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Bronquiolitis Obliterante , Glucocorticoides , Metilprednisolona , Humanos , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Metilprednisolona/administración & dosificación , Metilprednisolona/uso terapéutico , Niño , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Quimioterapia por Pulso , Administración Intravenosa , Resultado del TratamientoRESUMEN
Paraneoplastic pemphigus is a rare, life-threatening autoimmune disease that is clinically characterized by mostly extensive and refractory mucosal erosions and polymorphous skin lesions. We report here on a 16-year-old girl with isolated oral erosions, in whom mucosal pemphigoid was initially suspected and after treatment with prednisolone and dapsone marked improvement was achieved. However, a few months later the patient developed massive respiratory insufficiency as a result of bronchiolitis obliterans, so that a lung transplant was planned. As part of the preparatory diagnostic workup, unicentric, abdominally localized Castleman's disease was diagnosed, which ultimately led to the diagnosis of paraneoplastic pemphigus as evidenced by envoplakin autoantibodies. Tumor resection and subsequent lung transplantation achieved good results with sustained mucocutaneous remission.
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Enfermedad de Castleman , Síndromes Paraneoplásicos , Pénfigo , Humanos , Femenino , Enfermedad de Castleman/complicaciones , Enfermedad de Castleman/inmunología , Enfermedad de Castleman/diagnóstico , Enfermedad de Castleman/tratamiento farmacológico , Enfermedad de Castleman/patología , Adolescente , Pénfigo/diagnóstico , Pénfigo/inmunología , Pénfigo/complicaciones , Pénfigo/patología , Pénfigo/tratamiento farmacológico , Síndromes Paraneoplásicos/diagnóstico , Síndromes Paraneoplásicos/inmunología , Síndromes Paraneoplásicos/patología , Trasplante de Pulmón , Bronquiolitis Obliterante/inmunología , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/tratamiento farmacológicoRESUMEN
Lung and hematopoietic stem cell transplantation are therapeutic modalities in chronic pulmonary and hematological diseases, respectively. One of the complications in these patients is the development of bronchiolitis obliterans syndrome (BOS). The efficacy and safety of available treatment strategies in BOS remain a challenge. A few mechanisms have been recognized for BOS in lung transplant and graft-versus-host disease (GVHD) patients involving the TH-1 and TH-2 cells, NF-kappa B, TGF-b, several cytokines and chemokines, and cysteinyl leukotrienes (CysLT). Montelukast is a highly selective CysLT receptor antagonist that has been demonstrated to exert anti-inflammatory and anti-fibrotic effects in abundant experiments. One area of interest for the use of montelukast is lung transplants or GVHD-associated BOS. Herein, we briefly review data regarding the mechanisms involved in BOS development and montelukast administration as a treatment modality for BOS, and finally, the possible relationship between CysLTs antagonism and BOS improvement will be discussed.
A review of the therapeutic potential and possible mechanism of Montelukast in the treatment of bronchiolitis obliterans syndrome following lung and hematopoietic stem cell transplantationLung and bone marrow transplantation are therapeutic modalities in chronic diseases of the lungs and the blood, respectively. One of the complications in these patients is the development of Bronchiolitis obliterans syndrome (BOS). The efficacy and safety of available treatment strategies in BOS remain a challenge. A few mechanisms for BOS in lung transplant and graft-versus-host disease (GVHD) patients involving many immune components have been recognized. Cysteinyl leukotrienes are products of plasma membrane phospholipids that increase smooth muscle contraction, microvascular permeability, and airway mucus secretion. Montelukast is a highly selective cysteinyl leukotriene receptor blocker demonstrated to exert anti-inflammatory and anti-fibrotic effects. One area of interest for the use of montelukast is in lung transplant- or GVHD-associated BOS. In this article, we briefly review data regarding the mechanisms involved in BOS development and montelukast administration as a treatment modality for BOS. Finally, the possible relationship between cysteinyl leukotriene inhibition and BOS improvement will be discussed.
