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We conducted a retrospective observational study of the 289 HSCTs performed at the Hospital de la Princesa between January 2009 and June 2018&#44; and finally selected 42 patients who were diagnosed with BO&#46; The following variables were collected&#58; age at the time of transplantation&#44; sex&#44; baseline hematological disease&#44; lung function at diagnosis of BO and pre- and post-transplant&#44; microbiological isolates&#44; radiological findings&#44; clinical course&#44; involvement of other organs&#44; and mean survival&#46; Differences in survival by sex&#44; microbiological isolates&#44; or involvement of the lung only or of the lung and other organs were evaluated&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Of the 42 patients with BO&#44; 23 were men and 19 were women&#46; The prevalence of BO was 14&#46;8&#37;&#46; The mean age of the patients at transplantation was 48&#46;39&#8239;&#177;&#8239;12&#46;74 years&#46; The HSCT was performed mainly for acute myeloblastic leukemia &#40;34&#46;8&#37;&#41;&#44; myelodysplastic syndrome &#40;28&#46;3&#37;&#41;&#44; and acute lymphoblastic leukemia &#40;13&#37;&#41;&#46; In total&#44; 52&#46;4&#37; of the patients were former smokers with a pack&#47;year index of 22&#46;26&#8239;&#177;&#8239;13&#46;52&#46; Mean FEV<span class="elsevierStyleInf">1</span>&#37; was 96&#46;28&#37;&#8239;&#177;&#8239;11&#46;55 before transplantation&#59; 64&#46;6&#37;&#8239;&#177;&#8239;24&#46;43 at diagnosis of BO&#59; 66&#46;86&#37;&#8239;&#177;&#8239;31&#46;08 at 6 months&#59; and 69&#46;37&#37;&#8239;&#177;&#8239;25&#46;94 at 12 months&#46; Sputum culture was carried out in 19 patients&#58; 10 cases were positive for <span class="elsevierStyleItalic">Aspergillus fumigatus</span>&#44; 7 for <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> and 2 for <span class="elsevierStyleItalic">Haemophilus influenzae</span> and <span class="elsevierStyleItalic">Stenotrophomonas maltophilia&#46;</span> The findings on chest computed tomography &#40;CT&#41; were&#58; ground glass and bronchiectasis in 56&#46;4&#37;&#59; alveolar infiltrates in 30&#46;8&#37;&#59; air trapping in 15&#46;4&#37;&#44; and peribronchial thickening and peribronchial nodules in 12&#46;8&#37;&#46; No patient showed images consistent with pleuropulmonary fibroelastosis&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In 11 patients&#44; cGVHD was exclusively pulmonary&#44; while involvement of both the lungs and other organs was observed in the remaining patients &#40;74&#46;4&#37;&#41;&#46; The most frequently affected organ was the skin&#44; in 24 cases&#44; followed by ocular &#40;20 cases&#41;&#44; oral &#40;17 cases&#41;&#44; and hepatic &#40;17 cases&#41; manifestations&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Seventeen patients died&#44; 4 were lost to follow-up&#44; and 24 were still alive at the time of the study&#46; The causes of death were respiratory in 76&#46;4&#37; of the patients&#44; and neurological and digestive in 11&#46;7&#37; each&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows that the median survival of these patients was 175 months&#46; There were no differences in survival according to sex&#44; microbiological isolates or organ involvement&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">In this study&#44; we analyzed the prevalence and clinical characteristics of BO in HSCT&#46; The prevalence of BO in our hospital was 14&#46;8&#37;&#44; which is slightly higher than described in other studies&#44; perhaps due to earlier diagnosis&#46; In previous studies&#44; FEV<span class="elsevierStyleInf">1</span>&#37; at diagnosis ranged from 40&#37; to 59&#37;&#44; whereas in ours it was 64&#46;6&#37;&#44; suggesting that we may be diagnosing and treating patients with milder involvement&#46; However&#44; mortality was high&#44; and median survival was 175 months&#46; Limitations of our study include particularly the number of patients and the patient inclusion timeline&#44; so it was difficult to analyze all factors that could influence mortality&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In 2015&#44; the National Institutes of Health &#40;NIH&#41; modified their earlier 2009 criteria&#44; specifying that in the presence of any sign of cGVHD&#44; a clinical diagnosis of BO