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What we expected all along: Bronchiolitis obliterans syndrome is not specific for bronchiolitis obliterans in pediatric lung transplantation! Christian Benden, MD, FCCP From the Division of Pulmonary Medicine, University Hospital Zurich, Zurich, Switzerland.
Lung transplantation is nowadays considered a valuable therapy option in carefully selected pediatric patients with end-stage lung disease.1 To date, almost 2,000 pediatric lung and more than 600 pediatric heart-lung transplant procedures have been reported to the Registry of the International Society for Heart and Lung Transplantation (ISHLT).2 In recent years, outcome after pediatric lung transplantation has improved, mostly due to reduced early post-operative mortality; however, chronic lung allograft dysfunction (CLAD) remains the major hurdle for improved long-term survival after lung transplantation in adults and children alike.1 The term CLAD was first introduced in the lung transplant literature in 2010, and a definition of CLAD was proposed by a panel of experts in the field and published in the Journal of Heart and Lung Transplantation in 2014, aiming to help to “classify” the different phenotypes of CLAD in lung transplant patients.3 It is important to note that the document by Verleden et al3 has no particular pediatric focus. Overall, CLAD is an umbrella term that comprises all forms of chronic lung dysfunction after transplant. Bronchiolitis obliterans (BO) and its physiologic correlate, bronchiolitis obliterans syndrome (BOS), is the most common form of CLAD. According to recent ISHLT Registry figures, BO/BOS is the major cause of death beyond 3 years after transplant.2 Moreover, more than 50% of surviving pediatric patients experience BO/BOS by 5 years after lung transplantation.2 As proposed by the ISHLT, BOS was defined clinically based on lung function criteria as a progressive decline in forced expiratory volume in 1 second; however, so far, the diagnostic criteria have not specifically been adapted for the use in pediatric lung transplant recipients, particularly with regards to a clear definition of the best baseline values after transplantation
See Related Article, page 516 and the incorporation of somatic growth in children. Such a standardization of the definition of the lung function baseline values and criteria for BOS diagnosis in children is still urgently required. As defined, lung function loss has to be non-reversible and present on 2 separate occasions a minimum of 3 weeks apart to fulfill BOS criteria and exclude acute allograft rejection or infection. Unfortunately, there is a complete lack of data showing a correlation between changes in forced expiratory volume in 1 second and development of BO in pediatric lung transplantation to date. The article by Towe et al,5 from St. Louis, Missouri, in this issue of the Journal reports results of a single-center, retrospective study to determine the sensitivity, specificity, and positive and negative predictive values of BOS for predicting BO in pediatric lung transplant recipients.4 In their study, the overall sensitivity of BOS was 91%, demonstrating that spirometry is a reasonable BO screening tool; however, spirometry is not specific for the diagnosis of BO. Even though this is a single-center retrospective study including o100 samples for analysis (almost 50% of samples had to be excluded from analysis for various reasons), this is the largest pediatric data collection of its kind to date. More than 350 pediatric lung transplants have been performed to date in St. Louis, making it the biggest pediatric lung transplant program in the world. Overall, the Towe et al5 study adds meaningful new knowledge to the field of pediatric lung transplantation, in particular, that BOS is not the ideal surrogate marker for BO in the absence of other diagnostic tests, a fact that experts in the field of pediatric lung transplantation have expected all along. This finding has important implications for patients’ clinical
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2015.01.001
502
The Journal of Heart and Lung Transplantation, Vol 34, No 4, April 2015
management; specifically, avoidance of unnecessary overimmunosuppression if BO is incorrectly assumed. It is noteworthy that the study by Towe et al5 was originally designed and performed before the CLAD terminology was accepted and introduced broadly in daily clinical practice. In that sense, the authors diagnosed BOS correctly according to previously published ISHLT guidelines using spirometry, after the exclusion of other specific causes of CLAD, in the allograft (i.e., anastomotic strictures) and extra-allograft (i.e., pleural disease or diaphragmatic dysfunction). Full lung function tests were not readily available in a substantive part of the patients in the cohort because patients underwent transplants in an era where total lung capacity (TLC) measurements were not routinely obtained, even though older children would have principally been capable to perform full lung function tests. Such measurements of TLC and residual volumes would have been helpful to assist delineating obstructive vs mixed ventilation defects. In addition, computed tomography chest imaging and ventilation/perfusion scans would have been valuable diagnostic tools to facilitate phenotyping of CLAD, yet such tests were not usually performed during the old transplant era. In summary, one has to agree with the authors’ conclusion that BOS should not generally be used as a substitute diagnosis for BO, but what are its practical implications for our daily clinical work?
