challenging

Symptoms of bronchiolitis are typically dyspnea and cough, and patients may often be diagnosed with asthma or COPD initially. Pulmonary function testing may show signs of obstruction, restriction, or mixed disease with or without a reduction in Dlco. Chest radiography often appears normal, but high-resolution CT may show expiratory air trapping and centrilobular nodules. Advanced imaging modalities may augment or replace CT imaging in diagnosing bronchiolitis: investigators are evaluating pulmonary MRI and fluoroscopy with computerized ventilation analysis in clinical trials (NCT04080232).

Currently, open or thoracoscopic lung biopsy is typically required to make a definitive diagnosis. Because bronchiolitis is a patchy and heterogeneous process, transbronchial biopsy may provide insufficient yield, with a sensitivity of 29% to 70% reported in lung transplant literature (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

Recent studies have demonstrated transbronchial cryobiopsy to be a promising alternative to surgical biopsy, owing to larger tissue samples than conventional transbronchial lung biopsies. For example, in a recent case series four patients underwent transbronchial cryobiopsy. The procedure yielded adequate tissue for diagnosis of a chronic bronchiolitis in each case (Yamakawa H, et al. Internal Med Advance Publication. doi: 10.2169/internalmedicine.6028-20.
 

Treatment options are growing

Evidence for treatment of bronchiolitis remains limited. Options are extrapolated from lung transplant patients, where incidence of BOS ranges from 50% at 5 years to 76% at 10 years post transplant. Guidelines recommend a 3-month minimum trial of azithromycin, which has been shown to slow or reverse decline of lung function in some patients. Modification of immunosuppression is also recommended. In patients who have continued lung function decline, a systematic review concluded that extracorporeal photopheresis had the most robust evidence for efficacy with stabilized lung function and improved overall survival (Benden C, et al. J Heart Lung Transplant. 2017;36[9]:921). Other salvage therapies that have lower-quality evidence of benefit include total lymphoid irradiation, montelukast, and aerosolized cyclosporine.

In patients who have undergone hematopoietic stem cell transplant, steroids are typically the first line treatment for OB as it is thought to be a form of chronic graft-vs-host disease (GVHD). Ruxolitinib, a selective JAK1/2 inhibitor, demonstrated significant improvement overall in patients with steroid-refractory acute GVHD in a recent randomized clinical trial, although the trial did not examine its effect on pulmonary manifestations (Zeiser R, et al. N Engl J Med. 2020;382[19]:1800). To date, retrospective observational studies of ruxolitinib in patients with lung GVHD have shown conflicting results regarding benefit. Investigators are currently studying ruxolitinib in a phase II trial for patients with BOS following stem cell transplant (NCT03674047).

DIPNECH is unique from other bronchiolitis entities, as small airways dysfunction develops as a result of neuroendocrine cell proliferation in the airway mucosa, ultimately leading to bronchial narrowing. It most commonly presents in middle-aged nonsmoking women with years of chronic cough and dyspnea. While it has an indolent course in many patients, some patients develop progressive symptoms and obstructive lung disease. DIPNECH is considered a precursor to other pulmonary neuroendocrine tumors. The lesions demonstrate somatostatin receptor expression in many cases, prompting the use of somatostatin analogues as treatment. In the largest published case series, 42 patients from three different institutions were identified who were treated with somatostatin analogues for a mean of 38.8 months at the time of review. Symptomatic improvement was seen in 33 of the 42 (79%), and of the 15 with posttreatment PFT data, 14 (93%) showed improvement in PFTs (Al-Toubah, T, et al. Chest. 2020;158[1]:401). Other small studies have demonstrated varying results with symptomatic improvement in 29% to 76% of patients and improvement or stability of PFTs in 50% to 100% of patients (Samhouri BF, et al. ERJ Open Res. 2020;6[4]:527).

For patients who have not undergone lung transplant, and who do not have an identifiable exposure or underlying rheumatologic condition, a similar 3-month minimum trial of macrolide antibiotics is reasonable. Macrolides have been shown to double long-term survival rates to over 90% in patients with DPB. Evidence in this patient population is quite limited, and further research is needed to determine effective therapies for patients.
 

What’s next for bronchiolitis

While clinicians currently have few tools for diagnosing and treating these uncommon diseases, in the coming years, we should learn whether novel imaging modalities or less invasive procedures can aid in the diagnosis. Physicians hope these advances will preclude the need for invasive biopsies in more patients going forward. We should also learn whether newer, targeted agents like ruxolitinib are effective for BOS in patients with stem cell transplant. If so, this finding may open it and similar agents to investigation in other forms of bronchiolitis.
 

Dr. Poole and Dr. Callahan are with University of Utah Health, Salt Lake City, Utah.

What’s in a name?

Bronchiolitis, a group of diseases also referred to as “small airways diseases,” is characterized by inflammation and/or fibrosis in airways less than 2 mm in diameter. In pediatric patients, it is most commonly related to acute viral infections, while in adults, it is often associated with chronic diseases. Bronchiolitis is a well-recognized complication in a significant number of patients who have undergone lung or stem cell transplantation. Common associations also include connective tissue diseases, environmental or occupational inhalation exposures, aspiration, drug toxicity, and infections. Diagnosing bronchiolitis can be challenging for clinicians, and few treatment options exist apart from treating identifiable underlying etiologies. More research is needed into noninvasive diagnostic techniques and treatment modalities.

The terminology used to describe bronchiolitis has evolved over time. Bronchiolitis is now used to describe conditions where the primary pathologic condition is damage to the bronchiolar epithelium not attributable to a larger parenchymal disease (such as hypersensitivity pneumonitis). This change in nomenclature explains why the condition formerly known as “bronchiolitis obliterans organizing pneumonia” (BOOP) is now simply recognized as “organizing pneumonia.” Despite several proposed classification schemes focusing on histopathology, there is no consensus regarding the different subtypes of bronchiolitis, leading to confusion in some cases. Recently, authors have attempted to distinguish cases based on three main histologic patterns (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

• Obliterative/constrictive bronchiolitis (OB) – the terms “obliterative” and “constrictive” are used interchangeably throughout pulmonary literature. It is characterized by fibroblast-rich tissue accumulation in the sub-epithelium of bronchioles leading to progressive narrowing of the lumen. In addition to the transplant setting, it is often seen in patients with rheumatoid arthritis or other connective tissue diseases, inhalational exposures, or acute respiratory infections. More recently, clinicians have recognized diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) as a rare condition causing OB with potentially effective treatment.
• Follicular bronchiolitis (FB) – features peribronchiolar inflammation with subepithelial lymphoid deposits leading to luminal obstruction. FB is chiefly associated with conditions of impaired immunity or chronic airway infection, such as autoimmune connective tissues diseases (especially rheumatoid arthritis and Sjogren’s), severe combined immunodeficiency, HIV, cystic fibrosis, and primary ciliary dyskinesia. 
• Diffuse panbronchiolitis (DBP) – features bilateral bronchiolar lesions with lymphocytic inflammation of the bronchiolar wall, as well as peribronchiolar inflammation and accumulation of interstitial foamy macrophages. Patients afflicted with DBP may suffer repeated bacterial colonization or infection. There is a higher prevalence of DBP in Asia where it was first identified in the 1960s, potentially due to several HLA alleles that are more common in Asia. 

In addition to the above terminology, the transplant-setting diagnosis “bronchiolitis obliterans syndrome” (BOS) is used to denote progressive obstructive lung disease for which there is not another cause aside from chronic graft rejection. For these patients, clinicians assume the underlying disease entity is OB, but they often lack histopathologic confirmation. 
 

Diagnosis is challenging

Symptoms of bronchiolitis are typically dyspnea and cough, and patients may often be diagnosed with asthma or COPD initially. Pulmonary function testing may show signs of obstruction, restriction, or mixed disease with or without a reduction in Dlco. Chest radiography often appears normal, but high-resolution CT may show expiratory air trapping and centrilobular nodules. Advanced imaging modalities may augment or replace CT imaging in diagnosing bronchiolitis: investigators are evaluating pulmonary MRI and fluoroscopy with computerized ventilation analysis in clinical trials (NCT04080232).

Currently, open or thoracoscopic lung biopsy is typically required to make a definitive diagnosis. Because bronchiolitis is a patchy and heterogeneous process, transbronchial biopsy may provide insufficient yield, with a sensitivity of 29% to 70% reported in lung transplant literature (Urisman A, et al. Surg Pathol Clin. 2020;13[1]:189).

Recent studies have demonstrated transbronchial cryobiopsy to be a promising alternative to surgical biopsy, owing to larger tissue samples than conventional transbronchial lung biopsies. For example, in a recent case series four patients underwent transbronchial cryobiopsy. The procedure yielded adequate tissue for diagnosis of a chronic bronchiolitis in each case (Yamakawa H, et al. Internal Med Advance Publication. doi: 10.2169/internalmedicine.6028-20.
 

Treatment options are growing

Evidence for treatment of bronchiolitis remains limited. Options are extrapolated from lung transplant patients, where incidence of BOS ranges from 50% at 5 years to 76% at 10 years post transplant. Guidelines recommend a 3-month minimum trial of azithromycin, which has been shown to slow or reverse decline of lung function in some patients. Modification of immunosuppression is also recommended. In patients who have continued lung function decline, a systematic review concluded that extracorporeal photopheresis had the most robust evidence for efficacy with stabilized lung function and improved overall survival (Benden C, et al. J Heart Lung Transplant. 2017;36[9]:921). Other salvage therapies that have lower-quality evidence of benefit include total lymphoid irradiation, montelukast, and aerosolized cyclosporine.

In patients who have undergone hematopoietic stem cell transplant, steroids are typically the first line treatment for OB as it is thought to be a form of chronic graft-vs-host disease (GVHD). Ruxolitinib, a selective JAK1/2 inhibitor, demonstrated significant improvement overall in patients with steroid-refractory acute GVHD in a recent randomized clinical trial, although the trial did not examine its effect on pulmonary manifestations (Zeiser R, et al. N Engl J Med. 2020;382[19]:1800). To date, retrospective observational studies of ruxolitinib in patients with lung GVHD have shown conflicting results regarding benefit. Investigators are currently studying ruxolitinib in a phase II trial for patients with BOS following stem cell transplant (NCT03674047).

DIPNECH is unique from other bronchiolitis entities, as small airways dysfunction develops as a result of neuroendocrine cell proliferation in the airway mucosa, ultimately leading to bronchial narrowing. It most commonly presents in middle-aged nonsmoking women with years of chronic cough and dyspnea. While it has an indolent course in many patients, some patients develop progressive symptoms and obstructive lung disease. DIPNECH is considered a precursor to other pulmonary neuroendocrine tumors. The lesions demonstrate somatostatin receptor expression in many cases, prompting the use of somatostatin analogues as treatment. In the largest published case series, 42 patients from three different institutions were identified who were treated with somatostatin analogues for a mean of 38.8 months at the time of review. Symptomatic improvement was seen in 33 of the 42 (79%), and of the 15 with posttreatment PFT data, 14 (93%) showed improvement in PFTs (Al-Toubah, T, et al. Chest. 2020;158[1]:401). Other small studies have demonstrated varying results with symptomatic improvement in 29% to 76% of patients and improvement or stability of PFTs in 50% to 100% of patients (Samhouri BF, et al. ERJ Open Res. 2020;6[4]:527).

For patients who have not undergone lung transplant, and who do not have an identifiable exposure or underlying rheumatologic condition, a similar 3-month minimum trial of macrolide antibiotics is reasonable. Macrolides have been shown to double long-term survival rates to over 90% in patients with DPB. Evidence in this patient population is quite limited, and further research is needed to determine effective therapies for patients.
 

What’s next for bronchiolitis

While clinicians currently have few tools for diagnosing and treating these uncommon diseases, in the coming years, we should learn whether novel imaging modalities or less invasive procedures can aid in the diagnosis. Physicians hope these advances will preclude the need for invasive biopsies in more patients going forward. We should also learn whether newer, targeted agents like ruxolitinib are effective for BOS in patients with stem cell transplant. If so, this finding may open it and similar agents to investigation in other forms of bronchiolitis.
 

Dr. Poole and Dr. Callahan are with University of Utah Health, Salt Lake City, Utah.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

The coronavirus disease 2019 (COVID-19) pandemic has changed the way we deliver healthcare for the foreseeable future. Not only have we had to rapidly learn how to evaluate, diagnose, and treat this new disease, we have also had to shift how we screen, triage, and care for other patients for both their safety and ours. As the virus is primarily spread via respiratory droplets, aerosol-generating procedures (AGP), such as bronchoscopy and tracheostomy, are high-risk for viral transmission. We have therefore had to reassess the risk/benefit ratio of performing these procedures – what is the risk to the patient by procedure postponement vs the risk to the health-care personnel (HCP) involved by moving ahead with the procedure? And, if proceeding, how should we protect ourselves? How do we screen patients to help us stratify risk? In order to answer these questions, we generally divide patients into three categories: the asymptomatic outpatient, the symptomatic patient, and the critically ill patient.