syndrome would be given if all of the following criteria were met&#58; FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#8239;&#60;&#8239;70&#37; and FEV<span class="elsevierStyleInf">1</span> &#60; 75&#37; predicted with decline in FEV<span class="elsevierStyleInf">1</span>&#8239;&#8805;&#8239;10&#37; in less than 2 years&#44; absence of evidence of active respiratory tract infection at diagnosis from symptoms&#44; chest X-ray or chest CT and microbiological studies &#40;culture of sputum&#44; bronchial aspiration&#44; or bronchoalveolar lavage&#41;&#44; and one of the following&#58; presence of air trapping on expiratory acquisition slices&#44; small airway thickening&#44; or bronchiectasis on high-resolution CT of the chest or evidence of air trapping in lung function tests&#44; residual volume &#40;RV&#41;&#8239;&#62;&#8239;120&#37; predicted&#44; or RV&#47;total lung capacity &#40;TLC&#41;&#8239;&#62;&#8239;90&#37;&#46; If the patient already had a diagnosis of GVHD involving any organ&#44; then only the first of the 3 criteria was necessary for the diagnosis of BO&#46; If BO was the only clinical manifestation&#44; a lung biopsy would be required to establish the diagnosis&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The detection of BO requires lung function tests and chest CT tests with expiratory acquisition&#46; Some studies propose performing lung function tests every 3 months in the first 2 years after HSCT&#46; If BO is diagnosed during that period&#44; 3-monthly follow-ups are recommended&#46; In contrast&#44; in patients without BO after 2 years&#44; spirometric monitoring is only proposed in the case of respiratory symptoms<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;8</span></a>&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Recently&#44; the European Society for Blood and Marrow Transplantation published a consensus document containing recommendations for prophylaxis and treatment of GVHD<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; FAM therapy is recommended for the management of BO&#44; as follows&#58; inhaled fluticasone 440&#8239;&#956;g&#47;2 times daily&#44; azithromycin 250&#8239;mg&#47;3 times weekly&#44; and montelukast 10&#8239;mg&#47;once daily&#46; The guidelines also recommend discontinuing azithromycin once BO control has been achieved&#44; since the possibility of recurrence of underlying hematological disease associated with prolonged treatments has been described<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In this study&#44; we conclude that BO is a complication of cGVHD that affects around 15&#37; of patients with allogeneic HSCT and has a mortality rate of up to 45&#37;&#46; It may appear alone or with the involvement of other organs&#44; so management must be multidisciplinary&#46; The role of pulmonologists in the follow-up of these patients is of the utmost importance&#44; and regular functional tests are necessary after the HSCT&#44; along with radiological and microbiological studies in the case of respiratory symptoms&#44; in order to facilitate the early diagnosis and treatment of BO&#46;</p></span>"
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Scientific Letter
Clinical course of patients with bronchiolitis obliterans following hematopoietic stem cell transplantation
Evolución de los pacientes con bronquiolitis obliterante secundario a trasplante de progenitores hematopoyéticos
Adrián Martínez-Vergaraa,
Corresponding author
, Rosa M. Giróna, María Churruca-Arróspidea, Patricia López-Pereirab, Elena Sola-Apariciob, Beatriz Aguado-Buenob
a Servicio de Neumología, Hospital de La Princesa, Madrid, Spain
b Servicio de Hematología, Hospital de La Princesa, Madrid, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic graft-versus-host disease &#40;cGVHD&#41; is a multisystemic disease with high morbidity and mortality that develops as a complication in 30&#37;&#8211;70&#37; of allogeneic hematopoietic stem cell &#40;HSCT&#41; transplants<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; Bronchiolitis obliterans &#40;BO&#41; is the pulmonary manifestation of cGVHD&#44; and usually presents as fibrosis and scarring of the small distal airway and fixed airflow obstruction<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a>&#46; Its clinical presentation includes dyspnea&#44; exercise intolerance&#44; and