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Acetatos , Síndrome de Bronquiolitis Obliterante , Bronquiolitis Obliterante , Ciclopropanos , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Trasplante de Pulmón , Quinolinas , Sulfuros , Humanos , Antagonistas de Leucotrieno/efectos adversos , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Pulmón , Trasplante de Pulmón/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Leucotrienos/farmacología , Leucotrienos/uso terapéuticoRESUMEN
BACKGROUND: Postinfectious bronchiolitis obliterans is a rare lung disease; there are limited reports in South America. CASE REPORT: We report 10 patients with this disease diagnosed at the Instituto Nacional de Salud del Niño-Breña (Lima-Peru). The median age at diagnosis was 19 months and all patients had a history of severe acute respiratory infection. The most frequent symptoms were cough, respiratory distress, wheezing, and hypoxemia. The mosaic attenuation pattern was the most frequent on the tomography. All the patients had positive serology for adenovirus. The treatment received was methylprednisolone pulses, azithromycin, hydroxychloroquine, and inhaled corticosteroids. No patient died during the follow-up. CONCLUSIONS: In previously healthy children with a history of severe acute respiratory infection and persistent bronchial obstructive symptoms, the diagnosis of postinfectious bronchiolitis obliterans should be considered. This is the first report in Peru with a therapeutic regimen adapted to our institution.
INTRODUCCIÓN: La bronquiolitis obliterante postinfecciosa es una enfermedad pulmonar poco frecuente; existen limitados reportes en Sudamérica. CASO CLÍNICO: En esta serie se reportan 10 pacientes con esta enfermedad diagnosticados en el Instituto Nacional de Salud del Niño-Breña (Lima-Perú). La mediana de edad al diagnóstico fue de 19 meses. Todos los pacientes presentaron el antecedente de infección respiratoria aguda grave. Los síntomas más frecuentes fueron tos, dificultad respiratoria, sibilancias e hipoxemia; el patrón de atenuación en mosaico fue la característica más frecuente en la tomografía. Todos tenían serología positiva para adenovirus. Se administró tratamiento con pulsos de metilprednisolona, azitromicina, hidroxicloroquina y corticoides inhalados. Ningún paciente falleció durante el seguimiento. CONCLUSIONES: En los niños previamente sanos con antecedente de infección respiratoria aguda grave y sintomatología obstructivo bronquial persistente se debe considerar el diagnóstico de bronquiolitis obliterante postinfecciosa. Este es el primer reporte en Perú con un régimen terapéutico adaptado a nuestra institución.
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Bronquiolitis Obliterante , Hospitales Pediátricos , Humanos , Niño , Perú , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the lung manifestation of chronic graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). We assessed whether inhaled tiotropium add-on to the combination regimen including budesonide/formoterol improve pulmonary function and the chronic obstructive pulmonary disease assessment test (CAT) scores in patients with BOS. METHODS: Post-HSCT patients diagnosed as BOS in Seoul St. Mary's Hospital were reviewed retrospectively. Patients defined as BOS and treated with budesonide/formoterol/tiotropium combination therapy after budesonide/formoterol therapy from January 2011 to June 2019 were enrolled. RESULTS: Total of 86 patients were evaluated. After tiotropium add-on, the absolute FEV1 increased significantly from 1.47 ± 0.49 to 1.53 ± 0.57 L (p = 0.023) and the % predicted FEV1 from 45.0 ± 12.8 to 46.8 ± 14.5% (p = 0.031). The % predicted DLCO increased significantly after tiotropium add-on (from 61.6 ± 16.7 to 64.3 ± 16.3%, p = 0.028). Among 56 patients with complete CAT scores, no significant change was present in total CAT scores. In all, 30 of the 72 patients (41.7%) evidenced FEV1 increases > 100 mL, and 20 of 56 patients (35.7%) had CAT score decreases of ≥ 2 points. When the FEV1 and CAT scores were combined, the overall response rate to tiotropium add-on was 56.2% (41/73). The response group evidenced a significantly greater FVC increase, and a significant decrease in the RV/TLC ratio compared to the no-response group. CONCLUSIONS: Inhaled tiotropium add-on to combination budesonide/formoterol significantly improved lung function, but not respiratory symptoms, in patients with post-HSCT BOS.
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Bronquiolitis Obliterante , Trasplante de Células Madre Hematopoyéticas , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Bromuro de Tiotropio/uso terapéutico , Budesonida/uso terapéutico , Estudios Retrospectivos , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Combinación Budesonida y Fumarato de Formoterol/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , BroncodilatadoresRESUMEN
INTRODUCTION: Bronchiolitis obliterans is characterized by partial or total occlusion of the bronchioles due to inflammation and fibrosis, and the most common form is postinfectious bronchiolitis obliterans (PIBO). This study aimed to retrospectively present our intravenous immunoglobulin (IVIG) treatment experience in PIBO patients with a clinically severe course despite receiving commonly used treatment protocols. MATERIALS AND METHODS: The study included patients aged 0-18 with subtle immunological abnormalities who were followed up in our center for PIBO between 2010 and 2021. Clinical evaluation, body mass index (BMI), computerized tomography (CT) image scoring, and immunological parameters were recorded before and after IVIG treatment. RESULTS: Of the 11 patients included in the study, 90% were male, the mean age at diagnosis was 27.1 months (range: 5-68 months) and the mean current age was 81.4 months (range: 15-188 months). The number of hospital visits due to infection and the frequency of hospitalizations decreased markedly in the patients who underwent IVIG therapy. Oxygen therapy was discontinued in all patients, and improvements in radiological severity scores were observed. BMI z-scores improved over the baseline values after IVIG therapy. CONCLUSION: Corticosteroids are considered the best first-line treatment to control inflammation in PIBO. In our study group, PIBO patients showed favorable clinical and radiological responses to regular IVIG treatment, possibly due to minor immune deficiency secondary to steroids or as a result of undetected adaptive and innate immune defects involved in the etiology of severe PIBO.
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Bronquiolitis Obliterante , gammaglobulinas , Humanos , Masculino , Femenino , Estudios Retrospectivos , gammaglobulinas/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Pruebas de Función Respiratoria , Bronquiolitis Obliterante/diagnóstico por imagen , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Inflamación/complicacionesRESUMEN
BACKGROUND: To investigate the protective effect of p14ARF in a nitric acid (NA) aerosol inhalation-induced bronchiolitis obliterans (BO) mouse model and its potential regulatory mechanism. METHODS: A BO mouse model was established by NA aerosol inhalation. The expressions of p14ARF, phosphatidylinositol-3-kinase (PI3K), and protein kinase B (AKT) were detected by quantitative reverse transcription PCR (qRT-PCR) and western blot (WB). Hematoxylin (HE) staining, Masson staining, and periodic acid-Schiff (PAS) staining observed pulmonary histological changes. TdT-mediated dUTP nick end labeling (TUNEL) staining detected pulmonary cell apoptosis, and enzyme-linked immunosorbent assay (ELISA) measured matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), interleukon-6 (IL-6), and transforminh growth factor-ß (TGF-ß) levels in lung tissue and bronchoalveolar lavage fluid (BALF). RESULTS: The expressions of p14ARF, PI3K, and AKT showed a time gradient change, with a decrease trend (*P < 0.05 and **P < 0.01). Severe inflammatory infiltration and tracheal fibrosis were found in lung tissue in the modeling group (BO group) compared with the control group (Con group). The pH, PaO2, and PaO2/FiO2 values significantly reduced, while the PaCO2 value and the number of TUNEL-positive cells increased in BO group (P < 0.05). In addition, MMP-2, MMP-9, IL-6, and TGF-ß levels remarkably increased, with an increase in the number of white blood cells, neutrophils, and lymphocytes in BO group (P < 0.05). Furthermore, p14ARF up-regulation reversed the trend of the aforementioned indexes in BO mice. CONCLUSIONS: p14ARF ameliorated the inflammatory response and airway remodeling in a BO mouse model via the PI3K/AKT pathway.
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Bronquiolitis Obliterante , Metaloproteinasa 2 de la Matriz , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína p14ARF Supresora de Tumor , Ácido Nítrico , Metaloproteinasa 9 de la Matriz/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Remodelación de las Vías Aéreas (Respiratorias) , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Interleucina-6 , Aerosoles y Gotitas Respiratorias , Bronquiolitis Obliterante/inducido químicamente , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/metabolismo , Inflamación/tratamiento farmacológico , Factor de Crecimiento Transformador beta , Modelos Animales de EnfermedadRESUMEN
La infección por SARS-CoV-2 en la población pediátrica gene-ralmente se manifiesta con síntomas leves; sin embargo, en pacientes con co-morbilidades puede haber compromiso pulmonar grave. Se presenta el caso de un lactante de tres meses de edad con una infección por SARS-CoV-2, con sintomatología respiratoria persistente por 8 semanas después de la infección inicial, con RPC persistentemente positiva, requiriendo varias hospitalizaciones, oxígeno suplementario y ventilación mecánica invasiva. Se encontraron hallazgos clínicos y radiológicos compatibles con una bronquiolitis obliterante asociada a la infección por SARS-CoV-2. Hubo una adecuada respuesta clínica, después del inicio de tratamiento de primera línea para bronquiolitis obliterante, y una evolución favorable durante el seguimiento hasta la fecha, evidenciando la importancia de tener en cuenta esta asociación en la práctica clínica.
SARS-CoV-2 infection in the pediatric population usually manifests with mild symptoms; however, in patients with comorbidities, there may be a severe pulmonary compromise. We present the case of a 3-month-old patient with acute SARS-CoV-2 infection, with persistent respiratory symptoms up to 8 weeks after the initial infection, with a persistently positive PCR test, requiring several hospitalizations, supplemental oxygen, and even invasive mechanical ventilation. Clinical and radiological manifestations were found consistent with bronchiolitis obliterans associated with SARS-CoV-2 infection. An adequate clinical response was documented after starting first-line treatment for bronchiolitis obliterans with satisfactory evolution during follow-up to date, evidencing the importance of considering this association in clinical practice.
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Humanos , Masculino , Lactante , Bronquiolitis Obliterante/complicaciones , Bronquiolitis Obliterante/diagnóstico por imagen , COVID-19/complicaciones , COVID-19/diagnóstico por imagen , Bronquiolitis Obliterante/tratamiento farmacológico , Radiografía Torácica , Tomografía Computarizada por Rayos X , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a devastating complication that occurs after transplantation. Although azithromycin is currently used for the treatment of BOS, the evidence is sparse and controversial. The aim of this meta-analysis is to evaluate the effects of azithromycin on forced expiratory volume in 1 second (FEV1) and patient's survival. METHODS: PubMed, Embase, Cochrane library, Web of Science databases, and the ClinicalTrials.gov registry were systematically searched from inception until December 2020 for relevant original research articles. Random-effects models were used to calculate pooled-effect estimates. RESULTS: Searches identified 15 eligible studies involving 694 participants. For FEV1 (L), there was a significant increase after short-term (≤12 weeks; P = .00) and mid-term (12-24 weeks; P = .01) administration of azithromycin. For FEV1 (%) compared to baseline, there was a significant increase after short-term (≤12 weeks) administration of azithromycin (P = .02), while there were no statistically significant differences in the medium and long term. When pooled FEV1% was predicted, it exhibited a similar trend to FEV1 (%) compared to baseline. In addition, we discovered that azithromycin reduced the risk of death (hazard ratio = 0.26; 95% confidence interval = 0.17 to 0.40; P = .00) in patients with BOS post-lung transplantation. CONCLUSIONS: Azithromycin therapy is both effective and safe for lung function improvement in patients with posttransplant BOS after the short- and medium-term administration. Additionally, it has been demonstrated a significant survival benefit among patients with BOS post-lung transplant. Higher quality randomized controlled trials and more extensive prospective cohort studies are needed to confirm the effect of azithromycin on patients with posttransplant BOS.
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Bronquiolitis Obliterante , Trasplante de Pulmón , Antibacterianos , Azitromicina , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Volumen Espiratorio Forzado , Humanos , Trasplante de Pulmón/efectos adversos , Estudios Prospectivos , SíndromeRESUMEN
Bronchiolitis obliterans syndrome (BOS) is the most morbid form of chronic graft-versus-host disease (cGVHD) after hematopoietic cell transplantation (HCT). Progressive airway fibrosis leads to a 5-year survival of 40%. Treatment options for BOS are limited. A single arm, 52-week, Phase I study of pirfenidone was conducted. The primary outcome was tolerability defined as maintaining the recommended dose of pirfenidone (2403 mg/day) without a dose reduction totaling more than 21 days, due to adverse events (AEs) or severe AEs (SAEs). Secondary outcomes included pulmonary function tests (PFTs) and patient reported outcomes (PROs). Among 22 participants treated for 1 year, 13 (59%) tolerated the recommended dose, with an average daily tolerated dose of 2325.6 mg/day. Twenty-two SAEs were observed, with 90.9% related to infections, none were attributed to pirfenidone. There was an increase in the average percent predicted forced expiratory volume in 1 s (FEV1%) of 7 percentage points annually and improvements in PROs related to symptoms of cGVHD. In this Phase I study, treatment with pirfenidone was safe. The stabilization in PFTs and improvements in PROs suggest the potential of pirfenidone for BOS treatment and support the value of a randomized controlled trial to evaluate the efficacy of pirfenidone in BOS after HCT. The study is registered in ClinicalTrials.gov (NCT03315741).
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Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Pulmón , Piridonas/efectos adversosRESUMEN
BACKGROUND: The major obstacle for long-term survival after successful lung transplantation is the development of bronchiolitis obliterans (BO) which is one phenotype of chronic lung allograft dysfunction (CLAD). Nintedanib has beneficial effects treating neoplastic diseases and idiopathic pulmonary fibrosis by blocking tyrosine kinase receptors. These receptors play an important role in alloimmune-mediated proliferative diseases. The aim of this study was to determine the effect of nintedanib on proliferative airway changes after orthotopic trachea transplantation in mice. METHODS: C57BL/6 mice (H-2b) donor tracheas were orthotopically transplanted into CBA/J mice (H-2k). After transplantation, recipients were daily treated with nintedanib (60 mg/kg; p.o.). Histological and immunofluorescence analysis were performed after 30 days and intragraft gene expression measurements after 14 days of treatment, respectively. RESULTS: Tracheal allografts from mice treated with nintedanib showed significantly less features of chronic rejection than untreated allografts reflected in a higher epithelium/lamina propria ratio (ELR) [ELR: 0.65 ± 0.13 nintedanib vs. 0.50 ± 0.07 untreated controls; p < 0.05] and a reduced submucosal smooth muscle actin (SMA) content [SMA: 1.26% ± 0.78% nintedanib vs. 2.18% ± 1.01% untreated controls; p < 0.01]. Furthermore, lower T cell, macrophage and dendritic cell infiltration was detected in the nintedanib treated grafts. The protein and intragraft mRNA expression of receptor subtypes was considerably decreased in grafts of nintedanib treated mice. The mRNA expression of relevant immune mediators was affected by nintedanib treatment. CONCLUSION: Receptor blocking by nintedanib reduced alloimmune-induced inflammation and chronic airway changes in mouse trachea allografts and might be a promising approach to diminish the development of BO in lung transplants.
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Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Aloinjertos , Animales , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/patología , Modelos Animales de Enfermedad , Rechazo de Injerto/tratamiento farmacológico , Enfermedad Injerto contra Huésped/patología , Indoles , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , ARN Mensajero , Tráquea/trasplanteRESUMEN
A young girl in her teens presented with fever, rashes and various mucocutaneous symptoms. Flat erythematous macules were seen mainly on the limbs, without blisters or skin detachments. The lips were swollen with crusts and haemorrhage. The oral cavity and pharynx showed ulcerative lesions with exudate. Severe bilateral ocular lesions with pseudomembrane formation and corneal epithelial defects were present. Also, urogenital lesion and gastrointestinal symptoms with frequent haematochezia were observed. Her symptoms and pathological findings were consistent with Stevens-Johnson syndrome. She was treated with prednisolone and methylprednisolone pulse therapy. Her ocular and cutaneous symptoms improved without severe chronic complications. However, 1 month later, she developed dyspnoea, and a pulmonary function test revealed severe obstructive ventilation disorder. After discharge, she was regularly followed up for respiratory complications. High-resolution chest CT performed 9 months after onset revealed mosaic perfusions and bronchiectasis, consistent with bronchiolitis obliterans.
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Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Síndrome de Stevens-Johnson , Adolescente , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Disnea/complicaciones , Femenino , Enfermedad Injerto contra Huésped/complicaciones , Humanos , Prednisolona/uso terapéutico , Pruebas de Función Respiratoria , Síndrome de Stevens-Johnson/complicaciones , Síndrome de Stevens-Johnson/diagnósticoRESUMEN
Bronchiolitis obliterans syndrome (BOS) is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation (HCT). Montelukast interrupts cysteinyl leukotriene (CysLT) activity and may diminish the activation and homing of cells to bronchioles and subsequent fibrosis. We performed a prospective phase II trial to test whether montelukast altered lung decline for patients with BOS after HCT. In this single-arm, open-label, multi-institutional study, the primary endpoints were stability or improvement (<15% decline) in forced expiratory volume in 1 second (FEV1) and a <1-point decline in the slope of FEV1 after 6 months of treatment. Secondary endpoints included symptom and functional responses and immune correlates investigating the role of leukotrienes in BOS progression. The study enrolled 25 patients with moderate to severe lung disease after 3 months of stable cGVHD therapy. Montelukast was well tolerated, and no patient required escalation of BOS-directed therapy. At the primary endpoint, all 23 evaluable patients met the criteria for treatment success using FEV1% predicted, and all but 1 patient had stable or improved FEV1 slope. In those with a >5% improvement in FEV1, clinically meaningful improvements were seen in the Lee scores of breathing, energy, and mood. Improvements in the Human Activity Profile and 6-minute-walk test were observed in those with a <5% decline in FEV1. Overall survival was 87% at 2 years. Immune correlates showed elevated leukotriene receptor levels on blood eosinophils and monocytes versus healthy controls, elevated urine leukotrienes in 45% of the cohort, and CysLT receptors in bronchoalveolar lavage subsets and a predominance of Th2 cells, all pretreatment. These data suggest that montelukast may safely halt the progression of BOS after HCT, and that leukotrienes may play a role in the biology of BOS.
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Bronquiolitis Obliterante , Trasplante de Células Madre Hematopoyéticas , Acetatos/efectos adversos , Bronquiolitis Obliterante/tratamiento farmacológico , Ciclopropanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Prospectivos , Quinolinas , Sulfuros , SíndromeRESUMEN
Carbon monoxide (CO) is expected to attenuate the progression of obliterative bronchiolitis (OB), which is a serious complication after lung transplantation. However, issues in terms of feasible exogenous CO supply, such as continuousness and safety, remain unsolved. Here, we applied nano red blood cells, namely hemoglobin vesicles (Hb-V), as a CO cargo based on the biomimetic concept and investigated the therapeutic potential of CO-loaded Hb-V on OB in orthotopic tracheal transplant model mice. The CO-loaded Hb-V was comprised of negatively charged liposomes encapsulating carbonylhemoglobin with a size of ca. 220 nm. The results of histological evaluation showed that allograft luminal occlusion and fibrosis were significantly ameliorated by treatment with CO-loaded Hb-V compared to treatment with saline, cyclosporine, and Hb-V. The therapeutic effects of CO-loaded Hb-V on OB were due to the suppression of M1 macrophage activation in tracheal allografts, resulting from decreased IL-17A production. Furthermore, the expression of TNF-α and TGF-ß in tracheal allografts was decreased by CO-loaded Hb-V treatment but not saline and Hb-V treatment, indicating that CO liberated from CO-loaded Hb-V inhibits epithelial-mesenchymal transition. These findings suggest that CO-loaded Hb-V exerts strong therapeutic efficacy against OB via the regulation of macrophage activation by IL-17A and TGF-ß-driven epithelial-mesenchymal transition.
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Sustitutos Sanguíneos/farmacología , Bronquiolitis Obliterante/tratamiento farmacológico , Monóxido de Carbono/farmacología , Sistemas de Liberación de Medicamentos , Hemoglobinas/farmacología , Interleucina-17/metabolismo , Tráquea/trasplante , Animales , Sustitutos Sanguíneos/administración & dosificación , Monóxido de Carbono/administración & dosificación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Liposomas , Activación de Macrófagos , Ratones , Ratones Endogámicos C57BL , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
We herein report the rare case of a 72-year-old female who presented with paraneoplastic pemphigus (PNP) and bronchiolitis obliterans (BO) associated with follicular lymphoma (FL), who was successfully treated with obinutuzumab (GA101; G) and bendamustine (B). The patient had severe erosive stomatitis and bilateral conjunctival hyperemia that persisted for more than 6 months. A huge mass was found in the abdominal cavity, and a biopsy revealed grade 1 FL (stage IV). Based on a lip biopsy result, the patient was diagnosed with PNP associated FL. The patient received bendamustine and obinutuzumab (BG) chemotherapy and FL and PNP responded very well, but BO was additionally associated during the course of BG. BO progressed without exacerbation as BG therapy progressed to a 2 year maintenance therapy with G, and combination of azithromycin, inhaled bronchodilator therapy, and corticosteroid. She was followed up at the outpatient department with no pulmonary function decline or FL and PNP recurrence. Our case suggests that BG could be a promising treatment option for PNP and BO.
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Bronquiolitis Obliterante , Linfoma Folicular , Síndromes Paraneoplásicos , Pénfigo , Anciano , Anticuerpos Monoclonales Humanizados , Clorhidrato de Bendamustina/uso terapéutico , Bronquiolitis Obliterante/complicaciones , Bronquiolitis Obliterante/tratamiento farmacológico , Femenino , Humanos , Linfoma Folicular/complicaciones , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamiento farmacológico , Síndromes Paraneoplásicos/complicaciones , Síndromes Paraneoplásicos/etiología , Pénfigo/complicaciones , Pénfigo/tratamiento farmacológicoRESUMEN
We conducted a randomized, placebo-controlled, double-blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti-thymocyte globulin induction would reduce de novo donor-specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n = 15) or placebo (n = 12). No rituximab-treated subjects versus five placebo-treated subjects developed de novo DSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0-p, obliterative bronchiolitis or listing for retransplant). A post-hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0-p showed no difference in outcome (p = .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).
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Bronquiolitis Obliterante , Trasplante de Pulmón , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Niño , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Humanos , Pulmón , Trasplante de Pulmón/efectos adversos , Rituximab , Receptores de TrasplantesRESUMEN
Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6-32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.
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Bronquiolitis Obliterante , Trasplante de Pulmón , Administración por Inhalación , Bronquiolitis Obliterante/tratamiento farmacológico , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/prevención & control , Ciclosporina/uso terapéutico , Humanos , Pulmón , Trasplante de Pulmón/efectos adversosRESUMEN
BACKGROUND: Obliterative bronchiolitis (OB) was a main cause of deterioration of long-term prognosis in lung transplant recipients after the first posttransplant year. Proinflammatory cytokine interleukin-18 (IL-18) strengthened both the natural immunity and acquired immunity and played an important role in organ transplantation. The roles of IL-18 in the occurrence, development, and drug treatment of OB remained unclear. METHODS: Small interfering RNA (siRNA) against mouse IL-18 (siRNA-IL-18) was used to silence IL-18 expression. Mouse heterotopic tracheal transplantation model was used to simulate OB. Recipient mice were divided into 5 groups (n = 12) according to donor mouse strains and drug treatment: isograft group, allograft group, allograft+tacrolimus group, allograft+azithromycin group, and allograft+tacrolimus+azithromycin group. The luminal obliteration rates were pathological evaluation. Expressions of cytokines and MMPs were detected by real-time PCR, western blot, and enzyme chain immunosorbent assay (ELISA). RESULTS: The luminal obliteration rates of IL-18 of the siRNA-IL-18 group were significantly lower than those of the negative control group (p < 0.0001) and the blank control group (p = 0.0002). mRNA expressions of IFN-γ, EMMPRIN, MMP-8, and MMP-9 of the siRNA-IL-18 group were significantly lower than those of the negative and blank control groups. No tracheal occlusion occurred in grafts of the isograft group. The rates of tracheal occlusion of the allograft group, allograft+tacrolimus group, allograft+azithromycin group, and allograft+tacrolimus+azithromycin group were 72.17 ± 4.66%, 40.33 ± 3.00%, 38.50 ± 2.08%, and 23.33 ± 3.24%, respectively. There were significant differences between the 4 groups (p < 0.001). Serum protein expressions of IL-17 (p = 0.0017), IL-18 (p = 0.0036), IFN-γ (p = 0.0102), and MMP-9 (p = 0.0194) were significantly decreased in the allograft+tacrolimus+azithromycin group compared to the allograft group. CONCLUSIONS: IL-18 could be a novel molecular involved in the occurrence, development, and drug treatment of OB.
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Azitromicina/administración & dosificación , Bronquiolitis Obliterante/tratamiento farmacológico , Interleucina-18/genética , Trasplante de Pulmón/efectos adversos , ARN Interferente Pequeño/administración & dosificación , Tacrolimus/administración & dosificación , Animales , Azitromicina/farmacología , Basigina/genética , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/genética , Modelos Animales de Enfermedad , Humanos , Interferón gamma/genética , Interleucina-18/antagonistas & inhibidores , Masculino , Metaloproteinasa 8 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Ratones , ARN Interferente Pequeño/farmacología , Tacrolimus/farmacología , Trasplante Homólogo/efectos adversos , Resultado del TratamientoRESUMEN
During the COVID-19 pandemic, management of SARS-CoV-2 infection in children with underlying chronic lung disease has been challenging. There are limited studies in children with respiratory comorbidities, apart from asthma, presumably due to low morbidity of SARS-CoV-2 infection in the general pediatric population along with the low incidence of certain pulmonary conditions. Compassionate use of remdesivir has been shown to reduce time to clinical improvement in adults and has been retrospectively studied in small pediatric cohorts with promising results. Whether children with underlying respiratory conditions may benefit from antiviral treatment in the context of different pathophysiologic backgrounds and unknown drug safety and efficacy needs to be further evaluated. We present a case of COVID-19 infection in a 3-year old toddler with severe postinfectious bronchiolitis obliterans, who received compassionate treatment with 5-day-course of remdesivir, and recovered with favourable outcome.
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Bronquiolitis Obliterante , COVID-19 , Adenosina Monofosfato , Adulto , Alanina , Antivirales/uso terapéutico , Bronquiolitis Obliterante/complicaciones , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/tratamiento farmacológico , Niño , Preescolar , Humanos , Pandemias , Estudios Retrospectivos , SARS-CoV-2RESUMEN
BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare, acute and potentially fatal skin condition usually induced by drugs. Although much attention is focused on the life threatening acute cutaneous and sight threatening ocular manifestations of this disease, chronic pulmonary complications like bronchiolitis obliterans are occasionally encountered. However, little is known about its incidence, pathogenesis, clinical course and outcome in children recovering from TEN. CASE PRESENTATION: We report a five-year-old boy who presented four months after the first manifestation of drug-induced TEN with cough and shortness of breath and was subsequently diagnosed with bronchiolitis obliterans. He was treated with supportive therapy that improved his hypercapnia allowing him to be discharged on domiciliary oxygen, chest physiotherapy and bronchodilators. CONCLUSIONS: This case highlights the need to be vigilant for adverse drug reactions and consider chronic pulmonary complications like Bronchiolitis Obliterans in children recovering from TEN.