The asymptomatic outpatient

Early in the pandemic as cases began to spike in the US, many hospitals decided to postpone all elective procedures and surgeries. Guidelines quickly emerged stratifying bronchoscopic procedures into emergent, urgent, acute, subacute, and truly elective with recommendations on the subsequent timing of those procedures (Pritchett MA, et al. J Thorac Dis. 2020 May;12[5]:1781-1798). As we have obtained further data and our infrastructure has been bolstered, many physicians have begun performing more routine procedures. Preprocedural screening, both with symptom questionnaires and nasopharyngeal swabs, has been enacted as a measure to prevent inadvertent exposure to infected patients. While there are limited data regarding the reliability of this measure, emerging data have shown good concordance between nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) swabs and bronchoalveolar lavage (BAL) samples in low-risk patients (Oberg, et al. Personal communication, Sept 2020). Emergency procedures, such as foreign body aspiration, critical airway obstruction, and massive hemoptysis, were generally performed without delay throughout the pandemic. More recently, emphasis has been placed on prioritizing procedures for acute clinical diagnoses, such as biopsies for concerning lung nodules or masses in potentially early-stage patients, in those where staging is needed and in those where disease progression is suspected. Subacute procedures, such as inspection bronchoscopy for cough, minor hemoptysis, or airway stent surveillance, have generally been reintroduced while elective procedures, such as bronchial thermoplasty and bronchoscopic lung volume reduction, are considered elective, and their frequency and timing is determined mostly by the number of new cases of COVID-19 in the local community.

For all procedures, general modifications have been made. High-efficiency particulate air (HEPA) filters should be placed on all ventilatory circuits. When equivalent, flexible bronchoscopy is preferred over rigid bronchoscopy due to the closed circuit. Enhanced personal protective equipment (PPE) for all procedures is recommended – this typically includes a gown, gloves, hair bonnet, N-95 mask, and a face shield. Strict adherence to the Centers for Disease Control and Prevention (CDC) guidelines for postprocedure cleaning and sterilization is strongly recommended. In some cases, single-use bronchoscopes are being preferentially used, though no strong recommendations exist for this.
 

The symptomatic COVID-19 patient

In patients who have been diagnosed with SARS-CoV-2, we generally recommend postponing all procedures other than for life-threatening indications. For outpatients, we generally wait for two negative nasopharyngeal swabs prior to performing any nonemergent procedure. In inpatients, similar recommendations exist. Potential inpatient indications for bronchoscopy include diagnostic evaluation for alternate or coinfections, and therapeutic aspiration of clinically significant secretions. These should be carefully considered and performed only if deemed absolutely necessary. If bronchoscopy is needed in a patient with suspected or confirmed COVID-19, at a minimum, gown, gloves, head cover, face shield, and an N-95 mask should be worn. A powered air purifying respirator (PAPR) can be used and may provide increased protection. Proper donning and doffing techniques should be reviewed prior to any procedure. Personnel involved in the case should be limited to the minimum required. The procedure should be performed by experienced operators and limited in length. Removal and reinsertion of the bronchoscope should be minimized.

The critically ill COVID-19 patient

While the majority of patients infected with SARS-CoV-2 will have only mild symptoms, we know that a subset of patients will develop respiratory failure. Of those, a small but significant number will require prolonged mechanical ventilation during their clinical course. Thus, the consideration for tracheostomy comes into play.

Multiple issues arise when discussing tracheostomy placement in the COVID-19 world. Should it be done at all? If yes, what is the best technique and who should do it? When and where should it be done? Importantly – how do we care for patients once it is in place to facilitate recovery and, hopefully, decannulation?

Tracheostomy tubes are used in the ICU for patients who require prolonged mechanical ventilation for many reasons – patient comfort, decreased need for sedation, and to facilitate transfer out of the ICU to less acute care areas. These reasons are just as important in patients afflicted with respiratory failure from COVID-19, if not more so. As the patient volumes surge, health-care systems can quickly become overwhelmed. The ability to safely move patients out of the ICU frees up those resources for others who are more acutely ill.

The optimal technique for tracheostomy placement largely depends on the technological and human capital of each institution. Emphasis should be placed on procedural experience, efficiency, safety, and minimizing risk to HCP. While mortality rates do not differ between the surgical and percutaneous techniques, the percutaneous approach has been shown to require less procedural time (Iftikhar IH, et al. Lung. 2019[Jun];197[3]:267-275), an important infection control advantage in COVID-19 patients. Additionally, percutaneous tracheostomies are typically performed at the bedside, which offers the immediate benefit of minimizing patient transfer. This decreases exposure to multiple HCP, as well as contamination of other health-care areas. If performing a bronchoscopic-guided percutaneous tracheostomy, apnea should be maintained from insertion of the guiding catheter to tracheostomy insertion in order to minimize aerosolization. A novel technique involving placing the bronchoscope beside the endotracheal tube instead of through it has also been described (Angel L, et al. Ann Thorac Surg. 2020[Sep];110[3]:1006–1011).

Timing of tracheostomy placement in COVID-19 patients has varied widely. Initially, concern for the safety of HCP performing these procedures led to recommendations of waiting at least 21 days of intubation or until COVID-19 testing became negative. However, more recently, multiple recommendations have been made for tracheostomy placement after day 10 of intubation (McGrath, et al. Lancet Respir Med. 2020[Jul];8[7]:717-725).

Finally, once a tracheostomy tube has been placed, the care does not stop there. As patients are transitioned to rehabilitation centers or skilled nursing facilities and are assessed for weaning, downsizing, and decannulation, care should be taken to avoid virus aerosolization during key high-risk steps. Modifications such as performing spontaneous breathing trials using pressure support (a closed circuit) rather than tracheostomy mask, bypassing speaking valve trials in favor of direct tracheostomy capping, and avoiding routine tracheostomy downsizing are examples of simple steps that can be taken to facilitate patient progress while minimizing HCP risk (Divo, et al. Respir Care. 2020[Aug]5;respcare.08157).
 

What’s ahead?

As we move forward, we will continue to balance caring for patients effectively and efficiently while minimizing risk to ourselves and others. Ultimately until a vaccine exists, we will have to focus on prevention of infection and spread; therefore, the core principles of hand hygiene, mask wearing, and social distancing have never been more important. We encourage continued study, scrutiny, and collaboration in order to optimize procedural techniques as more information becomes available.
 

Dr. Oberg is with the Section of Interventional Pulmonology, David Geffen School of Medicine at UCLA; Dr. Beattie is with the Section of Interventional Pulmonology, Memorial Sloan Kettering Cancer Center, New York; and Dr. Folch is with the Section of Interventional Pulmonology, Massachusetts General Hospital, Harvard Medical School.

The coronavirus disease 2019 (COVID-19) pandemic has changed the way we deliver healthcare for the foreseeable future. Not only have we had to rapidly learn how to evaluate, diagnose, and treat this new disease, we have also had to shift how we screen, triage, and care for other patients for both their safety and ours. As the virus is primarily spread via respiratory droplets, aerosol-generating procedures (AGP), such as bronchoscopy and tracheostomy, are high-risk for viral transmission. We have therefore had to reassess the risk/benefit ratio of performing these procedures – what is the risk to the patient by procedure postponement vs the risk to the health-care personnel (HCP) involved by moving ahead with the procedure? And, if proceeding, how should we protect ourselves? How do we screen patients to help us stratify risk? In order to answer these questions, we generally divide patients into three categories: the asymptomatic outpatient, the symptomatic patient, and the critically ill patient.

The asymptomatic outpatient

Early in the pandemic as cases began to spike in the US, many hospitals decided to postpone all elective procedures and surgeries. Guidelines quickly emerged stratifying bronchoscopic procedures into emergent, urgent, acute, subacute, and truly elective with recommendations on the subsequent timing of those procedures (Pritchett MA, et al. J Thorac Dis. 2020 May;12[5]:1781-1798). As we have obtained further data and our infrastructure has been bolstered, many physicians have begun performing more routine procedures. Preprocedural screening, both with symptom questionnaires and nasopharyngeal swabs, has been enacted as a measure to prevent inadvertent exposure to infected patients. While there are limited data regarding the reliability of this measure, emerging data have shown good concordance between nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) swabs and bronchoalveolar lavage (BAL) samples in low-risk patients (Oberg, et al. Personal communication, Sept 2020). Emergency procedures, such as foreign body aspiration, critical airway obstruction, and massive hemoptysis, were generally performed without delay throughout the pandemic. More recently, emphasis has been placed on prioritizing procedures for acute clinical diagnoses, such as biopsies for concerning lung nodules or masses in potentially early-stage patients, in those where staging is needed and in those where disease progression is suspected. Subacute procedures, such as inspection bronchoscopy for cough, minor hemoptysis, or airway stent surveillance, have generally been reintroduced while elective procedures, such as bronchial thermoplasty and bronchoscopic lung volume reduction, are considered elective, and their frequency and timing is determined mostly by the number of new cases of COVID-19 in the local community.

For all procedures, general modifications have been made. High-efficiency particulate air (HEPA) filters should be placed on all ventilatory circuits. When equivalent, flexible bronchoscopy is preferred over rigid bronchoscopy due to the closed circuit. Enhanced personal protective equipment (PPE) for all procedures is recommended – this typically includes a gown, gloves, hair bonnet, N-95 mask, and a face shield. Strict adherence to the Centers for Disease Control and Prevention (CDC) guidelines for postprocedure cleaning and sterilization is strongly recommended. In some cases, single-use bronchoscopes are being preferentially used, though no strong recommendations exist for this.
 

The symptomatic COVID-19 patient

In patients who have been diagnosed with SARS-CoV-2, we generally recommend postponing all procedures other than for life-threatening indications. For outpatients, we generally wait for two negative nasopharyngeal swabs prior to performing any nonemergent procedure. In inpatients, similar recommendations exist. Potential inpatient indications for bronchoscopy include diagnostic evaluation for alternate or coinfections, and therapeutic aspiration of clinically significant secretions. These should be carefully considered and performed only if deemed absolutely necessary. If bronchoscopy is needed in a patient with suspected or confirmed COVID-19, at a minimum, gown, gloves, head cover, face shield, and an N-95 mask should be worn. A powered air purifying respirator (PAPR) can be used and may provide increased protection. Proper donning and doffing techniques should be reviewed prior to any procedure. Personnel involved in the case should be limited to the minimum required. The procedure should be performed by experienced operators and limited in length. Removal and reinsertion of the bronchoscope should be minimized.

The critically ill COVID-19 patient

While the majority of patients infected with SARS-CoV-2 will have only mild symptoms, we know that a subset of patients will develop respiratory failure. Of those, a small but significant number will require prolonged mechanical ventilation during their clinical course. Thus, the consideration for tracheostomy comes into play.

Multiple issues arise when discussing tracheostomy placement in the COVID-19 world. Should it be done at all? If yes, what is the best technique and who should do it? When and where should it be done? Importantly – how do we care for patients once it is in place to facilitate recovery and, hopefully, decannulation?

Tracheostomy tubes are used in the ICU for patients who require prolonged mechanical ventilation for many reasons – patient comfort, decreased need for sedation, and to facilitate transfer out of the ICU to less acute care areas. These reasons are just as important in patients afflicted with respiratory failure from COVID-19, if not more so. As the patient volumes surge, health-care systems can quickly become overwhelmed. The ability to safely move patients out of the ICU frees up those resources for others who are more acutely ill.

The optimal technique for tracheostomy placement largely depends on the technological and human capital of each institution. Emphasis should be placed on procedural experience, efficiency, safety, and minimizing risk to HCP. While mortality rates do not differ between the surgical and percutaneous techniques, the percutaneous approach has been shown to require less procedural time (Iftikhar IH, et al. Lung. 2019[Jun];197[3]:267-275), an important infection control advantage in COVID-19 patients. Additionally, percutaneous tracheostomies are typically performed at the bedside, which offers the immediate benefit of minimizing patient transfer. This decreases exposure to multiple HCP, as well as contamination of other health-care areas. If performing a bronchoscopic-guided percutaneous tracheostomy, apnea should be maintained from insertion of the guiding catheter to tracheostomy insertion in order to minimize aerosolization. A novel technique involving placing the bronchoscope beside the endotracheal tube instead of through it has also been described (Angel L, et al. Ann Thorac Surg. 2020[Sep];110[3]:1006–1011).

Timing of tracheostomy placement in COVID-19 patients has varied widely. Initially, concern for the safety of HCP performing these procedures led to recommendations of waiting at least 21 days of intubation or until COVID-19 testing became negative. However, more recently, multiple recommendations have been made for tracheostomy placement after day 10 of intubation (McGrath, et al. Lancet Respir Med. 2020[Jul];8[7]:717-725).

