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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.