non-productive cough<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a>&#46; Clinical manifestations are non-specific&#44; and many patients are initially asymptomatic&#44; so this disease can be diagnosed late&#46; The incidence in patients receiving allogeneic HSCT is estimated to be 2&#37;&#8211;5&#37; and 6&#37; in patients already diagnosed with cGVHD<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;5</span></a>&#44; but recent publications suggest that the incidence is on the rise&#46; Thus&#44; the study by Chien et al&#46; showed a prevalence of BO of 5&#46;5&#37; in general&#44; 10&#37; in patients who survived at least one year&#44; and 16&#37; in patients already diagnosed with cGVHD<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The aim of this study was to describe the prevalence&#44; clinical and spirometric characteristics&#44; and survival of patients with GVHD who developed BO in the previous 10 years&#46; The Hematology and Respiratory Medicine Departments of the Hospital de la Princesa have been collaborating for years in the joint follow-up of these patients&#46; We conducted a retrospective observational study of the 289 HSCTs performed at the Hospital de la Princesa between January 2009 and June 2018&#44; and finally selected 42 patients who were diagnosed with BO&#46; The following variables were collected&#58; age at the time of transplantation&#44; sex&#44; baseline hematological disease&#44; lung function at diagnosis of BO and pre- and post-transplant&#44; microbiological isolates&#44; radiological findings&#44; clinical course&#44; involvement of other organs&#44; and mean survival&#46; Differences in survival by sex&#44; microbiological isolates&#44; or involvement of the lung only or of the lung and other organs were evaluated&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Of the 42 patients with BO&#44; 23 were men and 19 were women&#46; The prevalence of BO was 14&#46;8&#37;&#46; The mean age of the patients at transplantation was 48&#46;39&#8239;&#177;&#8239;12&#46;74 years&#46; The HSCT was performed mainly for acute myeloblastic leukemia &#40;34&#46;8&#37;&#41;&#44; myelodysplastic syndrome &#40;28&#46;3&#37;&#41;&#44; and acute lymphoblastic leukemia &#40;13&#37;&#41;&#46; In total&#44; 52&#46;4&#37; of the patients were former smokers with a pack&#47;year index of 22&#46;26&#8239;&#177;&#8239;13&#46;52&#46; Mean FEV<span class="elsevierStyleInf">1</span>&#37; was 96&#46;28&#37;&#8239;&#177;&#8239;11&#46;55 before transplantation&#59; 64&#46;6&#37;&#8239;&#177;&#8239;24&#46;43 at diagnosis of BO&#59; 66&#46;86&#37;&#8239;&#177;&#8239;31&#46;08 at 6 months&#59; and 69&#46;37&#37;&#8239;&#177;&#8239;25&#46;94 at 12 months&#46; Sputum culture was carried out in 19 patients&#58; 10 cases were positive for <span class="elsevierStyleItalic">Aspergillus fumigatus</span>&#44; 7 for <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> and 2 for <span class="elsevierStyleItalic">Haemophilus influenzae</span> and <span class="elsevierStyleItalic">Stenotrophomonas maltophilia&#46;</span> The findings on chest computed tomography &#40;CT&#41; were&#58; ground glass and bronchiectasis in 56&#46;4&#37;&#59; alveolar infiltrates in 30&#46;8&#37;&#59; air trapping in 15&#46;4&#37;&#44; and peribronchial thickening and peribronchial nodules in 12&#46;8&#37;&#46; No patient showed images consistent with pleuropulmonary fibroelastosis&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In 11 patients&#44; cGVHD was exclusively pulmonary&#44; while involvement of both the lungs and other organs was observed in the remaining patients &#40;74&#46;4&#37;&#41;&#46; The most frequently affected organ was the skin&#44; in 24 cases&#44; followed by ocular &#40;20 cases&#41;&#44; oral &#40;17 cases&#41;&#44; and hepatic &#40;17 cases&#41; manifestations&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Seventeen patients died&#44; 4 were lost to follow-up&#44; and 24 were still alive at the time of the study&#46; The causes of death were respiratory in 76&#46;4&#37; of the patients&#44; and neurological and digestive in 11&#46;7&#37; each&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows that the median survival of these patients was 175 months&#46; There were no differences in survival according to sex&#44; microbiological isolates or organ involvement&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">In this study&#44; we analyzed the prevalence and clinical characteristics of BO in HSCT&#46; The prevalence of BO in our hospital was 14&#46;8&#37;&#44; which is slightly higher than described in other studies&#44; perhaps due to earlier diagnosis&#46; In previous studies&#44; FEV<span class="elsevierStyleInf">1</span>&#37; at diagnosis ranged from 40&#37; to 59&#37;&#44; whereas in ours it was 64&#46;6&#37;&#44; suggesting that we may be diagnosing and treating patients with milder involvement&#46; However&#44; mortality was high&#44; and median survival was 175 months&#46; Limitations of our study include particularly the number of patients and the patient inclusion timeline&#44; so it was difficult to analyze all factors that could influence mortality&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In 2015&#44; the National Institutes of Health &#40;NIH&#41; modified their earlier 2009 criteria&#44; specifying that in the presence of any sign of cGVHD&#44; a clinical diagnosis of BO syndrome would be given if all of the following criteria were met&#58; FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#8239;&#60;&#8239;70&#37; and FEV<span class="elsevierStyleInf">1</span> &#60; 75&#37; predicted with decline in FEV<span class="elsevierStyleInf">1</span>&#8239;&#8805;&#8239;10&#37; in less than 2 years&#44; absence of evidence of active respiratory tract infection at diagnosis from symptoms&#44; chest X-ray or chest CT and microbiological studies &#40;culture of sputum&#44; bronchial aspiration&#44; or bronchoalveolar lavage&#41;&#44; and one of the following&#58; presence of air trapping on expiratory acquisition slices&#44; small airway thickening&#44; or bronchiectasis on high-resolution CT of the chest or evidence of air trapping in lung function tests&#44; residual volume &#40;RV&#41;&#8239;&#62;&#8239;120&#37; predicted&#44; or RV&#47;total lung capacity &#40;TLC&#41;&#8239;&#62;&#8239;90&#37;&#46; If the patient already had a diagnosis of GVHD involving any organ&#44; then only the first of the 3 criteria was necessary for the diagnosis of BO&#46; If BO was the only clinical manifestation&#44; a lung biopsy would be required to establish the diagnosis&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The detection of BO requires lung function tests and chest CT tests with expiratory acquisition&#46; Some studies propose performing lung function tests every 3 months in the first 2 years after HSCT&#46; If BO is diagnosed during that period&#44; 3-monthly follow-ups are recommended&#46; In contrast&#44; in patients without BO after 2 years&#44; spirometric monitoring is only proposed in the case of respiratory symptoms<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;8</span></a>&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Recently&#44; the European Society for Blood and Marrow Transplantation published a consensus document containing recommendations for prophylaxis and treatment of GVHD<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; FAM therapy is recommended for the management of BO&#44; as follows&#58; inhaled fluticasone 440&#8239;&#956;g&#47;2 times daily&#44; azithromycin 250&#8239;mg&#47;3 times weekly&#44; and montelukast 10&#8239;mg&#47;once daily&#46; The guidelines also recommend discontinuing azithromycin once BO control has been achieved&#44; since the possibility of recurrence of underlying hematological disease associated with prolonged treatments has been described<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In this study&#44; we conclude that BO is a complication of cGVHD that affects around 15&#37; of patients with allogeneic HSCT and has a mortality rate of up to 45&#37;&#46; It may appear alone or with the involvement of other organs&#44; so management must be multidisciplinary&#46; The role of pulmonologists in the follow-up of these patients is of the utmost importance&#44; and regular functional tests are necessary after the HSCT&#44; along with radiological and microbiological studies in the case of respiratory symptoms&#44; in order to facilitate the early diagnosis and treatment of BO&#46;</p></span>"
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Article information
ISSN: 15792129
Original language: English
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