Finally, once a tracheostomy tube has been placed, the care does not stop there. As patients are transitioned to rehabilitation centers or skilled nursing facilities and are assessed for weaning, downsizing, and decannulation, care should be taken to avoid virus aerosolization during key high-risk steps. Modifications such as performing spontaneous breathing trials using pressure support (a closed circuit) rather than tracheostomy mask, bypassing speaking valve trials in favor of direct tracheostomy capping, and avoiding routine tracheostomy downsizing are examples of simple steps that can be taken to facilitate patient progress while minimizing HCP risk (Divo, et al. Respir Care. 2020[Aug]5;respcare.08157).
 

What’s ahead?

As we move forward, we will continue to balance caring for patients effectively and efficiently while minimizing risk to ourselves and others. Ultimately until a vaccine exists, we will have to focus on prevention of infection and spread; therefore, the core principles of hand hygiene, mask wearing, and social distancing have never been more important. We encourage continued study, scrutiny, and collaboration in order to optimize procedural techniques as more information becomes available.
 

Dr. Oberg is with the Section of Interventional Pulmonology, David Geffen School of Medicine at UCLA; Dr. Beattie is with the Section of Interventional Pulmonology, Memorial Sloan Kettering Cancer Center, New York; and Dr. Folch is with the Section of Interventional Pulmonology, Massachusetts General Hospital, Harvard Medical School.

The coronavirus disease 2019 (COVID-19) pandemic has changed the way we deliver healthcare for the foreseeable future. Not only have we had to rapidly learn how to evaluate, diagnose, and treat this new disease, we have also had to shift how we screen, triage, and care for other patients for both their safety and ours. As the virus is primarily spread via respiratory droplets, aerosol-generating procedures (AGP), such as bronchoscopy and tracheostomy, are high-risk for viral transmission. We have therefore had to reassess the risk/benefit ratio of performing these procedures – what is the risk to the patient by procedure postponement vs the risk to the health-care personnel (HCP) involved by moving ahead with the procedure? And, if proceeding, how should we protect ourselves? How do we screen patients to help us stratify risk? In order to answer these questions, we generally divide patients into three categories: the asymptomatic outpatient, the symptomatic patient, and the critically ill patient.

The asymptomatic outpatient

Early in the pandemic as cases began to spike in the US, many hospitals decided to postpone all elective procedures and surgeries. Guidelines quickly emerged stratifying bronchoscopic procedures into emergent, urgent, acute, subacute, and truly elective with recommendations on the subsequent timing of those procedures (Pritchett MA, et al. J Thorac Dis. 2020 May;12[5]:1781-1798). As we have obtained further data and our infrastructure has been bolstered, many physicians have begun performing more routine procedures. Preprocedural screening, both with symptom questionnaires and nasopharyngeal swabs, has been enacted as a measure to prevent inadvertent exposure to infected patients. While there are limited data regarding the reliability of this measure, emerging data have shown good concordance between nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) swabs and bronchoalveolar lavage (BAL) samples in low-risk patients (Oberg, et al. Personal communication, Sept 2020). Emergency procedures, such as foreign body aspiration, critical airway obstruction, and massive hemoptysis, were generally performed without delay throughout the pandemic. More recently, emphasis has been placed on prioritizing procedures for acute clinical diagnoses, such as biopsies for concerning lung nodules or masses in potentially early-stage patients, in those where staging is needed and in those where disease progression is suspected. Subacute procedures, such as inspection bronchoscopy for cough, minor hemoptysis, or airway stent surveillance, have generally been reintroduced while elective procedures, such as bronchial thermoplasty and bronchoscopic lung volume reduction, are considered elective, and their frequency and timing is determined mostly by the number of new cases of COVID-19 in the local community.

For all procedures, general modifications have been made. High-efficiency particulate air (HEPA) filters should be placed on all ventilatory circuits. When equivalent, flexible bronchoscopy is preferred over rigid bronchoscopy due to the closed circuit. Enhanced personal protective equipment (PPE) for all procedures is recommended – this typically includes a gown, gloves, hair bonnet, N-95 mask, and a face shield. Strict adherence to the Centers for Disease Control and Prevention (CDC) guidelines for postprocedure cleaning and sterilization is strongly recommended. In some cases, single-use bronchoscopes are being preferentially used, though no strong recommendations exist for this.
 

The symptomatic COVID-19 patient

In patients who have been diagnosed with SARS-CoV-2, we generally recommend postponing all procedures other than for life-threatening indications. For outpatients, we generally wait for two negative nasopharyngeal swabs prior to performing any nonemergent procedure. In inpatients, similar recommendations exist. Potential inpatient indications for bronchoscopy include diagnostic evaluation for alternate or coinfections, and therapeutic aspiration of clinically significant secretions. These should be carefully considered and performed only if deemed absolutely necessary. If bronchoscopy is needed in a patient with suspected or confirmed COVID-19, at a minimum, gown, gloves, head cover, face shield, and an N-95 mask should be worn. A powered air purifying respirator (PAPR) can be used and may provide increased protection. Proper donning and doffing techniques should be reviewed prior to any procedure. Personnel involved in the case should be limited to the minimum required. The procedure should be performed by experienced operators and limited in length. Removal and reinsertion of the bronchoscope should be minimized.

The critically ill COVID-19 patient

While the majority of patients infected with SARS-CoV-2 will have only mild symptoms, we know that a subset of patients will develop respiratory failure. Of those, a small but significant number will require prolonged mechanical ventilation during their clinical course. Thus, the consideration for tracheostomy comes into play.

Multiple issues arise when discussing tracheostomy placement in the COVID-19 world. Should it be done at all? If yes, what is the best technique and who should do it? When and where should it be done? Importantly – how do we care for patients once it is in place to facilitate recovery and, hopefully, decannulation?

Tracheostomy tubes are used in the ICU for patients who require prolonged mechanical ventilation for many reasons – patient comfort, decreased need for sedation, and to facilitate transfer out of the ICU to less acute care areas. These reasons are just as important in patients afflicted with respiratory failure from COVID-19, if not more so. As the patient volumes surge, health-care systems can quickly become overwhelmed. The ability to safely move patients out of the ICU frees up those resources for others who are more acutely ill.

The optimal technique for tracheostomy placement largely depends on the technological and human capital of each institution. Emphasis should be placed on procedural experience, efficiency, safety, and minimizing risk to HCP. While mortality rates do not differ between the surgical and percutaneous techniques, the percutaneous approach has been shown to require less procedural time (Iftikhar IH, et al. Lung. 2019[Jun];197[3]:267-275), an important infection control advantage in COVID-19 patients. Additionally, percutaneous tracheostomies are typically performed at the bedside, which offers the immediate benefit of minimizing patient transfer. This decreases exposure to multiple HCP, as well as contamination of other health-care areas. If performing a bronchoscopic-guided percutaneous tracheostomy, apnea should be maintained from insertion of the guiding catheter to tracheostomy insertion in order to minimize aerosolization. A novel technique involving placing the bronchoscope beside the endotracheal tube instead of through it has also been described (Angel L, et al. Ann Thorac Surg. 2020[Sep];110[3]:1006–1011).

Timing of tracheostomy placement in COVID-19 patients has varied widely. Initially, concern for the safety of HCP performing these procedures led to recommendations of waiting at least 21 days of intubation or until COVID-19 testing became negative. However, more recently, multiple recommendations have been made for tracheostomy placement after day 10 of intubation (McGrath, et al. Lancet Respir Med. 2020[Jul];8[7]:717-725).

Finally, once a tracheostomy tube has been placed, the care does not stop there. As patients are transitioned to rehabilitation centers or skilled nursing facilities and are assessed for weaning, downsizing, and decannulation, care should be taken to avoid virus aerosolization during key high-risk steps. Modifications such as performing spontaneous breathing trials using pressure support (a closed circuit) rather than tracheostomy mask, bypassing speaking valve trials in favor of direct tracheostomy capping, and avoiding routine tracheostomy downsizing are examples of simple steps that can be taken to facilitate patient progress while minimizing HCP risk (Divo, et al. Respir Care. 2020[Aug]5;respcare.08157).
 

What’s ahead?

As we move forward, we will continue to balance caring for patients effectively and efficiently while minimizing risk to ourselves and others. Ultimately until a vaccine exists, we will have to focus on prevention of infection and spread; therefore, the core principles of hand hygiene, mask wearing, and social distancing have never been more important. We encourage continued study, scrutiny, and collaboration in order to optimize procedural techniques as more information becomes available.
 

Dr. Oberg is with the Section of Interventional Pulmonology, David Geffen School of Medicine at UCLA; Dr. Beattie is with the Section of Interventional Pulmonology, Memorial Sloan Kettering Cancer Center, New York; and Dr. Folch is with the Section of Interventional Pulmonology, Massachusetts General Hospital, Harvard Medical School.

Big data scientists and health-care experts have tried preparing physicians and patients for the arrival of telemedicine for years. Health tracking applications are on our smartphones. Compact ambulatory devices diagnose hypertension and atrial fibrillation.  Advanced imaging modalities make the stethoscope more of a neck accessory than a practical tool. Despite these efficient technologic advancements, the idea of making the sacred in-person office visit remote and through a screen appealed to few. In fact, prior to the COVID-19 pandemic, only 15% of medical practices offered telehealth services and 8% of Americans joined in remote visits annually (Mann DM et al. J Am Med Inform Assoc. 2019 Feb 1;26[2]:106-114).

When the COVID-19 pandemic hit New York City and admissions for hypoxemic respiratory failure skyrocketed, ED and in-person clinic visits for other acute and chronic conditions plummeted. Prior to clinics officially closing their doors, doctors in New York City asked their patients to reserve office visits for emergency issues only ,with most patients willingly staying home to avoid exposure to the virus. Suddenly, after years of disinterest in adopting telehealth, hospitals and clinics were catapulted into a full-on need for this technology. Overnight, our division’s secretaries and medical assistants became IT support staff.  We all learned together what worked, what didn’t work, and how to adapt our workflow to meet everyone’s needs.

Previously, longstanding issues with accessibility and reimbursement presented barriers to widespread adoption of telemedicine. Once the pandemic hit, though, many regulatory changes were quickly made to accommodate telehealth. 

Three such changes are worth highlighting (Centers for Medicare and Medicaid Services. COVID-19 emergency declaration blanket waivers for health care providers. March 30, 2020). 

First, patient privacy rules became more lenient.  Prior to the pandemic, HIPAA mandated that both doctor and patient use embedded video interfaces with high levels of security.  Now, health-care providers can use commonplace video chat applications such as FaceTime, Google Hangouts, Zoom, or Skype to provide telehealth without risk of penalty for HIPAA noncompliance.  When connectivity concerns arose with our EMR’s embedded telehealth application, a quick transition to one of these platforms mitigated patient and provider frustration. 

Second, prior to the pandemic, some private insurance providers reimbursed for televisits, but there were stipulations on how the visit could be conducted. Now, many of the commercial insurers plus Medicare and Medicaid in New York State reimburse the same amount for televisits as in-person visits (fee-for-service rate).  Reimbursement rates of audio-only encounters were increased.   If these changes are continued postpandemic, it will have an expansive impact on the future of an outpatient practice.  

Third, restrictive government regulations relaxed with regard to telehealth deployment.  Gone are the demands on providers and patients to be physically face-to-face.  Many colleagues worked from home, safely social distancing. 

Even though remote medical visits were a crucial part of flattening the curve during the peak of the pandemic in New York City, the telehealth experience is not without flaws. 

An informal survey of providers in our own division garnered diverse and spirited viewpoints about seeing patients remotely.  Instead of using a stethoscope to pick up a subtle finding, telehealth visits require the use of our eyes to scan a patient’s home environment for insights explaining their chronic cough (Where is the mold? Where is the water damage? Where is the bird?).  We use our ears to hear the intonation of our patient’s voice to know when he or she is concerned, anxious, or are at their baselines.  We would implore patients to put on their pulse oximeter and perform activities of daily living and/or exertion. On multiple occasions, patients would perform their own, unsolicited walks about their home to show us what they could and couldn’t do, where they place their concentrators, and where they are likely to trip over oxygen tubing. We learned to depend on them to reach the conclusion that they were at their normal state of health.

For straight-forward encounters with existing patients, most of our colleagues appreciated the simplicity and efficiency of telemedicine. But when it came to new patients, some colleagues struggled with whether they should see them for the first time over video. Universally, providers felt feelings of inadequacy without an in-person examination and review of diagnostic information. 

Along those lines, many of our colleagues worried about their ability to perform the most fundamental role of a physician over the phone/internet for all patients: building trust with a patient.  Eye contact, the physical exam, and verbal and nonverbal communication that engenders confidence and displays empathy remain a challenge.  Multiple colleagues commented on the difficulty of communicating a new horrible diagnosis over a spotty internet connection.  Others expressed concern about the inability to review chest imaging in-person with patients as this often enhances patient comprehension and relieves anxiety about diagnostic possibilities. 