Perform flexible bronchoscopy with bronchoalveolar lavage and transbronchial biopsy early in the evaluation of lung function decline in pediatric lung transplant recipients, exactly as the St. Louis team described as their standard clinical practice. Full lung function testing comprising TLC measurements and residual volumes should be done wherever possible and
additional diagnostic tools used, including high-resolution computed tomography chest imaging (in inspiration/ expiration), and ideally, diagnosis of BO confirmed on lung tissue biopsy. However, an invasive procedure is required to obtain a tissue sample, and the risks and benefits of such a diagnostic procedure have to be balanced very carefully, in particular, in a child with an already progressively impaired lung function. Because small airway lesions in BO are mostly patchy in nature, specimens from transbronchial lung biopsies are often unsuccessful in providing a definite tissue diagnosis, and tissue sampling has to be achieved by other means, such as video-assisted thoracoscopic surgery or open lung biopsy.
Disclosure statement The author has no financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Benden C. Specific aspects of children and adolescents undergoing lung transplantation. Curr Opin Organ Transplant 2012;17:509-14. 2. Benden C, Goldfarb SB, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart-lung transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:1025-33. 3. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant 2014;33:127-33. 4. Towe C, Ogborn AC, Ferkol T, et al. Bronchiolitis obliterans syndrome is not specific for bronchiolitis obliterans in pediatric lung transplant. J Heart Lung Transplant 2015;34:516-21.
What we expected all along: Bronchiolitis obliterans syndrome is not specific for bronchiolitis obliterans in pediatric lung transplantation! Christian Benden, MD, FCCP From the Division of Pulmonary Medicine, University Hospital Zurich, Zurich, Switzerland.
Lung transplantation is nowadays considered a valuable therapy option in carefully selected pediatric patients with end-stage lung disease.1 To date, almost 2,000 pediatric lung and more than 600 pediatric heart-lung transplant procedures have been reported to the Registry of the International Society for Heart and Lung Transplantation (ISHLT).2 In recent years, outcome after pediatric lung transplantation has improved, mostly due to reduced early post-operative mortality; however, chronic lung allograft dysfunction (CLAD) remains the major hurdle for improved long-term survival after lung transplantation in adults and children alike.1 The term CLAD was first introduced in the lung transplant literature in 2010, and a definition of CLAD was proposed by a panel of experts in the field and published in the Journal of Heart and Lung Transplantation in 2014, aiming to help to “classify” the different phenotypes of CLAD in lung transplant patients.3 It is important to note that the document by Verleden et al3 has no particular pediatric focus. Overall, CLAD is an umbrella term that comprises all forms of chronic lung dysfunction after transplant. Bronchiolitis obliterans (BO) and its physiologic correlate, bronchiolitis obliterans syndrome (BOS), is the most common form of CLAD. According to recent ISHLT Registry figures, BO/BOS is the major cause of death beyond 3 years after transplant.2 Moreover, more than 50% of surviving pediatric patients experience BO/BOS by 5 years after lung transplantation.2 As proposed by the ISHLT, BOS was defined clinically based on lung function criteria as a progressive decline in forced expiratory volume in 1 second; however, so far, the diagnostic criteria have not specifically been adapted for the use in pediatric lung transplant recipients, particularly with regards to a clear definition of the best baseline values after transplantation
See Related Article, page 516 and the incorporation of somatic growth in children. Such a standardization of the definition of the lung function baseline values and criteria for BOS diagnosis in children is still urgently required. As defined, lung function loss has to be non-reversible and present on 2 separate occasions a minimum of 3 weeks apart to fulfill BOS criteria and exclude acute allograft rejection or infection. Unfortunately, there is a complete lack of data showing a correlation between changes in forced expiratory volume in 1 second and development of BO in pediatric lung transplantation to date. The article by Towe et al,5 from St. Louis, Missouri, in this issue of the Journal reports results of a single-center, retrospective study to determine the sensitivity, specificity, and positive and negative predictive values of BOS for predicting BO in pediatric lung transplant recipients.4 In their study, the overall sensitivity of BOS was 91%, demonstrating that spirometry is a reasonable BO screening tool; however, spirometry is not specific for the diagnosis of BO. Even though this is a single-center retrospective study including o100 samples for analysis (almost 50% of samples had to be excluded from analysis for various reasons), this is the largest pediatric data collection of its kind to date. More than 350 pediatric lung transplants have been performed to date in St. Louis, making it the biggest pediatric lung transplant program in the world. Overall, the Towe et al5 study adds meaningful new knowledge to the field of pediatric lung transplantation, in particular, that BOS is not the ideal surrogate marker for BO in the absence of other diagnostic tests, a fact that experts in the field of pediatric lung transplantation have expected all along. This finding has important implications for patients’ clinical
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2015.01.001
502
The Journal of Heart and Lung Transplantation, Vol 34, No 4, April 2015
management; specifically, avoidance of unnecessary overimmunosuppression if BO is incorrectly assumed. It is noteworthy that the study by Towe et al5 was originally designed and performed before the CLAD terminology was accepted and introduced broadly in daily clinical practice. In that sense, the authors diagnosed BOS correctly according to previously published ISHLT guidelines using spirometry, after the exclusion of other specific causes of CLAD, in the allograft (i.e., anastomotic strictures) and extra-allograft (i.e., pleural disease or diaphragmatic dysfunction). Full lung function tests were not readily available in a substantive part of the patients in the cohort because patients underwent transplants in an era where total lung capacity (TLC) measurements were not routinely obtained, even though older children would have principally been capable to perform full lung function tests. Such measurements of TLC and residual volumes would have been helpful to assist delineating obstructive vs mixed ventilation defects. In addition, computed tomography chest imaging and ventilation/perfusion scans would have been valuable diagnostic tools to facilitate phenotyping of CLAD, yet such tests were not usually performed during the old transplant era. In summary, one has to agree with the authors’ conclusion that BOS should not generally be used as a substitute diagnosis for BO, but what are its practical implications for our daily clinical work?
Perform flexible bronchoscopy with bronchoalveolar lavage and transbronchial biopsy early in the evaluation of lung function decline in pediatric lung transplant recipients, exactly as the St. Louis team described as their standard clinical practice. Full lung function testing comprising TLC measurements and residual volumes should be done wherever possible and
additional diagnostic tools used, including high-resolution computed tomography chest imaging (in inspiration/ expiration), and ideally, diagnosis of BO confirmed on lung tissue biopsy. However, an invasive procedure is required to obtain a tissue sample, and the risks and benefits of such a diagnostic procedure have to be balanced very carefully, in particular, in a child with an already progressively impaired lung function. Because small airway lesions in BO are mostly patchy in nature, specimens from transbronchial lung biopsies are often unsuccessful in providing a definite tissue diagnosis, and tissue sampling has to be achieved by other means, such as video-assisted thoracoscopic surgery or open lung biopsy.
Disclosure statement The author has no financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Benden C. Specific aspects of children and adolescents undergoing lung transplantation. Curr Opin Organ Transplant 2012;17:509-14. 2. Benden C, Goldfarb SB, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart-lung transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:1025-33. 3. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant 2014;33:127-33. 4. Towe C, Ogborn AC, Ferkol T, et al. Bronchiolitis obliterans syndrome is not specific for bronchiolitis obliterans in pediatric lung transplant. J Heart Lung Transplant 2015;34:516-21.
