Ventilatory capacity in CLAD is driven by dysfunctional airway structure.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) encompasses three main phenotypes: bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS) and a Mixed phenotype combining both pathologies. How the airway structure in its entirety is affected in these phenotypes is still poorly understood. METHODS: A detailed analysis of airway morphometry was applied to gain insights on the effects of airway remodelling on the distribution of alveolar ventilation in end-stage CLAD. Ex vivo whole lung µCT and tissue-core µCT scanning of six control, six BOS, three RAS and three Mixed explant lung grafts (9 male, 9 female, 2014-2021, Leuven, Belgium) were used for digital airway reconstruction and calculation of airway dimensions in relation to luminal obstructions. FINDINGS: BOS and Mixed explants demonstrated airway obstructions of proximal bronchioles (starting at generation five), while RAS explants particularly had airway obstructions in the most distal bronchioles (generation >12). In BOS and Mixed explants 76% and 84% of bronchioles were obstructed, respectively, while this was 22% in RAS. Bronchiolar obstructions were mainly caused by lymphocytic inflammation of the airway wall or fibrotic remodelling, i.e. constrictive bronchiolitis. Proximal bronchiolectasis and imbalance in distal lung ventilation were present in all CLAD phenotypes and explain poor lung function and deterioration of specific lung function parameters. INTERPRETATION: Alterations in the structure of conducting bronchioles revealed CLAD to affect alveolar ventilatory distribution in a regional fashion. The significance of various obstructions, particularly those associated with mucus, is highlighted. FUNDING: This research was funded with the National research fund Flanders (G060322N), received by R.V.

Prognostic Value of Chest CT Findings at BOS Diagnosis in Lung Transplant Recipients.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) after lung transplantation is characterized by fibrotic small airway remodeling, recognizable on high-resolution computed tomography (HRCT). We studied the prognostic value of key HRCT features at BOS diagnosis after lung transplantation. METHODS: The presence and severity of bronchiectasis, mucous plugging, peribronchial thickening, parenchymal anomalies, and air trapping, summarized in a total severity score, were assessed using a simplified Brody II scoring system on HRCT at BOS diagnosis, in a cohort of 106 bilateral lung transplant recipients transplanted between January 2004 and January 2016. Obtained scores were subsequently evaluated regarding post-BOS graft survival, spirometric parameters, and preceding airway infections. RESULTS: A high total Brody II severity score at BOS diagnosis (P = 0.046) and high subscores for mucous plugging (P = 0.0018), peribronchial thickening (P = 0.0004), or parenchymal involvement (P = 0.0121) are related to worse graft survival. A high total Brody II score was associated with a shorter time to BOS onset (P = 0.0058), lower forced expiratory volume in 1 s (P = 0.0006) forced vital capacity (0.0418), more preceding airway infections (P = 0.004), specifically with Pseudomonas aeruginosa (P = 0.002), and increased airway inflammation (P = 0.032). CONCLUSIONS: HRCT findings at BOS diagnosis after lung transplantation provide additional information regarding its underlying pathophysiology and for future prognosis of graft survival.

Successful treatment of postinfectious bronchiolitis obliterans with gamma globulin in a tertiary center: 10 years of experience.

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.

Percentage of low attenuation area on computed tomography detects chronic lung allograft dysfunction, especially bronchiolitis obliterans syndrome, after bilateral lung transplantation.

INTRODUCTION: The percentage of low attenuation area (%LAA) on computed tomography (CT) is useful for evaluating lung emphysema, and higher %LAA was observed in patients with chronic lung allograft dysfunction (CLAD). This study investigated the relationship between the %LAA and the development of CLAD after bilateral lung transplantation (LT). METHODS: We conducted a single-center retrospective study of 75 recipients who underwent bilateral LT; the recipients were divided into a CLAD group (n = 30) and a non-CLAD group (n = 45). The %LAA was calculated using CT and compared between the two groups from 4 years before to 4 years after the diagnosis of CLAD. The relationships between the %LAA and the percent baseline values of the pulmonary function test parameters were also calculated. RESULTS: The %LAA was significantly higher in the CLAD group than in the non-CLAD group from 2 years before to 2 years after the diagnosis of CLAD (P < .05). In particular, patients with bronchiolitis obliterans syndrome (BOS) exhibited significant differences even from 4 years before to 4 years after diagnosis (P < .05). Significant negative correlations between the %LAA and the percent baseline values of the forced expiratory volume in 1 s (r = -.36, P = .0031), the forced vital capacity (r = -.27, P = .027), and the total lung capacity (r = -.40, P < .001) were seen at the time of CLAD diagnosis. CONCLUSION: The %LAA on CT was associated with the development of CLAD and appears to have the potential to predict CLAD, especially BOS, after bilateral LT.

Transition from BOS to RAS impairs prognosis after lung transplantation-CLAD subtype analysis by CT volumetry.

BACKGROUND: Chronic lung allograft dysfunction (CLAD), subclassified into bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS), limits survival after lung transplantation. Information concerning transition from BOS to RAS is limited. We aimed to characterize the lung volume change after BOS diagnosis by computed tomography (CT) volumetry and to determine the incidence, risk factors and clinical significance of BOS to RAS transition. METHODS: CT volumetry measurements were performed from 63 patients with CLAD initially classified as BOS by CT volumetry. BOS patients with lung volume remaining >85% of baseline were classified as persistent BOS, whereas BOS patients whose lung volume permanently decreased to ≤85% of baseline were classified as BOS to RAS transition. RESULTS: During follow-up (median 9.8 years) eight patients (12.7%) were classified as BOS to RAS transition, which decreased recipient (p = 0.004) and graft survival (p = 0.020) in comparison to patients with persistent BOS. Opacities on chest imaging preceded BOS to RAS transition in 88% of patients. Opacities on chest imaging at BOS diagnosis and early CLAD diagnosis after transplantation were risk factors for transition. CONCLUSION: Based on lung volume decrease measured by CT volumetry, a small proportion of BOS patients transitioned to RAS which had an adverse effect on recipient and graft survival.

Bronquiolitis obliterante y SARS-CoV-2: el inicio de una asociación / Bronchiolitis obliterans and SARS-CoV-2: the beginning of an association

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.

Quantitative CT lung densitometry as an obstructive marker for the diagnosis of bronchiolitis obliterans in children.

The purpose of this study is to evaluate the quantitative diagnostic performance of computed tomography (CT) densitometry in pediatric patients with bronchiolitis obliterans (BO). We measured the mean lung density (MLD) and represented the difference of MLD in inspiratory and expiratory phases (MLDD), the ratio of the MLD (E/I MLD), and the relative volume percentage of lung density at 50-Hounsfield unit (HU) interval threshold (E600 to E950). We calculated the sensitivity, specificity, and diagnostic accuracy of the lung density indices for the diagnosis of BO. A total of 81 patients, including 51 patients with BO and 30 controls, were included in this study. In the BO patients, expiratory (EXP) MLD and MLDD were significantly lower, and E/I MLD and expiratory low attenuation areas below the threshold of -850 HU to -950 HU (E850, E900, and E950) were statistically significantly higher than controls. Multivariate logistic regression analysis showed that MLDD (odds ratio [OR] = 0.98, p < .001), E/I MLD (OR = 1.39, p < .001), and E850 to E950 were significant densitometry parameters for BO diagnosis. In a receiver-operating characteristic analysis, E900 (cutoff, 1.4%; AUC = 0.920), E/I MLD (cutoff, 0.87; AUC = 0.887), and MLDD (cutoff, 109 HU; AUC = 0.867) showed high accuracy for the diagnosis of BO. In conclusion, the lung CT densitometry can serve as a quantitative marker providing additional indications of expiratory airflow limitation in pediatric patients with BO.

Constrictive bronchiolitis obliterans with a presumptive etiology of preceding feline herpesvirus infection in a cat.

BACKGROUND: Bronchiolar disorders are rarely recognized in cats. Constrictive bronchiolitis obliterans is characterized by concentric peribronchiolar fibrosis and inflammation of the bronchioles, but the underlying causes remain poorly understood in current small animal medicine. CASE PRESENTATION: A 9-year-old cat presented with paroxysmal tachypnea, infrequent cough and persistent labor breathing. Thoracic radiography showed lung hyperinflation and bronchointerstitial pattern, and pulmonary function assessment revealed flow limitation in the late-expiratory phase and poor response to short-acting bronchodilator. Dorsally distributed subpleural ground glass opacities with distinct margin and tree-in-bud opacities were observed on lung high-resolution computed tomography. The cat underwent bronchoalveolar lavage (BAL) and showed severe neutrophilic inflammation. Feline herpesvirus was the only pathogen detected in the BAL fluid. Multiple therapeutic attempts were unsuccessful and the cat died 8 weeks after the initial presentation. Necropsy revealed the infiltration of inflammatory cells, obstruction of the bronchiolar lumen, and submucosal concentric fibrosis suggesting constrictive bronchiolitis obliterans. Combining the pre- and post-mortem findings, as well as the time from symptom onset or BAL to necropsy, constrictive bronchiolitis obliterans was possibly triggered by a preceding feline herpesvirus infection in this case. CONCLUSIONS: The history of nonvaccinated status, lower airway neutrophilic inflammation, and presence of feline herpesvirus in the BAL fluid without coexistence of other pathogens led to the presumption that constrictive bronchiolitis obliterans was induced by a preceding feline herpesvirus infection in this cat. The pathological changes of bronchiolitis obliterans induced by a preceding feline herpesvirus infection could be different from that of cats with acute herpesvirus pneumonia, such as intranuclear inclusions would disappear over time and were no longer found 7-10 days after inoculation. The presence of patchy distribution of subpleural ground glass opacities on lung high-resolution computed tomography should raise the suspicion of peribronchiolar fibrosis. Clinical awareness of bronchiolar disorders as a differential diagnosis is important in cats with lung hyperinflation and labored breathing who show poor reversibility to bronchodilator.

Artificial Intelligence Algorithm-Based High-Resolution Computed Tomography Image in the Treatment of Children with Bronchiolitis Obliterans by Traditional Chinese Medicine Method of Resolving Phlegm and Removing Blood Stasis.

This research was aimed to explore the application of high-resolution computed tomography (HRCT) based on intelligent iterative reconstruction technique in the early diagnosis and treatment of bronchiolitis obliterans (BO) in children and to explore the efficacy of traditional Chinese medicine (TCM) in resolving phlegm and removing blood stasis. Sixty pediatric patients with BO were selected as the study subjects and diagnosed by HRCT scanning, and the scanned images were processed by iterative reconstruction technique. The patients were treated with TCM therapy of resolving phlegm and removing blood stasis alone (group A), HRCT-guided TCM therapy of resolving phlegm and removing blood stasis (group B), and iterative reconstruction HRCT-guided TCM therapy of resolving phlegm and removing blood stasis (group C). The results showed that the lung HRCT image after iterative reconstruction was closer to the original image than that after filtered back projection reconstruction, and the edge of the image after filtered back projection reconstruction was more blurred and the noise was higher. The image obtained by iterative reconstruction technique was smoother and clearer, and the image stability after iterative reconstruction was higher. The treatment results showed that the proportion of moderate and severe obstruction in group C was 5.18%, which was significantly lower than that in group A (18.75%) and group B (11.29%), and group B was significantly lower than that in group A (18.75%) (P < 0.05). The proportion of clinical effect in group C after treatment was 70.18%, significantly higher than that in group A (55.5%) and group B (63.34%), and that in group B was significantly higher than that in group A (55.5%) (P < 0.05). In summary, the lung HRCT after iterative reconstruction can more clearly and intuitively show the lesion site, which has a key role in guiding the early diagnosis and treatment planning of BO; the HRCT image based on iterative reconstruction technique combined with TCM treatment of removing blood stasis and resolving phlegm has a better therapeutic effect on children, with a high application value.

Chronic lung allograft dysfunction and restrictive allograft syndrome: are phenotypes robust and helpful?

PURPOSE OF REVIEW: New chronic lung allograft dysfunction (CLAD) consensus documents were published in 2019, defining four phenotypes; bronchiolitis obliterans syndrome, restrictive allograft syndrome, mixed and undefined. Clearly, validation of these guidelines in a real life cohort is critical. RECENT FINDINGS: Indeed, validation has been performed recently, both after bilateral lung transplantation (LTx) and after single LTx illustrating that precise phenotyping based on pulmonary function alone can be difficult. Undertaking regular chest computed tomography scanning does appear very helpful in establishing the prognosis of the patients with CLAD. SUMMARY: Pulmonary function changes may not always identify the exact phenotype of CLAD and we provide further evidence for the important role of chest imaging at diagnosis and during the follow-up of patients with CLAD.

Idiopathic Obliterative Bronchiolitis in a Young Woman: A Rare Case of a Transbronchial Lung Biopsy Contributing to the Diagnosis.

Idiopathic obliterative bronchiolitis (OB) is a rare disease that usually requires a surgical lung biopsy. A 25-year-old woman with progressive exertional dyspnea for several months showed a severe mixed restrictive and obstructive pattern on spirometry. Chest computed tomography showed a mosaic pattern, and pulmonary ventilation-perfusion scintigraphy showed a matched defect. The bronchoscopic specimens obtained from both the alveolar and bronchiolar regions of the predicted lesion area contributed to the diagnosis of OB. She had no underlying causes of secondary OB, and she was diagnosed with idiopathic OB. Since lung transplantation was indicated, she was referred to a lung transplantation-certified hospital.

Quantitative CT Correlates with Local Inflammation in Lung of Patients with Subtypes of Chronic Lung Allograft Dysfunction.

Chronic rejection of lung allografts has two major subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), which present radiologically either as air trapping with small airways disease or with persistent pleuroparenchymal opacities. Parametric response mapping (PRM), a computed tomography (CT) methodology, has been demonstrated as an objective readout of BOS and RAS and bears prognostic importance, but has yet to be correlated to biological measures. Using a topological technique, we evaluate the distribution and arrangement of PRM-derived classifications of pulmonary abnormalities from lung transplant recipients undergoing redo-transplantation for end-stage BOS (N = 6) or RAS (N = 6). Topological metrics were determined from each PRM classification and compared to structural and biological markers determined from microCT and histopathology of lung core samples. Whole-lung measurements of PRM-defined functional small airways disease (fSAD), which serves as a readout of BOS, were significantly elevated in BOS versus RAS patients (p = 0.01). At the core-level, PRM-defined parenchymal disease, a potential readout of RAS, was found to correlate to neutrophil and collagen I levels (p < 0.05). We demonstrate the relationship of structural and biological markers to the CT-based distribution and arrangement of PRM-derived readouts of BOS and RAS.

Late-Onset, Noninfectious Pulmonary Complications following Allogeneic Hematopoietic Stem Cell Transplantation: A Nationwide Cohort Study of Long-Term Survivors.

BACKGROUND: Survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk for pulmonary adverse events. Data on late-onset noninfectious pulmonary complications in long-term adult survivors of allo-HSCT are limited and incomplete. OBJECTIVES: This study aimed (1) to determine occurrence and degree of pulmonary sequelae in adult survivors of allo-HSCT and (2) to identify associations between pulmonary function, high-resolution CT (HRCT), and clinical characteristics. METHOD: In a nationwide, single-center cross-sectional study, 103 survivors (aged median [range] 35 [17-58] years, 53% females) were examined 17 (6-32) years after allo-HSCT and compared with healthy controls (n = 105). Methods included pulmonary function tests and HRCT. RESULTS: Chronic graft-versus-host disease was diagnosed in 33% of survivors, including 12% with bronchiolitis obliterans syndrome (BOS). Mean lung volumes (TLC, FVC, and FEV1) and gas diffusing capacity were >80% of predicted for the survivors as a group, but significantly lower than in healthy controls. Pathological HRCT findings were detected in 48% of the survivors (71% airways disease, 35% interstitial lung disease, and 24% apical subpleural interstitial thickening). Air trapping (%) on HRCT correlated with % predicted FEV1, p < 0.001. In a multiple logistic regression model, both BOS and pathological findings on HRCT were associated with chemotherapy prior to allo-HSCT, p < 0.05. CONCLUSIONS: Long-term allo-HSCT survivors had significantly lower pulmonary function than age- and gender-matched healthy controls and nearly half had pathological findings on HRCT. Longitudinal data will determine if pulmonary sequelae will remain stable or progress. We recommend lifelong monitoring of pulmonary function in allo-HSCT survivors. HRCT provides additional information, but is not suited for surveillance.

Chronic lung allograft dysfunction subtype analysis by computed tomography volumetry.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplantation. Of the two subtypes, restrictive allograft syndrome (RAS) is characterized by a larger lung volume decrease and worse prognosis than bronchiolitis obliterans syndrome (BOS). We used computed tomography (CT) volumetry to classify CLAD subtypes and determined their clinical impact. METHODS: Adult primary lung transplants performed 2003-2015 (n = 167) were retrospectively evaluated for CLAD and subclassified with CT volumetry. Lung volume decrease of < 15% from baseline resulted in BOSCT-vol and ≥15% resulted in RASCT-vol diagnosis. Clinical impact of CLAD subtypes was defined, and the prognostic value of different lung function, radiological, and lung volume parameters present at the time of CLAD diagnosis were compared. RESULTS: CLAD affected 43% of patients and was classified with CT volumetry as BOSCT-vol in 89% and RASCT-vol in 11%. Median graft survival estimate in RASCT-vol was significantly decreased compared to BOSCT-vol (1.6 vs. 9.7 years, P = .038). At CLAD onset, RASCT-vol diagnosis (P = .05), increased lung density (P = .007), and more severe FEV1 (P = .004) decline from baseline, increased graft loss risk in multivariate analysis. CONCLUSIONS: CT volumetry serves to identify lung transplant patients with a poor clinical outcome but should be validated in prospective trials.