Providers also noted that telehealth implementation is not the same for all individuals. Just as COVID-19 disproportionately affects the most vulnerable populations (NYC Health. COVID-19: data. Accessed July 1, 2020. https://www1.nyc.gov/site/doh/covid/covid-19-data.page), practicing telehealth has uncovered more ways in which racial/ethnic minorities, low income communities, and older patients are at a disadvantage (Garg S, et al. MMWR Morb Mortal Wkly Rep. 2020;69[15]:458). The relatively quick transition to telemedicine revealed that many of our patients don’t have emails or home computers to connect with online platforms. Similarly, some do not have smart phones with internet capabilities. Many do not speak English and cannot partake in video visits since translators are not yet embedded into the EMR’s video system. Elderly patients were frequently very anxious with telemedicine because of unfamiliarity with the technology, and many preferred a phone conversation.  Thus, while more fortunate patients get to use a video interface and its association with higher patient understanding and satisfaction, our most vulnerable populations are often denied the same access to such care (Voils CI et al. J Genet Couns. 2018;27[2]:339).  

Telemedicine will continue to have a significant impact on the future of health care long after the COVID-19 pandemic abates.  There will be growing pains, refinement of technology, improvements in policy, and an ongoing general evolution of the system. Patients and providers will grow together as its utilization continues. We suspect patient surveys about their attitudes and preferences for telemedicine will be as varied as the providers surveyed here.  A recent survey of 1000 patients about their telehealth experiences during the pandemic reported that over 75% were very or completely satisfied with their virtual care experiences and over 50% indicated they would be willing to switch providers to have virtual visits on a regular basis (Patient Perspectives on Virtual Care Report, Accessed July 7, 2020, https://www.kyruus.com/2020-virtual-care-report).

One hopes that with time and on-going feedback, the fundamental purpose of the physician-patient relationship can be maintained and both sides can still appreciate the conveniences and power of telehealth technology.  

Dr. Fedyna and Dr. McGroder are affiliated with the Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, New York, NY.

Big data scientists and health-care experts have tried preparing physicians and patients for the arrival of telemedicine for years. Health tracking applications are on our smartphones. Compact ambulatory devices diagnose hypertension and atrial fibrillation.  Advanced imaging modalities make the stethoscope more of a neck accessory than a practical tool. Despite these efficient technologic advancements, the idea of making the sacred in-person office visit remote and through a screen appealed to few. In fact, prior to the COVID-19 pandemic, only 15% of medical practices offered telehealth services and 8% of Americans joined in remote visits annually (Mann DM et al. J Am Med Inform Assoc. 2019 Feb 1;26[2]:106-114).

When the COVID-19 pandemic hit New York City and admissions for hypoxemic respiratory failure skyrocketed, ED and in-person clinic visits for other acute and chronic conditions plummeted. Prior to clinics officially closing their doors, doctors in New York City asked their patients to reserve office visits for emergency issues only ,with most patients willingly staying home to avoid exposure to the virus. Suddenly, after years of disinterest in adopting telehealth, hospitals and clinics were catapulted into a full-on need for this technology. Overnight, our division’s secretaries and medical assistants became IT support staff.  We all learned together what worked, what didn’t work, and how to adapt our workflow to meet everyone’s needs.

Previously, longstanding issues with accessibility and reimbursement presented barriers to widespread adoption of telemedicine. Once the pandemic hit, though, many regulatory changes were quickly made to accommodate telehealth. 

Three such changes are worth highlighting (Centers for Medicare and Medicaid Services. COVID-19 emergency declaration blanket waivers for health care providers. March 30, 2020). 

First, patient privacy rules became more lenient.  Prior to the pandemic, HIPAA mandated that both doctor and patient use embedded video interfaces with high levels of security.  Now, health-care providers can use commonplace video chat applications such as FaceTime, Google Hangouts, Zoom, or Skype to provide telehealth without risk of penalty for HIPAA noncompliance.  When connectivity concerns arose with our EMR’s embedded telehealth application, a quick transition to one of these platforms mitigated patient and provider frustration. 

Second, prior to the pandemic, some private insurance providers reimbursed for televisits, but there were stipulations on how the visit could be conducted. Now, many of the commercial insurers plus Medicare and Medicaid in New York State reimburse the same amount for televisits as in-person visits (fee-for-service rate).  Reimbursement rates of audio-only encounters were increased.   If these changes are continued postpandemic, it will have an expansive impact on the future of an outpatient practice.  

Third, restrictive government regulations relaxed with regard to telehealth deployment.  Gone are the demands on providers and patients to be physically face-to-face.  Many colleagues worked from home, safely social distancing. 

Even though remote medical visits were a crucial part of flattening the curve during the peak of the pandemic in New York City, the telehealth experience is not without flaws. 

An informal survey of providers in our own division garnered diverse and spirited viewpoints about seeing patients remotely.  Instead of using a stethoscope to pick up a subtle finding, telehealth visits require the use of our eyes to scan a patient’s home environment for insights explaining their chronic cough (Where is the mold? Where is the water damage? Where is the bird?).  We use our ears to hear the intonation of our patient’s voice to know when he or she is concerned, anxious, or are at their baselines.  We would implore patients to put on their pulse oximeter and perform activities of daily living and/or exertion. On multiple occasions, patients would perform their own, unsolicited walks about their home to show us what they could and couldn’t do, where they place their concentrators, and where they are likely to trip over oxygen tubing. We learned to depend on them to reach the conclusion that they were at their normal state of health.

For straight-forward encounters with existing patients, most of our colleagues appreciated the simplicity and efficiency of telemedicine. But when it came to new patients, some colleagues struggled with whether they should see them for the first time over video. Universally, providers felt feelings of inadequacy without an in-person examination and review of diagnostic information. 

Along those lines, many of our colleagues worried about their ability to perform the most fundamental role of a physician over the phone/internet for all patients: building trust with a patient.  Eye contact, the physical exam, and verbal and nonverbal communication that engenders confidence and displays empathy remain a challenge.  Multiple colleagues commented on the difficulty of communicating a new horrible diagnosis over a spotty internet connection.  Others expressed concern about the inability to review chest imaging in-person with patients as this often enhances patient comprehension and relieves anxiety about diagnostic possibilities. 

Providers also noted that telehealth implementation is not the same for all individuals. Just as COVID-19 disproportionately affects the most vulnerable populations (NYC Health. COVID-19: data. Accessed July 1, 2020. https://www1.nyc.gov/site/doh/covid/covid-19-data.page), practicing telehealth has uncovered more ways in which racial/ethnic minorities, low income communities, and older patients are at a disadvantage (Garg S, et al. MMWR Morb Mortal Wkly Rep. 2020;69[15]:458). The relatively quick transition to telemedicine revealed that many of our patients don’t have emails or home computers to connect with online platforms. Similarly, some do not have smart phones with internet capabilities. Many do not speak English and cannot partake in video visits since translators are not yet embedded into the EMR’s video system. Elderly patients were frequently very anxious with telemedicine because of unfamiliarity with the technology, and many preferred a phone conversation.  Thus, while more fortunate patients get to use a video interface and its association with higher patient understanding and satisfaction, our most vulnerable populations are often denied the same access to such care (Voils CI et al. J Genet Couns. 2018;27[2]:339).  

Telemedicine will continue to have a significant impact on the future of health care long after the COVID-19 pandemic abates.  There will be growing pains, refinement of technology, improvements in policy, and an ongoing general evolution of the system. Patients and providers will grow together as its utilization continues. We suspect patient surveys about their attitudes and preferences for telemedicine will be as varied as the providers surveyed here.  A recent survey of 1000 patients about their telehealth experiences during the pandemic reported that over 75% were very or completely satisfied with their virtual care experiences and over 50% indicated they would be willing to switch providers to have virtual visits on a regular basis (Patient Perspectives on Virtual Care Report, Accessed July 7, 2020, https://www.kyruus.com/2020-virtual-care-report).

One hopes that with time and on-going feedback, the fundamental purpose of the physician-patient relationship can be maintained and both sides can still appreciate the conveniences and power of telehealth technology.  

Dr. Fedyna and Dr. McGroder are affiliated with the Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, New York, NY.

Big data scientists and health-care experts have tried preparing physicians and patients for the arrival of telemedicine for years. Health tracking applications are on our smartphones. Compact ambulatory devices diagnose hypertension and atrial fibrillation.  Advanced imaging modalities make the stethoscope more of a neck accessory than a practical tool. Despite these efficient technologic advancements, the idea of making the sacred in-person office visit remote and through a screen appealed to few. In fact, prior to the COVID-19 pandemic, only 15% of medical practices offered telehealth services and 8% of Americans joined in remote visits annually (Mann DM et al. J Am Med Inform Assoc. 2019 Feb 1;26[2]:106-114).

When the COVID-19 pandemic hit New York City and admissions for hypoxemic respiratory failure skyrocketed, ED and in-person clinic visits for other acute and chronic conditions plummeted. Prior to clinics officially closing their doors, doctors in New York City asked their patients to reserve office visits for emergency issues only ,with most patients willingly staying home to avoid exposure to the virus. Suddenly, after years of disinterest in adopting telehealth, hospitals and clinics were catapulted into a full-on need for this technology. Overnight, our division’s secretaries and medical assistants became IT support staff.  We all learned together what worked, what didn’t work, and how to adapt our workflow to meet everyone’s needs.

Previously, longstanding issues with accessibility and reimbursement presented barriers to widespread adoption of telemedicine. Once the pandemic hit, though, many regulatory changes were quickly made to accommodate telehealth. 

Three such changes are worth highlighting (Centers for Medicare and Medicaid Services. COVID-19 emergency declaration blanket waivers for health care providers. March 30, 2020). 

First, patient privacy rules became more lenient.  Prior to the pandemic, HIPAA mandated that both doctor and patient use embedded video interfaces with high levels of security.  Now, health-care providers can use commonplace video chat applications such as FaceTime, Google Hangouts, Zoom, or Skype to provide telehealth without risk of penalty for HIPAA noncompliance.  When connectivity concerns arose with our EMR’s embedded telehealth application, a quick transition to one of these platforms mitigated patient and provider frustration. 

Second, prior to the pandemic, some private insurance providers reimbursed for televisits, but there were stipulations on how the visit could be conducted. Now, many of the commercial insurers plus Medicare and Medicaid in New York State reimburse the same amount for televisits as in-person visits (fee-for-service rate).  Reimbursement rates of audio-only encounters were increased.   If these changes are continued postpandemic, it will have an expansive impact on the future of an outpatient practice.  

Third, restrictive government regulations relaxed with regard to telehealth deployment.  Gone are the demands on providers and patients to be physically face-to-face.  Many colleagues worked from home, safely social distancing. 

Even though remote medical visits were a crucial part of flattening the curve during the peak of the pandemic in New York City, the telehealth experience is not without flaws. 

An informal survey of providers in our own division garnered diverse and spirited viewpoints about seeing patients remotely.  Instead of using a stethoscope to pick up a subtle finding, telehealth visits require the use of our eyes to scan a patient’s home environment for insights explaining their chronic cough (Where is the mold? Where is the water damage? Where is the bird?).  We use our ears to hear the intonation of our patient’s voice to know when he or she is concerned, anxious, or are at their baselines.  We would implore patients to put on their pulse oximeter and perform activities of daily living and/or exertion. On multiple occasions, patients would perform their own, unsolicited walks about their home to show us what they could and couldn’t do, where they place their concentrators, and where they are likely to trip over oxygen tubing. We learned to depend on them to reach the conclusion that they were at their normal state of health.

For straight-forward encounters with existing patients, most of our colleagues appreciated the simplicity and efficiency of telemedicine. But when it came to new patients, some colleagues struggled with whether they should see them for the first time over video. Universally, providers felt feelings of inadequacy without an in-person examination and review of diagnostic information. 

Along those lines, many of our colleagues worried about their ability to perform the most fundamental role of a physician over the phone/internet for all patients: building trust with a patient.  Eye contact, the physical exam, and verbal and nonverbal communication that engenders confidence and displays empathy remain a challenge.  Multiple colleagues commented on the difficulty of communicating a new horrible diagnosis over a spotty internet connection.  Others expressed concern about the inability to review chest imaging in-person with patients as this often enhances patient comprehension and relieves anxiety about diagnostic possibilities. 

Providers also noted that telehealth implementation is not the same for all individuals. Just as COVID-19 disproportionately affects the most vulnerable populations (NYC Health. COVID-19: data. Accessed July 1, 2020. https://www1.nyc.gov/site/doh/covid/covid-19-data.page), practicing telehealth has uncovered more ways in which racial/ethnic minorities, low income communities, and older patients are at a disadvantage (Garg S, et al. MMWR Morb Mortal Wkly Rep. 2020;69[15]:458). The relatively quick transition to telemedicine revealed that many of our patients don’t have emails or home computers to connect with online platforms. Similarly, some do not have smart phones with internet capabilities. Many do not speak English and cannot partake in video visits since translators are not yet embedded into the EMR’s video system. Elderly patients were frequently very anxious with telemedicine because of unfamiliarity with the technology, and many preferred a phone conversation.  Thus, while more fortunate patients get to use a video interface and its association with higher patient understanding and satisfaction, our most vulnerable populations are often denied the same access to such care (Voils CI et al. J Genet Couns. 2018;27[2]:339).  

Telemedicine will continue to have a significant impact on the future of health care long after the COVID-19 pandemic abates.  There will be growing pains, refinement of technology, improvements in policy, and an ongoing general evolution of the system. Patients and providers will grow together as its utilization continues. We suspect patient surveys about their attitudes and preferences for telemedicine will be as varied as the providers surveyed here.  A recent survey of 1000 patients about their telehealth experiences during the pandemic reported that over 75% were very or completely satisfied with their virtual care experiences and over 50% indicated they would be willing to switch providers to have virtual visits on a regular basis (Patient Perspectives on Virtual Care Report, Accessed July 7, 2020, https://www.kyruus.com/2020-virtual-care-report).

One hopes that with time and on-going feedback, the fundamental purpose of the physician-patient relationship can be maintained and both sides can still appreciate the conveniences and power of telehealth technology.  

Dr. Fedyna and Dr. McGroder are affiliated with the Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, New York, NY.

Cystic fibrosis (CF) is an autosomal recessive disorder affecting thousands of people worldwide. When this genetic disease was first discovered in the first half of the 20th century, the median survival was approximately 5 years of age. Since then, median survival for patients with CF has steadily improved. Today, it is 47.4 years based on Cystic Fibrosis Foundation registry data from 2018. Patients with CF are living longer and staying healthier; the discussion to follow is how patients, researchers, and the CF Foundation reached this point.

In 1938, pediatrician and pathologist Dorothy Anderson observed on the autopsies of children thought to have celiac disease pancreatic lesions she termed “cystic fibrosis of the pancreas.” In addition to the abnormal pancreas, she noted abnormal lungs filled with mucus that obstructed the airways.

Paul Di Sant’Agnese recognized during a heatwave in late 1948 that children with CF were routinely being diagnosed with heatstroke and dehydration. This helped lead to the discovery that these children had elevated salt content in their sweat, paving the way for the development of the sweat chloride test in 1959 by Gibson and Cooke. Not only did Dr. Di Sant’Agnese recognize excess salt in the sweat of patients with CF, but with the help of several concerned parents of children with CF, he established the Cystic Fibrosis Foundation in 1955. The Foundation helped organize the care center model over the next decades, increasing from 30 care centers in 1962 to over 100 in 1978. The care center model also developed a patient registry to track patient care longitudinally.

In June 1989, Francis Collins and Lap-Chee Tsui discovered the location of the CF transmembrane conductance regulator (CFTR) protein using a novel technique called chromosome jumping (Rommens JM, et al. Science. 1989;245[4922]1059). The discovery was a breakthrough in basic science research, but it would take 3 more decades before this discovery could be translated into a medication that could be used by most patients for everyday care.

In the early 1990s, when median survival for patients with CF was 29 years of age, the CF Foundation and Genentech, Inc., coordinated a 24-week multicenter double-blind randomized control trial (RCT) for a new inhaled medication that digested the extracellular DNA from the neutrophils that accumulated in the airways of patients with CF. Inhaled recombinant human DNase in these patients reduced the risk of pulmonary exacerbations and also had a small improvement in pulmonary function in the group compared with the placebo group (Fuchs H, et al. N Engl J Med. 1994;331:637). Five years later, another double-blind RCT demonstrated that inhaled tobramycin in patients with CF whose disease was colonized with Pseudomonas aeruginosa improved pulmonary function and reduced the risk of hospitalizations (Ramsey B, et al. N Engl J Med. 1999;340:23). In 2006, the use of hypertonic saline solution in patients with CF decreased the overall pulmonary exacerbation rate (Elkins MR, et al. N Engl J Med. 2006;354:229). The combination of these inhaled medications, along with inhaled aztreonam, formed the backbone of inhalation therapy for CF care today.

In 1998, even with the ongoing development and approval of new CF medications by the pharmaceutical industry, Robert Beall, CEO of the CF Foundation, realized that he needed to challenge the current drug development paradigm. Instead of trying to convince companies to develop CF medications, he started a concept called venture philanthropy. This concept entailed the CF Foundation financially investing in pharmaceutical companies’ development of new medications. The Foundation first invested in a small company named Aurora Biosciences (known today as Vertex Pharmaceuticals) in 2000. Aurora Biosciences specialized in high throughput screening. This process uses a unique technology allowing one to test the therapeutic reaction of airway cells to thousands of chemical compounds in a single day, instead of using the traditional process of tediously pipetting compounds one by one. Today, the CF Foundation has invested millions of dollars into bioscience research to advance CF care.

In 2011, the results of a study were published in which a small molecule altered defective CFTR protein in patients with CF with the CFTR mutation G551D, thus improving chloride transport at the airway surface. In the original study, after 24 weeks of therapy receiving the medication known as ivacaftor, predicted FEV1 in patients with CF improved 10.6%, and the patients were 55% less likely to have a pulmonary exacerbation compared with those receiving a placebo. This breakthrough provided patients with CF the first medication that could correct the CFTR at the source of the problem (Ramsey BW, et al. N Engl J Med. 2011;365:1663). Ivacaftor was approved by the US FDA in 2012.

Ivacaftor provided proof of concept that using small molecules could improve CFTR function. Ivacaftor was only beneficial to a small percentage of patients and was not effective in patients with CF who had either 1 or 2 F508del CFTR mutations. In 2015, patients with CF with F508del homozygous treated with a combination therapy of lumacaftor/ivacaftor had predicted FEV1% improved 2.6% to 4.0%. More importantly, there was a significant reduction in the number of pulmonary exacerbations per year compared with placebo. Unexpectedly, some of the patients experienced bronchoconstriction while receiving lumacaftor/ivacaftor (Wainwright CE, et al. N Engl J Med. 2015; 373:220). The problem was recognized, and a new small molecule to improve the processing and trafficking of CFTR called tezacaftor was developed. The combination of tezacaftor/ivacaftor in patients with CF who were F508del homozygous demonstrated a similar reduction in pulmonary exacerbations, an absolute improvement of predicted FEV₁ of 4%, and no increased respiratory symptoms compared with the placebo arm (Taylor-Cousar JL, et al. N Engl J Med. 2017;377[21]2013).

CFTR modulators were a major breakthrough for patients with CF, but the efficacy of these therapies was dependent on the patients’ genotype and ranged from mildly to moderately effective. Unfortunately, these therapies were ineffective for the patients who were delta 508 heterozygotes. Starting in the summer of 2018, VX 445-tezacaftor-ivacaftor (ETI) was compared with placebo in patients with CF who were 1 copy of F508del and a second CFTR mutation that has minimal function. The study found an absolute improvement in predicted FEV1 of 14.3% and a 63% reduction in exacerbations at 24 weeks compared with placebo (Middleton PG, et al. N Engl J Med. 2019;381:1809). In late 2019, based on these data, ETI was approved by the FDA for all patients with CF who were F508del heterozygous. This innovation provided effective therapy to 90% of the CF population.

With the discovery of many highly effective therapies beneficial in most patients, the CF Foundation started a program called Path to a Cure to find therapies for the 10% of patients with CF who were not candidates for ETI or other CFTR modulators. This program looks to develop novel methods to restore CFTR protein function and repair or replace the CFTR protein via gene editing or gene transfer. This process creates many challenges that are quite complex, but patients, researchers, physicians, and CF Foundation will not stop working until CF stands for CURE FOUND.

Today, patients with CF are living longer, and many are eligible or have already started ETI therapy. This medication and the many others being developed will hopefully lead to patients with CF living a normal lifespan in the near future.
 

Dr. Finklea is Assistant Professor of Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, Texas. Dr. Finklea receives grant support from the Cystic Fibrosis Foundation.

Cystic fibrosis (CF) is an autosomal recessive disorder affecting thousands of people worldwide. When this genetic disease was first discovered in the first half of the 20th century, the median survival was approximately 5 years of age. Since then, median survival for patients with CF has steadily improved. Today, it is 47.4 years based on Cystic Fibrosis Foundation registry data from 2018. Patients with CF are living longer and staying healthier; the discussion to follow is how patients, researchers, and the CF Foundation reached this point.

In 1938, pediatrician and pathologist Dorothy Anderson observed on the autopsies of children thought to have celiac disease pancreatic lesions she termed “cystic fibrosis of the pancreas.” In addition to the abnormal pancreas, she noted abnormal lungs filled with mucus that obstructed the airways.

Paul Di Sant’Agnese recognized during a heatwave in late 1948 that children with CF were routinely being diagnosed with heatstroke and dehydration. This helped lead to the discovery that these children had elevated salt content in their sweat, paving the way for the development of the sweat chloride test in 1959 by Gibson and Cooke. Not only did Dr. Di Sant’Agnese recognize excess salt in the sweat of patients with CF, but with the help of several concerned parents of children with CF, he established the Cystic Fibrosis Foundation in 1955. The Foundation helped organize the care center model over the next decades, increasing from 30 care centers in 1962 to over 100 in 1978. The care center model also developed a patient registry to track patient care longitudinally.

In June 1989, Francis Collins and Lap-Chee Tsui discovered the location of the CF transmembrane conductance regulator (CFTR) protein using a novel technique called chromosome jumping (Rommens JM, et al. Science. 1989;245[4922]1059). The discovery was a breakthrough in basic science research, but it would take 3 more decades before this discovery could be translated into a medication that could be used by most patients for everyday care.

In the early 1990s, when median survival for patients with CF was 29 years of age, the CF Foundation and Genentech, Inc., coordinated a 24-week multicenter double-blind randomized control trial (RCT) for a new inhaled medication that digested the extracellular DNA from the neutrophils that accumulated in the airways of patients with CF. Inhaled recombinant human DNase in these patients reduced the risk of pulmonary exacerbations and also had a small improvement in pulmonary function in the group compared with the placebo group (Fuchs H, et al. N Engl J Med. 1994;331:637). Five years later, another double-blind RCT demonstrated that inhaled tobramycin in patients with CF whose disease was colonized with Pseudomonas aeruginosa improved pulmonary function and reduced the risk of hospitalizations (Ramsey B, et al. N Engl J Med. 1999;340:23). In 2006, the use of hypertonic saline solution in patients with CF decreased the overall pulmonary exacerbation rate (Elkins MR, et al. N Engl J Med. 2006;354:229). The combination of these inhaled medications, along with inhaled aztreonam, formed the backbone of inhalation therapy for CF care today.

In 1998, even with the ongoing development and approval of new CF medications by the pharmaceutical industry, Robert Beall, CEO of the CF Foundation, realized that he needed to challenge the current drug development paradigm. Instead of trying to convince companies to develop CF medications, he started a concept called venture philanthropy. This concept entailed the CF Foundation financially investing in pharmaceutical companies’ development of new medications. The Foundation first invested in a small company named Aurora Biosciences (known today as Vertex Pharmaceuticals) in 2000. Aurora Biosciences specialized in high throughput screening. This process uses a unique technology allowing one to test the therapeutic reaction of airway cells to thousands of chemical compounds in a single day, instead of using the traditional process of tediously pipetting compounds one by one. Today, the CF Foundation has invested millions of dollars into bioscience research to advance CF care.

In 2011, the results of a study were published in which a small molecule altered defective CFTR protein in patients with CF with the CFTR mutation G551D, thus improving chloride transport at the airway surface. In the original study, after 24 weeks of therapy receiving the medication known as ivacaftor, predicted FEV1 in patients with CF improved 10.6%, and the patients were 55% less likely to have a pulmonary exacerbation compared with those receiving a placebo. This breakthrough provided patients with CF the first medication that could correct the CFTR at the source of the problem (Ramsey BW, et al. N Engl J Med. 2011;365:1663). Ivacaftor was approved by the US FDA in 2012.

Ivacaftor provided proof of concept that using small molecules could improve CFTR function. Ivacaftor was only beneficial to a small percentage of patients and was not effective in patients with CF who had either 1 or 2 F508del CFTR mutations. In 2015, patients with CF with F508del homozygous treated with a combination therapy of lumacaftor/ivacaftor had predicted FEV1% improved 2.6% to 4.0%. More importantly, there was a significant reduction in the number of pulmonary exacerbations per year compared with placebo. Unexpectedly, some of the patients experienced bronchoconstriction while receiving lumacaftor/ivacaftor (Wainwright CE, et al. N Engl J Med. 2015; 373:220). The problem was recognized, and a new small molecule to improve the processing and trafficking of CFTR called tezacaftor was developed. The combination of tezacaftor/ivacaftor in patients with CF who were F508del homozygous demonstrated a similar reduction in pulmonary exacerbations, an absolute improvement of predicted FEV₁ of 4%, and no increased respiratory symptoms compared with the placebo arm (Taylor-Cousar JL, et al. N Engl J Med. 2017;377[21]2013).

CFTR modulators were a major breakthrough for patients with CF, but the efficacy of these therapies was dependent on the patients’ genotype and ranged from mildly to moderately effective. Unfortunately, these therapies were ineffective for the patients who were delta 508 heterozygotes. Starting in the summer of 2018, VX 445-tezacaftor-ivacaftor (ETI) was compared with placebo in patients with CF who were 1 copy of F508del and a second CFTR mutation that has minimal function. The study found an absolute improvement in predicted FEV1 of 14.3% and a 63% reduction in exacerbations at 24 weeks compared with placebo (Middleton PG, et al. N Engl J Med. 2019;381:1809). In late 2019, based on these data, ETI was approved by the FDA for all patients with CF who were F508del heterozygous. This innovation provided effective therapy to 90% of the CF population.

With the discovery of many highly effective therapies beneficial in most patients, the CF Foundation started a program called Path to a Cure to find therapies for the 10% of patients with CF who were not candidates for ETI or other CFTR modulators. This program looks to develop novel methods to restore CFTR protein function and repair or replace the CFTR protein via gene editing or gene transfer. This process creates many challenges that are quite complex, but patients, researchers, physicians, and CF Foundation will not stop working until CF stands for CURE FOUND.

Today, patients with CF are living longer, and many are eligible or have already started ETI therapy. This medication and the many others being developed will hopefully lead to patients with CF living a normal lifespan in the near future.
 

Dr. Finklea is Assistant Professor of Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, Texas. Dr. Finklea receives grant support from the Cystic Fibrosis Foundation.

Cystic fibrosis (CF) is an autosomal recessive disorder affecting thousands of people worldwide. When this genetic disease was first discovered in the first half of the 20th century, the median survival was approximately 5 years of age. Since then, median survival for patients with CF has steadily improved. Today, it is 47.4 years based on Cystic Fibrosis Foundation registry data from 2018. Patients with CF are living longer and staying healthier; the discussion to follow is how patients, researchers, and the CF Foundation reached this point.

In 1938, pediatrician and pathologist Dorothy Anderson observed on the autopsies of children thought to have celiac disease pancreatic lesions she termed “cystic fibrosis of the pancreas.” In addition to the abnormal pancreas, she noted abnormal lungs filled with mucus that obstructed the airways.

Paul Di Sant’Agnese recognized during a heatwave in late 1948 that children with CF were routinely being diagnosed with heatstroke and dehydration. This helped lead to the discovery that these children had elevated salt content in their sweat, paving the way for the development of the sweat chloride test in 1959 by Gibson and Cooke. Not only did Dr. Di Sant’Agnese recognize excess salt in the sweat of patients with CF, but with the help of several concerned parents of children with CF, he established the Cystic Fibrosis Foundation in 1955. The Foundation helped organize the care center model over the next decades, increasing from 30 care centers in 1962 to over 100 in 1978. The care center model also developed a patient registry to track patient care longitudinally.

In June 1989, Francis Collins and Lap-Chee Tsui discovered the location of the CF transmembrane conductance regulator (CFTR) protein using a novel technique called chromosome jumping (Rommens JM, et al. Science. 1989;245[4922]1059). The discovery was a breakthrough in basic science research, but it would take 3 more decades before this discovery could be translated into a medication that could be used by most patients for everyday care.

In the early 1990s, when median survival for patients with CF was 29 years of age, the CF Foundation and Genentech, Inc., coordinated a 24-week multicenter double-blind randomized control trial (RCT) for a new inhaled medication that digested the extracellular DNA from the neutrophils that accumulated in the airways of patients with CF. Inhaled recombinant human DNase in these patients reduced the risk of pulmonary exacerbations and also had a small improvement in pulmonary function in the group compared with the placebo group (Fuchs H, et al. N Engl J Med. 1994;331:637). Five years later, another double-blind RCT demonstrated that inhaled tobramycin in patients with CF whose disease was colonized with Pseudomonas aeruginosa improved pulmonary function and reduced the risk of hospitalizations (Ramsey B, et al. N Engl J Med. 1999;340:23). In 2006, the use of hypertonic saline solution in patients with CF decreased the overall pulmonary exacerbation rate (Elkins MR, et al. N Engl J Med. 2006;354:229). The combination of these inhaled medications, along with inhaled aztreonam, formed the backbone of inhalation therapy for CF care today.

In 1998, even with the ongoing development and approval of new CF medications by the pharmaceutical industry, Robert Beall, CEO of the CF Foundation, realized that he needed to challenge the current drug development paradigm. Instead of trying to convince companies to develop CF medications, he started a concept called venture philanthropy. This concept entailed the CF Foundation financially investing in pharmaceutical companies’ development of new medications. The Foundation first invested in a small company named Aurora Biosciences (known today as Vertex Pharmaceuticals) in 2000. Aurora Biosciences specialized in high throughput screening. This process uses a unique technology allowing one to test the therapeutic reaction of airway cells to thousands of chemical compounds in a single day, instead of using the traditional process of tediously pipetting compounds one by one. Today, the CF Foundation has invested millions of dollars into bioscience research to advance CF care.

In 2011, the results of a study were published in which a small molecule altered defective CFTR protein in patients with CF with the CFTR mutation G551D, thus improving chloride transport at the airway surface. In the original study, after 24 weeks of therapy receiving the medication known as ivacaftor, predicted FEV1 in patients with CF improved 10.6%, and the patients were 55% less likely to have a pulmonary exacerbation compared with those receiving a placebo. This breakthrough provided patients with CF the first medication that could correct the CFTR at the source of the problem (Ramsey BW, et al. N Engl J Med. 2011;365:1663). Ivacaftor was approved by the US FDA in 2012.

Ivacaftor provided proof of concept that using small molecules could improve CFTR function. Ivacaftor was only beneficial to a small percentage of patients and was not effective in patients with CF who had either 1 or 2 F508del CFTR mutations. In 2015, patients with CF with F508del homozygous treated with a combination therapy of lumacaftor/ivacaftor had predicted FEV1% improved 2.6% to 4.0%. More importantly, there was a significant reduction in the number of pulmonary exacerbations per year compared with placebo. Unexpectedly, some of the patients experienced bronchoconstriction while receiving lumacaftor/ivacaftor (Wainwright CE, et al. N Engl J Med. 2015; 373:220). The problem was recognized, and a new small molecule to improve the processing and trafficking of CFTR called tezacaftor was developed. The combination of tezacaftor/ivacaftor in patients with CF who were F508del homozygous demonstrated a similar reduction in pulmonary exacerbations, an absolute improvement of predicted FEV₁ of 4%, and no increased respiratory symptoms compared with the placebo arm (Taylor-Cousar JL, et al. N Engl J Med. 2017;377[21]2013).

CFTR modulators were a major breakthrough for patients with CF, but the efficacy of these therapies was dependent on the patients’ genotype and ranged from mildly to moderately effective. Unfortunately, these therapies were ineffective for the patients who were delta 508 heterozygotes. Starting in the summer of 2018, VX 445-tezacaftor-ivacaftor (ETI) was compared with placebo in patients with CF who were 1 copy of F508del and a second CFTR mutation that has minimal function. The study found an absolute improvement in predicted FEV1 of 14.3% and a 63% reduction in exacerbations at 24 weeks compared with placebo (Middleton PG, et al. N Engl J Med. 2019;381:1809). In late 2019, based on these data, ETI was approved by the FDA for all patients with CF who were F508del heterozygous. This innovation provided effective therapy to 90% of the CF population.

With the discovery of many highly effective therapies beneficial in most patients, the CF Foundation started a program called Path to a Cure to find therapies for the 10% of patients with CF who were not candidates for ETI or other CFTR modulators. This program looks to develop novel methods to restore CFTR protein function and repair or replace the CFTR protein via gene editing or gene transfer. This process creates many challenges that are quite complex, but patients, researchers, physicians, and CF Foundation will not stop working until CF stands for CURE FOUND.

Today, patients with CF are living longer, and many are eligible or have already started ETI therapy. This medication and the many others being developed will hopefully lead to patients with CF living a normal lifespan in the near future.
 

Dr. Finklea is Assistant Professor of Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern, Dallas, Texas. Dr. Finklea receives grant support from the Cystic Fibrosis Foundation.

Lung transplants are increasing, with 2,562 performed in the United States in 2018 – a 31% increase over the preceding 5 years. With this increased demand for donor lungs, waitlist mortality in the United States is 9.4 deaths per 100 waitlist-years for obstructive lung diseases and as high as 29.7 deaths per 100 waitlist-years for restrictive lung diseases (Valapour M, et al. Lung. Am J Transplant. 2020;20[suppl s1]:427). Conversely, lungs are utilized from eligible multiorgan donors only 15% to 20% of the time, usually due to concerns over donor history or organ quality (Young KA, et al. Chest. 2019;155[3]:465). In light of this imbalance of supply and demand, lung transplant specialists are making significant efforts to expand the donor pool of available organs. Three of these strategies include: (1) applications of ex-vivo lung perfusion (EVLP) technology; (2) use of lungs from hepatitis C-positive donors for hep-C negative recipients; and (3) increasing utilization of donation after cardiac death.

Normothermic ex-vivo lung perfusion is a technology which allows donor lungs to be perfused and ventilated after removal from the donor but before transplant into the recipient. This is in contrast to the traditional method of cold static preservation. The proposed advantage of using this technology is to allow time for a more thorough assessment of graft quality and to improve function of grafts not meeting established criteria for transplant, all-the-while decreasing organ ischemia despite an increased cross-clamp time. There are currently four commercial systems available capable of EVLP. Broadly speaking, three EVLP management protocols exist (Toronto, Lund, and OCS), which differ in perfusate composition, target flow, pulmonary arterial pressure, left atrial pressure, and ventilatory settings. Notably, the Toronto protocol uses a closed left atrium, whereas the Lund and OCS protocol use an open left atrium. There are excellent published reviews of the different systems (Possoz J, et al. J Thorac Dis. 2019;11[4]:1635). EVLP has now been studied for two different goals: (1) to allow an extended evaluation of lungs of questionable quality before transplant; or (2) for routine use in all lung transplantations in place of cold static preservation.

In most studies concerning the use of EVLP for reconditioning of donor lungs, “high risk” or “extended criteria” refers to one or more of the following: P/F ratios < 300 on arterial blood gas, macroscopic abnormalities (eg, pulmonary edema, poor lung compliance), donation after circulatory death, or high-risk history (eg, aspiration). The largest cohort with the longest follow-up addressing the role of EVLP for donation of lungs with extended criteria was published from the Toronto Lung Transplant Group. Their results have demonstrated equivalent graft survival and rates of chronic lung allograft dysfunction (CLAD) up to 9 years posttransplant compared with standard criteria donor lungs, despite utilizing lower quality lungs and having a longer median preservation (Divithotawela C, et al. JAMA Surg. 2019;154[12]:1143). The group’s subsequent lung transplant rates have increased over the past decade.

A separate study addressed the same question but differed in that it was a single-arm, multicenter, international trial that tracked the outcomes of 93 extended criteria lungs placed on EVLP (including a large proportion acquired via donation after circulatory death) (Loor G, et al. Lancet Respir Med. 2019;7[11]:975). Among these, 87% of eligible lungs were transplanted, and outcomes were excellent, albeit shorter in follow-up compared with the Toronto cohort (eg, primary graft dysfunction grade 3 (PGD3) within 72 hours was 44% and 1-year survival was 91%). Based on these trials and many other retrospective reports, it has been concluded by many experts in the field that EVLP-treated extended criteria donor lungs perform equally well to standard criteria donor lungs.

Two RCTs have been conducted to evaluate whether EVLP is noninferior to static cold storage with donor lungs meeting “standard criteria” for transplant. The first was a single center study at the Medical University of Vienna, that looked at 80 recipient/donor pairs. Lungs in the EVLP arm underwent 4 hours of perfusion with frequent reassessment of quality before transplant, whereas the lungs in the control arm went directly to transplant. This study met noninferiority criteria looking at primary outcomes of PGD grade >1 and 30-day survival (Slama A, et al. J Heart Lung Transplant. 2017;36[7]:744). The second study was a phase 3, multicenter, international trial that included 320 recipient/donor pairs randomized to either EVLP (without a prespecified time on the EVLP system) or static cold storage. This trial met noninferiority for safety endpoints (lung graft-related adverse events within 30 days) and a composite primary outcome of PGD grade 3 incidence within 72 hours and 30-day survival (Warnecke G, et al. Lancet Respir Med. 2018;6[5]:357). The authors also tested and found superiority of EVLP in lower PGD grade 3 frequency compared with control. While these RCTs may suggest a role for EVLP in the procurement process of standard criteria organs in addition to extended criteria organs in the future, major criticisms for these trials include the lack of a demonstrable clinical benefit over cold storage beyond the lower PGD3 rates.

In the era of direct-acting antiviral agents available to treat HCV infection, there has been efforts to study the early use of anti-HCV medications to prevent infection as a result of heart or lung transplant from HCV viremic donors to HCV-negative recipients. In one major trial on efficacy, it was found that 4 weeks of sofosbuvir and velpatasvir, when started within a few hours of transplant, was sufficient to achieve a sustained (undetectable) virologic response at 12 weeks after completion of the antiviral regimen (Woolley AE, et al. N Engl J Med. 2019;380[17]:1606). Therefore, many transplant centers have adopted protocols to increase the donor pool (by CDC estimates about 4% of solid organ donors are HCV-positive) by accepting HCV nucleic acid amplification test (NAT)-positive donors for HCV-negative recipients, after appropriate informed consent.

Donation after cardiac death (DCD), which is alternatively known as donation after circulatory determination of death (DCDD), generally refers to organ procurement taking place after cessation of circulation, often after inpatient withdrawal of support. This is in contrast to the much more common practice of donation after brain death (DBD). Addressing concerns over the quality of lungs donated in the context of DCD compared with DBD, analyses of ISHLT registry data have demonstrated no differences in hospital length of stay or survival at 1 or 5 years (Van Raemdonck D, et al. J Heart Lung Transplant. 2019;38[12]:1235). Outcomes comparing specific mechanisms of donor death in DCD remain relatively unknown, such as outcomes from donors withdrawn from life support vs donors who had an uncontrolled cardiac death.

These methods for expanding the donor pool are not mutually exclusive, and, in fact, application of EVLP for lungs obtained in the context of DCD seems to be increasingly common. Optimization of protocols with collaboration between lung transplant centers will be paramount as we move forward in advancing this field. As we do so, efforts to successfully increase the donor pool will serve to provide a life-saving therapy to an ever-growing number of patients with end-stage lung disease.

Dr. Sala and Dr. Tomic are with the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois.

Lung transplants are increasing, with 2,562 performed in the United States in 2018 – a 31% increase over the preceding 5 years. With this increased demand for donor lungs, waitlist mortality in the United States is 9.4 deaths per 100 waitlist-years for obstructive lung diseases and as high as 29.7 deaths per 100 waitlist-years for restrictive lung diseases (Valapour M, et al. Lung. Am J Transplant. 2020;20[suppl s1]:427). Conversely, lungs are utilized from eligible multiorgan donors only 15% to 20% of the time, usually due to concerns over donor history or organ quality (Young KA, et al. Chest. 2019;155[3]:465). In light of this imbalance of supply and demand, lung transplant specialists are making significant efforts to expand the donor pool of available organs. Three of these strategies include: (1) applications of ex-vivo lung perfusion (EVLP) technology; (2) use of lungs from hepatitis C-positive donors for hep-C negative recipients; and (3) increasing utilization of donation after cardiac death.

Normothermic ex-vivo lung perfusion is a technology which allows donor lungs to be perfused and ventilated after removal from the donor but before transplant into the recipient. This is in contrast to the traditional method of cold static preservation. The proposed advantage of using this technology is to allow time for a more thorough assessment of graft quality and to improve function of grafts not meeting established criteria for transplant, all-the-while decreasing organ ischemia despite an increased cross-clamp time. There are currently four commercial systems available capable of EVLP. Broadly speaking, three EVLP management protocols exist (Toronto, Lund, and OCS), which differ in perfusate composition, target flow, pulmonary arterial pressure, left atrial pressure, and ventilatory settings. Notably, the Toronto protocol uses a closed left atrium, whereas the Lund and OCS protocol use an open left atrium. There are excellent published reviews of the different systems (Possoz J, et al. J Thorac Dis. 2019;11[4]:1635). EVLP has now been studied for two different goals: (1) to allow an extended evaluation of lungs of questionable quality before transplant; or (2) for routine use in all lung transplantations in place of cold static preservation.

In most studies concerning the use of EVLP for reconditioning of donor lungs, “high risk” or “extended criteria” refers to one or more of the following: P/F ratios < 300 on arterial blood gas, macroscopic abnormalities (eg, pulmonary edema, poor lung compliance), donation after circulatory death, or high-risk history (eg, aspiration). The largest cohort with the longest follow-up addressing the role of EVLP for donation of lungs with extended criteria was published from the Toronto Lung Transplant Group. Their results have demonstrated equivalent graft survival and rates of chronic lung allograft dysfunction (CLAD) up to 9 years posttransplant compared with standard criteria donor lungs, despite utilizing lower quality lungs and having a longer median preservation (Divithotawela C, et al. JAMA Surg. 2019;154[12]:1143). The group’s subsequent lung transplant rates have increased over the past decade.

A separate study addressed the same question but differed in that it was a single-arm, multicenter, international trial that tracked the outcomes of 93 extended criteria lungs placed on EVLP (including a large proportion acquired via donation after circulatory death) (Loor G, et al. Lancet Respir Med. 2019;7[11]:975). Among these, 87% of eligible lungs were transplanted, and outcomes were excellent, albeit shorter in follow-up compared with the Toronto cohort (eg, primary graft dysfunction grade 3 (PGD3) within 72 hours was 44% and 1-year survival was 91%). Based on these trials and many other retrospective reports, it has been concluded by many experts in the field that EVLP-treated extended criteria donor lungs perform equally well to standard criteria donor lungs.

Two RCTs have been conducted to evaluate whether EVLP is noninferior to static cold storage with donor lungs meeting “standard criteria” for transplant. The first was a single center study at the Medical University of Vienna, that looked at 80 recipient/donor pairs. Lungs in the EVLP arm underwent 4 hours of perfusion with frequent reassessment of quality before transplant, whereas the lungs in the control arm went directly to transplant. This study met noninferiority criteria looking at primary outcomes of PGD grade >1 and 30-day survival (Slama A, et al. J Heart Lung Transplant. 2017;36[7]:744). The second study was a phase 3, multicenter, international trial that included 320 recipient/donor pairs randomized to either EVLP (without a prespecified time on the EVLP system) or static cold storage. This trial met noninferiority for safety endpoints (lung graft-related adverse events within 30 days) and a composite primary outcome of PGD grade 3 incidence within 72 hours and 30-day survival (Warnecke G, et al. Lancet Respir Med. 2018;6[5]:357). The authors also tested and found superiority of EVLP in lower PGD grade 3 frequency compared with control. While these RCTs may suggest a role for EVLP in the procurement process of standard criteria organs in addition to extended criteria organs in the future, major criticisms for these trials include the lack of a demonstrable clinical benefit over cold storage beyond the lower PGD3 rates.

In the era of direct-acting antiviral agents available to treat HCV infection, there has been efforts to study the early use of anti-HCV medications to prevent infection as a result of heart or lung transplant from HCV viremic donors to HCV-negative recipients. In one major trial on efficacy, it was found that 4 weeks of sofosbuvir and velpatasvir, when started within a few hours of transplant, was sufficient to achieve a sustained (undetectable) virologic response at 12 weeks after completion of the antiviral regimen (Woolley AE, et al. N Engl J Med. 2019;380[17]:1606). Therefore, many transplant centers have adopted protocols to increase the donor pool (by CDC estimates about 4% of solid organ donors are HCV-positive) by accepting HCV nucleic acid amplification test (NAT)-positive donors for HCV-negative recipients, after appropriate informed consent.

Donation after cardiac death (DCD), which is alternatively known as donation after circulatory determination of death (DCDD), generally refers to organ procurement taking place after cessation of circulation, often after inpatient withdrawal of support. This is in contrast to the much more common practice of donation after brain death (DBD). Addressing concerns over the quality of lungs donated in the context of DCD compared with DBD, analyses of ISHLT registry data have demonstrated no differences in hospital length of stay or survival at 1 or 5 years (Van Raemdonck D, et al. J Heart Lung Transplant. 2019;38[12]:1235). Outcomes comparing specific mechanisms of donor death in DCD remain relatively unknown, such as outcomes from donors withdrawn from life support vs donors who had an uncontrolled cardiac death.

These methods for expanding the donor pool are not mutually exclusive, and, in fact, application of EVLP for lungs obtained in the context of DCD seems to be increasingly common. Optimization of protocols with collaboration between lung transplant centers will be paramount as we move forward in advancing this field. As we do so, efforts to successfully increase the donor pool will serve to provide a life-saving therapy to an ever-growing number of patients with end-stage lung disease.

Dr. Sala and Dr. Tomic are with the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois.

Lung transplants are increasing, with 2,562 performed in the United States in 2018 – a 31% increase over the preceding 5 years. With this increased demand for donor lungs, waitlist mortality in the United States is 9.4 deaths per 100 waitlist-years for obstructive lung diseases and as high as 29.7 deaths per 100 waitlist-years for restrictive lung diseases (Valapour M, et al. Lung. Am J Transplant. 2020;20[suppl s1]:427). Conversely, lungs are utilized from eligible multiorgan donors only 15% to 20% of the time, usually due to concerns over donor history or organ quality (Young KA, et al. Chest. 2019;155[3]:465). In light of this imbalance of supply and demand, lung transplant specialists are making significant efforts to expand the donor pool of available organs. Three of these strategies include: (1) applications of ex-vivo lung perfusion (EVLP) technology; (2) use of lungs from hepatitis C-positive donors for hep-C negative recipients; and (3) increasing utilization of donation after cardiac death.

Normothermic ex-vivo lung perfusion is a technology which allows donor lungs to be perfused and ventilated after removal from the donor but before transplant into the recipient. This is in contrast to the traditional method of cold static preservation. The proposed advantage of using this technology is to allow time for a more thorough assessment of graft quality and to improve function of grafts not meeting established criteria for transplant, all-the-while decreasing organ ischemia despite an increased cross-clamp time. There are currently four commercial systems available capable of EVLP. Broadly speaking, three EVLP management protocols exist (Toronto, Lund, and OCS), which differ in perfusate composition, target flow, pulmonary arterial pressure, left atrial pressure, and ventilatory settings. Notably, the Toronto protocol uses a closed left atrium, whereas the Lund and OCS protocol use an open left atrium. There are excellent published reviews of the different systems (Possoz J, et al. J Thorac Dis. 2019;11[4]:1635). EVLP has now been studied for two different goals: (1) to allow an extended evaluation of lungs of questionable quality before transplant; or (2) for routine use in all lung transplantations in place of cold static preservation.

In most studies concerning the use of EVLP for reconditioning of donor lungs, “high risk” or “extended criteria” refers to one or more of the following: P/F ratios < 300 on arterial blood gas, macroscopic abnormalities (eg, pulmonary edema, poor lung compliance), donation after circulatory death, or high-risk history (eg, aspiration). The largest cohort with the longest follow-up addressing the role of EVLP for donation of lungs with extended criteria was published from the Toronto Lung Transplant Group. Their results have demonstrated equivalent graft survival and rates of chronic lung allograft dysfunction (CLAD) up to 9 years posttransplant compared with standard criteria donor lungs, despite utilizing lower quality lungs and having a longer median preservation (Divithotawela C, et al. JAMA Surg. 2019;154[12]:1143). The group’s subsequent lung transplant rates have increased over the past decade.

A separate study addressed the same question but differed in that it was a single-arm, multicenter, international trial that tracked the outcomes of 93 extended criteria lungs placed on EVLP (including a large proportion acquired via donation after circulatory death) (Loor G, et al. Lancet Respir Med. 2019;7[11]:975). Among these, 87% of eligible lungs were transplanted, and outcomes were excellent, albeit shorter in follow-up compared with the Toronto cohort (eg, primary graft dysfunction grade 3 (PGD3) within 72 hours was 44% and 1-year survival was 91%). Based on these trials and many other retrospective reports, it has been concluded by many experts in the field that EVLP-treated extended criteria donor lungs perform equally well to standard criteria donor lungs.

Two RCTs have been conducted to evaluate whether EVLP is noninferior to static cold storage with donor lungs meeting “standard criteria” for transplant. The first was a single center study at the Medical University of Vienna, that looked at 80 recipient/donor pairs. Lungs in the EVLP arm underwent 4 hours of perfusion with frequent reassessment of quality before transplant, whereas the lungs in the control arm went directly to transplant. This study met noninferiority criteria looking at primary outcomes of PGD grade >1 and 30-day survival (Slama A, et al. J Heart Lung Transplant. 2017;36[7]:744). The second study was a phase 3, multicenter, international trial that included 320 recipient/donor pairs randomized to either EVLP (without a prespecified time on the EVLP system) or static cold storage. This trial met noninferiority for safety endpoints (lung graft-related adverse events within 30 days) and a composite primary outcome of PGD grade 3 incidence within 72 hours and 30-day survival (Warnecke G, et al. Lancet Respir Med. 2018;6[5]:357). The authors also tested and found superiority of EVLP in lower PGD grade 3 frequency compared with control. While these RCTs may suggest a role for EVLP in the procurement process of standard criteria organs in addition to extended criteria organs in the future, major criticisms for these trials include the lack of a demonstrable clinical benefit over cold storage beyond the lower PGD3 rates.

In the era of direct-acting antiviral agents available to treat HCV infection, there has been efforts to study the early use of anti-HCV medications to prevent infection as a result of heart or lung transplant from HCV viremic donors to HCV-negative recipients. In one major trial on efficacy, it was found that 4 weeks of sofosbuvir and velpatasvir, when started within a few hours of transplant, was sufficient to achieve a sustained (undetectable) virologic response at 12 weeks after completion of the antiviral regimen (Woolley AE, et al. N Engl J Med. 2019;380[17]:1606). Therefore, many transplant centers have adopted protocols to increase the donor pool (by CDC estimates about 4% of solid organ donors are HCV-positive) by accepting HCV nucleic acid amplification test (NAT)-positive donors for HCV-negative recipients, after appropriate informed consent.

Donation after cardiac death (DCD), which is alternatively known as donation after circulatory determination of death (DCDD), generally refers to organ procurement taking place after cessation of circulation, often after inpatient withdrawal of support. This is in contrast to the much more common practice of donation after brain death (DBD). Addressing concerns over the quality of lungs donated in the context of DCD compared with DBD, analyses of ISHLT registry data have demonstrated no differences in hospital length of stay or survival at 1 or 5 years (Van Raemdonck D, et al. J Heart Lung Transplant. 2019;38[12]:1235). Outcomes comparing specific mechanisms of donor death in DCD remain relatively unknown, such as outcomes from donors withdrawn from life support vs donors who had an uncontrolled cardiac death.

These methods for expanding the donor pool are not mutually exclusive, and, in fact, application of EVLP for lungs obtained in the context of DCD seems to be increasingly common. Optimization of protocols with collaboration between lung transplant centers will be paramount as we move forward in advancing this field. As we do so, efforts to successfully increase the donor pool will serve to provide a life-saving therapy to an ever-growing number of patients with end-stage lung disease.

Dr. Sala and Dr. Tomic are with the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois.

The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention.  
Advances in technology over the last century, as well as the exportation of many high exposure jobs, nearly eliminated lung diseases caused by occupational exposure to respirable dust (the pneumoconioses) in the United States. One such example of this near elimination is black lung, or coal workers' pneumoconiosis (CWP), following the 1969 Federal Coal Mine Health and Safety Act. The Act established permissible exposure limits to respirable dust, designed to prevent the most severe forms of CWP from occurring, and a national respiratory health screening program for underground coal miners. Between 1970 and the mid-1990s, disease prevalence plummeted from nearly 35% to less than 5% prevalence among longer tenured miners, and from 3% to less than 1% in miners with less than 10 years of mining tenure (Hall NB, et al. Curr Environ Health Rep. 2019;6[3]:137).

Resources for clinicians  

CWP is most commonly identified using plain posterior-anterior chest radiography and presence/severity of fibrotic change is described using an international standard established by the International Labour Office (International Labour Office. Guidelines for the use of the ILO international classification of radiographs of pneumoconioses. Geneva: International Labour Office; 2011). In the United States, NIOSH operates the B Reader Training and Certification Program, which offers a free self-study syllabus, https://www.cdc.gov/niosh/topics/chestradiography/breader.html, and in-person training courses on occasion, to assist physicians in learning and demonstrating continuous competency in classifying chest radiographs of dust-exposed workers according to the ILO Standards (Halldin CN, et al. J Occup Environ Med. 2019;61[12]:1045). The B Reader Program and ILO Standards are currently undergoing a decade-long revision process where both will feature digitally acquired chest radiograph images. This process should be fully complete in the following months. 
To educate miners, mine operators, and others about the risks of respirable dust, NIOSH produced an educational video, Faces of Black Lung, in 2008 that featured two miners in their 50s and 60s who had complicated Black Lung. Because of the resurgence of disease and particularly severe cases being identified among much younger miners, NIOSH recently released an updated version of the video, Faces of Black Lung II, where three Kentucky underground miners, ages 39, 42, and 48, describe the incredible disability and quality of life lost due to a disease caused by gross overexposure of respirable coal mine dust.  
Unfortunately, the 42-year-old miner died from complications stemming from Black Lung less than a year after filming his part in the video, and the other two miners have been advised to be evaluated for lung transplantation. We hope that these men's stories will help younger miners relate to the risks of respirable coal mine dust and help others understand the severity of disease as all three of these men struggled to breathe just describing their day to day tasks.

 
Parting message 

No one should ever have to consider a lung transplant at the age of 40 because they went to work attempting to provide for their family. No one should ever be faced with end-of-life planning while their kids are in grade school because of a disease they acquired at work. Respirable coal mine dust is the only cause of black lung, and the coal mining industry has the necessary technology and tools to prevent harmful exposures to respirable dust, and, together with miners, must successfully and consistently implement dust suppression controls. There is no cure for black lung; it's irreversible and can be first recognized and continue to progress even after a miner has left exposure. However, early identification and appropriate intervention can prevent progression to the most disabling manifestations. The role of the clinician is to be part of the early identification of black lung through including CWP in the differential diagnosis for unusual or unexpected respiratory illness in otherwise healthy primarily working aged miners. The public health community must continue to monitor disease prevalence in working populations and implement policies and recommendations to support the efforts of those on the frontline - the miners, industry, and health-care workers.  
The Energy Information Agency projects that coal will continue to be a substantial source of U.S. energy production and consumption well into the mid- to late-century. Unfortunately, Black Lung has made a resurgence and is killing miners, and each of us has a role to play in eliminating it once and for all. We will continue to carry out our mandate to screen working coal miners for respiratory disease; however, given the continued contraction of the coal mining industry, it's much more likely for cases of disease to be recognized in the clinic setting. Therefore, we reiterate our previous plea to clinicians: when identifying an individual with interstitial fibrosis consider their full occupational history. 
 
Dr. Halldin and Dr. Laney are from the Surveillance Branch, Respiratory Health Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV.

The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention.  
Advances in technology over the last century, as well as the exportation of many high exposure jobs, nearly eliminated lung diseases caused by occupational exposure to respirable dust (the pneumoconioses) in the United States. One such example of this near elimination is black lung, or coal workers' pneumoconiosis (CWP), following the 1969 Federal Coal Mine Health and Safety Act. The Act established permissible exposure limits to respirable dust, designed to prevent the most severe forms of CWP from occurring, and a national respiratory health screening program for underground coal miners. Between 1970 and the mid-1990s, disease prevalence plummeted from nearly 35% to less than 5% prevalence among longer tenured miners, and from 3% to less than 1% in miners with less than 10 years of mining tenure (Hall NB, et al. Curr Environ Health Rep. 2019;6[3]:137).

Resources for clinicians  

CWP is most commonly identified using plain posterior-anterior chest radiography and presence/severity of fibrotic change is described using an international standard established by the International Labour Office (International Labour Office. Guidelines for the use of the ILO international classification of radiographs of pneumoconioses. Geneva: International Labour Office; 2011). In the United States, NIOSH operates the B Reader Training and Certification Program, which offers a free self-study syllabus, https://www.cdc.gov/niosh/topics/chestradiography/breader.html, and in-person training courses on occasion, to assist physicians in learning and demonstrating continuous competency in classifying chest radiographs of dust-exposed workers according to the ILO Standards (Halldin CN, et al. J Occup Environ Med. 2019;61[12]:1045). The B Reader Program and ILO Standards are currently undergoing a decade-long revision process where both will feature digitally acquired chest radiograph images. This process should be fully complete in the following months. 
To educate miners, mine operators, and others about the risks of respirable dust, NIOSH produced an educational video, Faces of Black Lung, in 2008 that featured two miners in their 50s and 60s who had complicated Black Lung. Because of the resurgence of disease and particularly severe cases being identified among much younger miners, NIOSH recently released an updated version of the video, Faces of Black Lung II, where three Kentucky underground miners, ages 39, 42, and 48, describe the incredible disability and quality of life lost due to a disease caused by gross overexposure of respirable coal mine dust.  
Unfortunately, the 42-year-old miner died from complications stemming from Black Lung less than a year after filming his part in the video, and the other two miners have been advised to be evaluated for lung transplantation. We hope that these men's stories will help younger miners relate to the risks of respirable coal mine dust and help others understand the severity of disease as all three of these men struggled to breathe just describing their day to day tasks.

 
Parting message 

No one should ever have to consider a lung transplant at the age of 40 because they went to work attempting to provide for their family. No one should ever be faced with end-of-life planning while their kids are in grade school because of a disease they acquired at work. Respirable coal mine dust is the only cause of black lung, and the coal mining industry has the necessary technology and tools to prevent harmful exposures to respirable dust, and, together with miners, must successfully and consistently implement dust suppression controls. There is no cure for black lung; it's irreversible and can be first recognized and continue to progress even after a miner has left exposure. However, early identification and appropriate intervention can prevent progression to the most disabling manifestations. The role of the clinician is to be part of the early identification of black lung through including CWP in the differential diagnosis for unusual or unexpected respiratory illness in otherwise healthy primarily working aged miners. The public health community must continue to monitor disease prevalence in working populations and implement policies and recommendations to support the efforts of those on the frontline - the miners, industry, and health-care workers.  
The Energy Information Agency projects that coal will continue to be a substantial source of U.S. energy production and consumption well into the mid- to late-century. Unfortunately, Black Lung has made a resurgence and is killing miners, and each of us has a role to play in eliminating it once and for all. We will continue to carry out our mandate to screen working coal miners for respiratory disease; however, given the continued contraction of the coal mining industry, it's much more likely for cases of disease to be recognized in the clinic setting. Therefore, we reiterate our previous plea to clinicians: when identifying an individual with interstitial fibrosis consider their full occupational history. 
 
Dr. Halldin and Dr. Laney are from the Surveillance Branch, Respiratory Health Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV.

The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention.  
Advances in technology over the last century, as well as the exportation of many high exposure jobs, nearly eliminated lung diseases caused by occupational exposure to respirable dust (the pneumoconioses) in the United States. One such example of this near elimination is black lung, or coal workers' pneumoconiosis (CWP), following the 1969 Federal Coal Mine Health and Safety Act. The Act established permissible exposure limits to respirable dust, designed to prevent the most severe forms of CWP from occurring, and a national respiratory health screening program for underground coal miners. Between 1970 and the mid-1990s, disease prevalence plummeted from nearly 35% to less than 5% prevalence among longer tenured miners, and from 3% to less than 1% in miners with less than 10 years of mining tenure (Hall NB, et al. Curr Environ Health Rep. 2019;6[3]:137).

Resources for clinicians  

CWP is most commonly identified using plain posterior-anterior chest radiography and presence/severity of fibrotic change is described using an international standard established by the International Labour Office (International Labour Office. Guidelines for the use of the ILO international classification of radiographs of pneumoconioses. Geneva: International Labour Office; 2011). In the United States, NIOSH operates the B Reader Training and Certification Program, which offers a free self-study syllabus, https://www.cdc.gov/niosh/topics/chestradiography/breader.html, and in-person training courses on occasion, to assist physicians in learning and demonstrating continuous competency in classifying chest radiographs of dust-exposed workers according to the ILO Standards (Halldin CN, et al. J Occup Environ Med. 2019;61[12]:1045). The B Reader Program and ILO Standards are currently undergoing a decade-long revision process where both will feature digitally acquired chest radiograph images. This process should be fully complete in the following months. 
To educate miners, mine operators, and others about the risks of respirable dust, NIOSH produced an educational video, Faces of Black Lung, in 2008 that featured two miners in their 50s and 60s who had complicated Black Lung. Because of the resurgence of disease and particularly severe cases being identified among much younger miners, NIOSH recently released an updated version of the video, Faces of Black Lung II, where three Kentucky underground miners, ages 39, 42, and 48, describe the incredible disability and quality of life lost due to a disease caused by gross overexposure of respirable coal mine dust.  
Unfortunately, the 42-year-old miner died from complications stemming from Black Lung less than a year after filming his part in the video, and the other two miners have been advised to be evaluated for lung transplantation. We hope that these men's stories will help younger miners relate to the risks of respirable coal mine dust and help others understand the severity of disease as all three of these men struggled to breathe just describing their day to day tasks.

 
Parting message 

No one should ever have to consider a lung transplant at the age of 40 because they went to work attempting to provide for their family. No one should ever be faced with end-of-life planning while their kids are in grade school because of a disease they acquired at work. Respirable coal mine dust is the only cause of black lung, and the coal mining industry has the necessary technology and tools to prevent harmful exposures to respirable dust, and, together with miners, must successfully and consistently implement dust suppression controls. There is no cure for black lung; it's irreversible and can be first recognized and continue to progress even after a miner has left exposure. However, early identification and appropriate intervention can prevent progression to the most disabling manifestations. The role of the clinician is to be part of the early identification of black lung through including CWP in the differential diagnosis for unusual or unexpected respiratory illness in otherwise healthy primarily working aged miners. The public health community must continue to monitor disease prevalence in working populations and implement policies and recommendations to support the efforts of those on the frontline - the miners, industry, and health-care workers.  
The Energy Information Agency projects that coal will continue to be a substantial source of U.S. energy production and consumption well into the mid- to late-century. Unfortunately, Black Lung has made a resurgence and is killing miners, and each of us has a role to play in eliminating it once and for all. We will continue to carry out our mandate to screen working coal miners for respiratory disease; however, given the continued contraction of the coal mining industry, it's much more likely for cases of disease to be recognized in the clinic setting. Therefore, we reiterate our previous plea to clinicians: when identifying an individual with interstitial fibrosis consider their full occupational history. 
 
Dr. Halldin and Dr. Laney are from the Surveillance Branch, Respiratory Health Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV.