Bronchiolitis Obliterans Research Articles

A Systematic Review of Global Research on Post Infectious Bronchiolitis Obliterans in Children

A Systematic Review of Global Research on Post Infectious Bronchiolitis Obliterans in Children

Ventilatory capacity in CLAD is driven by dysfunctional airway structure

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. 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. Exvivo 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. 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. 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. This research was funded with the National research fund Flanders (G060322N), received by R.V.

Bronquiolitis obliterante posinfecciosa secundaria a adenovirus

Bronchiolitis obliterans is a rare chronic obstructive respiratory disease secondary to damage of the lower respiratory tract causing inflammation and partial or total obliteration of it. There are different causes, being infectious the most frequent in pediatrics, mainly due to adenovirus. We present the case of an 18-month-old male infant with a history of admission to the Pediatric Intensive Care Unit at 8 months of age due to bronchitis secondary to respiratory syncytial virus and adenovirus. After this episode, he presented persistent respiratory distress and pathological pulmonary auscultation. High resolution pulmonary computed tomography showed a mosaic pattern with areas of air trapping and decreased vascular caliber in the affected areas, findings suggestive of bronchiolitis obliterans.

Detection of Bronchiolitis Obliterans Syndrome Using Nitrogen Multiple Breath Washout in Children Posthemopoietic Stem Cell Transplant

Bronchiolitis obliterans syndrome (BOS) is a severe complication following hemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI2.5) derived from the nitrogen multiple breath washout (N2MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. We aimed to examine the feasibility of performing surveillance N2MBW in children post-HSCT, and in an exploratory analysis, determine if LCI2.5 led to earlier detection of BOS when compared to spirometric indices. Participants aged 5 to 17 years were recruited prior to receiving HSCT into a prospective, single-center, feasibility study at the Royal Children's Hospital, Melbourne. N2MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9, and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. Twenty-one (12 male) children with a mean age of 13.4 (range 9.2 to 17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI2.5, while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV1). Ninety-nine percent of N2MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while 2 participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI2.5 ranging from 3 to 5 units and mean reductions in FEV1 % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI2.5 values were significantly worse when compared with the no BOS group (P < .001). Relative changes in LCI2.5 and FEV1 were both predictive of BOS at 6 months post HSCT. This study demonstrates that N2MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI2.5 did not lead to earlier detection of BOS, when compared to spirometry.

Construction of a risk prediction model for bronchiolitis obliterans in children with refractory Mycoplasma pneumoniae pneumonia

To explore the establishment of a risk prediction model for concurrent bronchiolitis obliterans (BO) in children with refractory Mycoplasma pneumoniae pneumonia (RMPP). A retrospective study included 116 RMPP children treated in the Department of Pediatrics of Xiangya Changde Hospital from June 2021 to December 2023. Eighty-one cases were allocated to the training set and thirty-five cases to the validation set based on a 7:3 ratio. Among them, 26 cases in the training set developed BO, while 55 did not. The multivariate logistic regression was used to select variable factors for constructing the BO risk prediction model. Nomograms were drawn, and the receiver operating characteristic (ROC) curve was used to assess the discriminative ability of the model, while calibration curves and Hosmer-Lemeshow tests evaluated the model's calibration. Multivariate logistic regression analysis indicated that several factors were significantly associated with concurrent BO in RMPP children, including length of hospital stay, duration of fever, atelectasis, neutrophil percentage (NEUT%), peak lactate dehydrogenase (LDH), ferritin, peak C reactive protein (CRP), oxygenation index (PaO2/FiO2), ≥2/3 lung lobe consolidation, pleural effusion, bronchial mucous plugs, bronchial mucosal necrosis, and arterial oxygen partial pressure (PaO2) (P<0.05). ROC curve analysis for the training set indicated an area under the curve of 0.904 with 88% sensitivity and 83% specificity; the validation set showed an area under the curve of 0.823 with 76% sensitivity and 93% specificity. The Hosmer-Lemeshow test's Chi-square values for the training and validation sets were 2.17 and 1.92, respectively, with P values of 0.221 and 0.196, respectively. The risk prediction model for BO in RMPP children based on logistic regression has good performance. Variables such as length of hospital stay, duration of fever, atelectasis, peak LDH, peak CRP, NEUT%, ferritin, ≥2/3 lung lobe consolidation, pleural effusion, bronchial mucous plugs, bronchial mucosal necrosis, PaO2/FiO2, andPaO2 can be used as predictors.

Towards Early Detection of Post-Allogeneic Bone Marrow Transplant Bronchiolitis Obliterans Syndrome (BOS) – the Use of Portable Airway Oscillometry

Towards Early Detection of Post-Allogeneic Bone Marrow Transplant Bronchiolitis Obliterans Syndrome (BOS) – the Use of Portable Airway Oscillometry

An in Vitro Patient-Derived Model of Bronchiolitis Obliterans Syndrome Yields New Insight into Steroid Sensitivity and Resistance

An in Vitro Patient-Derived Model of Bronchiolitis Obliterans Syndrome Yields New Insight into Steroid Sensitivity and Resistance

Risk factors for the development of bronchiolitis obliterans in children after suffering from adenovirus pneumonia.

Bronchiolitis obliterans (BO) is an irreversible chronic obstructive lung disease in small airways. The aim of this study was to identify the relevant risk factors for the development of BO in children after suffering from adenovirus (ADV) pneumonia. An observational cohort study that included 112 children suffering from ADV pneumonia in our institution from March 2019 to March 2020 was performed. We divided the children into a BO group and a non-BO group based on whether they did develop BO or not. Univariate analysis and multivariate logistic regression analysis were applied to identify risk factors for the development of BO. The prediction probability model was evaluated by receiver operating characteristic (ROC) curve analysis. Twenty-eight children (25%) did develop BO after suffering from ADV pneumonia, while 84 children did not. Respiratory support (OR 6.772, 95% CI 2.060-22.260, P = 0.002), extended length of wheezing days (OR 1.112, 95% CI 1.040-1.189, P = 0.002) and higher lactic dehydrogenase (LDH) levels (OR 1.002, 95% CI 1.000-1.003, P = 0.012) were independently associated with the development of BO. The predictive value of this prediction probability model was validated by the ROC curve, with an area under the curve of 0.870 (95% CI 0.801-0.939, P < 0.001), a standard error of 0.035, a maximum Youden's index of 0.608, a sensitivity of 0.929, and a specificity of 0.679. After suffering an ADV pneumonia, children who have needed respiratory support, had a longer length of wheezing days or had higher LDH levels are more likely to develop BO.

Utility of pulmonary function test screening for bronchiolitis obliterans syndrome stage 0-p among recipients of allogeneic hematopoietic stem cell transplantation conditioned with antithymocyte globulin

INTRODUCTION Timely diagnosis of bronchiolitis obliterans syndrome (BOS) following allogeneic hematopoietic cell transplantation (allo-HCT) is challenging due to the paucity of symptoms early in the disease course. Pulmonary function tests (PFT) are proposed as a screening tool to identify patients at risk of developing BOS in this population. METHODS We performed a retrospective study including patients who underwent allo-HCT with antithymocyte globulin (ATG) conditioning between May 2010 and August 2020, survived without relapse for at least 3 months, and had a pre-transplant PFT and at least 2 post-transplant PFTs. Patients met BOS-0p if their PFTs demonstrated a sustained >10% drop in FEV1 or >25% drop in FEF25-75. A competing risks regression model was used to estimate the cumulative incidence of BOS and BOS-0p. Test performance characteristics for BOS-0p were calculated using 2x2 tables. RESULTS The cumulative incidence of BOS was 2.1% (CI 0.8-4.6) at 12 months and 5.4% (CI 2.8-9.3) at 60 months post-transplant. Meeting BOS-0p during the first 2 years post-transplantation yielded a sensitivity of 64% (CI 31-89), specificity of 71% (CI 64-77), PPV of 10% (CI 4-20), and NPV of 97% (CI 93-99) for subsequent development of BOS. Meeting BOS-0p was associated with increased mortality (HR 2.27, p = 0.006). CONCLUSION Although patients who meet BOS-0p within 2 years of transplant are more likely to develop BOS, prompt repeat testing is needed to confirm entry into the stage if a patient meets spirometric criteria on a single PFT.

A review of the therapeutic potential of the cysteinyl leukotriene antagonist Montelukast in the treatment of bronchiolitis obliterans syndrome following lung and hematopoietic-stem cell transplantation and its possible mechanisms.

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.

Risk factors for bronchiolitis obliterans complicating adenovirus pneumonia in children: a meta-analysis.

To preliminarily explore the risk factors for post-infectious bronchiolitis obliterans (PIBO) complicating adenovirus pneumonia (ADVP) in children through a meta-analysis. A systematic search was conducted on three English-language databases (PubMed, Web of Science and The National Library of Medicine) and two Chinese-language databases (China National Knowledge Infrastructure and the Wanfang Database) between database inception and 1 January 2023. Data analysis was conducted using Stata 15.1 software. A total of 10 articles, reporting 14 risk factors, were included in the analysis, with 8 risk factors taken into consideration. Through the meta-analysis, 5 risk factors were identified for PIBO complicating ADVP in paediatric patients: hypoxaemia [odds ratio (OR) = 9.37, 95% CI: 4.22, 20.77, p < 0.001], persistent wheezing (OR = 4.65, 95% CI: 2.20, 9.82, p < 0.001), mechanical ventilation (OR = 3.87, 95% CI: 2.37, 6.33, p < 0.001), length of hospital stay (LoHS) (OR = 1.25, 95% CI: 1.09, 1.43, p < 0.001) and fever duration (OR = 1.08, 95% CI: 1.02, 1.14, p = 0.009). Existing evidence suggests that hypoxaemia, persistent wheezing, mechanical ventilation, LoHS and fever duration are risk factors for PIBO complicating ADVP in children. These findings underscore the need for enhanced assessment and management in clinical practice. This study may provide such a clinical prediction model from the identified 5 risk factors for PIBO and offer valuable insights for preventing bronchiolitis obliterans in children with ADVP.

Obstructive and Restrictive Lung Disease After Hematopoietic Stem Cell Transplantation

Pulmonary complications are frequently encountered by clinicians in patients who have undergone hematopoietic stem cell transplantation and are associated with increased morbidity and mortality in these patients. Complications involving the lung are caused by both infectious and non-infectious etiologies, with non- infectious complications associated with significant long-term effect on the quality of life and can occur several years after transplantation. One manifestation of non-infectious post-transplant complication is a change in pulmonary function testing compared to pre-transplant testing. These changes can either be of an obstructive or restrictive pattern with each being associated with specific post-transplant complications. An improved understanding of obstructive and restrictive lung disease after hematopoietic stem cell transplant is necessary for both primary care physicians and specialists to recognize these diseases early in their course in order to facilitate work-up, treatment, and necessary follow-up. This review will provide an overview of obstructive and restrictive lung disease after hematopoietic stem cell transplant focusing on the etiologies, diagnosis, treatment, and outcomes. We will highlight bronchiolitis obliterans syndrome as an example of obstructive disease after transplant and will discuss pleuroparenchymal fibroelastosis as a cause for restrictive findings on pulmonary function testing. Improvements in the knowledge of the underlying etiologies and pathophysiology of obstructive and restrictive lung disease after hematopoietic stem cell transplant will allow for the identification of novel biomarkers to facilitate the diagnosis of these patients and will assist in the design of future targeted therapies to improve treatment and prognosis.

Azithromycin Effectiveness in Children with Mutated Mycoplasma Pneumoniae Pneumonia.

Mycoplasma pneumoniae (MP) is highly resistant to macrolides in China. However, macrolides still exhibit clinical effectiveness in some macrolide-resistant patients. We tend to explore azithromycin effectiveness in Mycoplasma pneumoniae pneumonia (MPP) children with A2063/2064G mutation. This retrospective observational cohort study was conducted at the Children's Hospital of the Chongqing Medical University. Children with macrolide-resistant mutations (A2063/2064G) diagnosed as MPP were retrospectively enrolled. Receiver operating characteristic (ROC) curves and logistic regression analysis were used to evaluate and identify independent risk factors for treatment failure (progress to refractory Mycoplasma pneumoniae pneumonia [RMPP]) in macrolide-unresponsive Mycoplasma pneumoniae pneumonia (MUMPP) children with the A2063/2064G mutation. One hundred fifty-five children were retrospectively enrolled. More than 20% (36/155, 23.23%) of patients experienced defervescence within 3 days of azithromycin treatment. RMPP was diagnosed in 54 patients (54/155, 34.84%) and the incidence of RMPP during hospitalization was 22.72 per 1000 person-days. Logistic regression analysis showed that lactate dehydrogenase (LDH) ≥ 399 (U/L) was an independent risk factor for RMPP (odds ratio [OR] 4.66, 95% confidence interval [CI] 1.31-17.10, P=0.017). During the year followed, RMPP patients had a significantly higher incidence of bronchiolitis obliterans and bronchiectasis than non-RMPP patients (16.67% vs 1.98%, P=0.001; 9.26% vs 0.00%, P=0.005, respectively). Azithromycin was effective in children with MPP with the A2063/2064G mutation. For MUMPP children with A2063/2064G mutation, children with LDH ≥ 399 (U/L) had significant higher risk for progression to RMPP, and should consider to be treated with alternative antibiotics (eg tetracyclines, and fluoroquinolones).

Risk factors and prediction models for bronchiolitis obliterans after severe adenoviral pneumonia.

Age < 1year, PICU admission, long fever duration, and bilateral lung infection are independent risk factors for PIBO in children with SAP. The nomogram model may aid clinicians in the early diagnosis and intervention of PIBO. • Adenoviruses are the most common pathogens associated with PIBO. • Wheezing, tachypnoea, hypoxemia, and mechanical ventilation are the risk factors for PIBO. • Age < 1year, admission to PICU, long duration of fever days, and bilateral lung infection are independent risk factors for PIBO in children with SAP. • A prediction model presented as a nomogram may help clinicians in the early diagnosis and intervention of PIBO.

Castleman disease of plasma cell type accompanied with bronchiolitis obliterans: a case report and review of the literature

BackgroundCastleman disease, also known as giant lymph node hyperplasia or angiofollicular lymph node hyperplasia, is a highly heterogeneous clinicopathological entity that belongs to the family lymphoproliferative disorders. Castleman disease accompanied by bronchiolitis obliterans is uncommon and often poses a great diagnostic challenge, which is easily confused with respiratory diseases and impeding the correct diagnosis and treatment. The main aim in presenting such rare case studies is to raise awareness and expand the diagnostic horizon of clinicians for appropriate management.Case presentationHere, we present a 69-year-old Chinese male who was admitted to our hospital due to right chest pain for 6 months, accompanied by cough, expectoration, and fever. Laboratory examinations revealed elevated immunoglobulin G and C-reactive protein, and normal serum levels of tumor markers and interleukin-6. Computed tomography scan detected diffuse bronchial wall thickening and patchy area of air trapping consistent with small airway disease. Pulmonary function test showed mild small airway obstructive ventilation dysfunction and moderate decrease in diffusion capacity. The pathological result of the right axillary lymph node was consistent with the plasma cell type Castleman disease. According to the above examinations, the patient was finally diagnosed with the plasma cell type Castleman disease accompanied with bronchiolitis obliterans. He received immunosuppressive medication after surgery and has been followed up for 11 months. Now the patient is currently in stable condition without recurrence.ConclusionCastleman disease is a rare lymphoproliferative disorder with a variety of symptoms. At present, the treatment of Castleman disease accompanied with bronchiolitis obliterans is mostly based on experiences or previous case reports, and there is no standard treatment. Here, we report an uncommon case of Castleman disease accompanied with bronchiolitis obliterans in which the patient received immunosuppressive medication after surgery and has been followed up for 11 months without experiencing a recurrence, which may deepen and extend our understanding of this disease.

Single-cell resolution of human airway epithelial cells exposed to bronchiolitis obliterans-associated chemicals.

Bronchiolitis obliterans (BO) is a fibrotic lung disease characterized by progressive luminal narrowing and obliteration of the small airways. In the nontransplant population, inhalation exposure to certain chemicals is associated with BO; however, the mechanisms contributing to disease induction remain poorly understood. This study's objective was to use single-cell RNA sequencing for the identification of transcriptomic signatures common to primary human airway epithelial cells after chemical exposure to BO-associated chemicals-diacetyl or nitrogen mustard-to help explain BO induction. Primary airway epithelial cells were cultured at air-liquid interface and exposed to diacetyl, nitrogen mustard, or control vapors. Cultures were dissociated and sequenced for single-cell RNA. Differential gene expression and functional pathway analyses were compared across exposures. In total, 75,663 single cells were captured and sequenced from all exposure conditions. Unbiased clustering identified 11 discrete phenotypes, including 5 basal, 2 ciliated, and 2 secretory cell clusters. With chemical exposure, the proportion of cells assigned to keratin 5+ basal cells decreased, whereas the proportion of cells aligned to secretory cell clusters increased compared with control exposures. Functional pathway analysis identified interferon signaling and antigen processing/presentation as pathways commonly upregulated after diacetyl or nitrogen mustard exposure in a ciliated cell cluster. Conversely, the response of airway basal cells differed significantly with upregulation of the unfolded protein response in diacetyl-exposed basal cells, not seen in nitrogen mustard-exposed cultures. These new insights provide early identification of airway epithelial signatures common to BO-associated chemical exposures.NEW & NOTEWORTHY Bronchiolitis obliterans (BO) is a devastating fibrotic lung disease of the small airways, or bronchioles. This original manuscript uses single-cell RNA sequencing for identifying common signatures of chemically exposed airway epithelial cells in BO induction. Chemical exposure reduced the proportion of keratin 5+ basal cells while increasing the proportion of keratin 4+ suprabasal cells. Functional pathways contributory to these shifts differed significantly across exposures. These new results highlight similarities and differences in BO induction across exposures.

Sleep and quality of life characteristics in a pediatric population with chronic obstructive respiratory diseases.

To describe sleep and quality of life of pediatric patients with chronic obstructive respiratory diseases and toascertain whether or notsleep quality correlates with quality of life in this population. Participants aged 5 to 18 years with cystic fibrosis (CF), severe asthma, or postinfectious bronchiolitis obliterans (PIBO) receiving regular follow-up at a pediatric respiratory medicine center were recruited. Two questionnaires were used: the Brazilian version of the Sleep Disturbance Scale for Children (SDSC) and the Pediatric Quality of Life Inventory (Peds-QL). A total of 46 individuals were included: 30 with CF, 9 with severe asthma, and 7 with PIBO. Almost two-thirds of the patients and their parents or guardians scored at least 39 points on the SDSC, suggesting poor sleep quality. Significantly higher overall median scores were observed in those with severe asthma. Patients and their parents or guardians scored a median of 77 and 80 points respectively on the Peds-QL, with parents of patients withCF scoring higher than any other group. There was a moderate inverse correlation between sleep disorders and quality of life (r = - 0.532 for patients and r = - 0.606 for parents; p < 0.001). Children and adolescents with chronic obstructive respiratory diseases experience impairment in their sleep quality and quality of life. Sleep disorders and quality of life have a moderate negative correlation.

Impulse Oscillometry Versus Spirometry to Detect Bronchiolitis Obliterans Syndrome in Bilateral Lung Transplant Recipients: A Prospective Diagnostic Study.

Chronic lung allograft dysfunction (CLAD), and especially bronchiolitis obliterans syndrome (BOS), remain dominant causes of morbidity and mortality after lung transplantation. Interest is growing in the forced oscillation technique, of which impulse oscillometry (IOS) is a form, as a tool to improve our understanding of these disorders. However, data remain limited and no longitudinal studies have been published, meaning there is no information regarding any capacity IOS may have for the early detection of CLAD. We conducted a prospective longitudinal study enrolling a consecutive sample of adult bilateral lung transplant recipients with healthy lung allografts or CLAD and performed ongoing paired IOS and spirometry tests on a clinically determined basis. We assessed for correlations between IOS and spirometry and examined any predictive value either modality may hold for the early detection of BOS. We enrolled 91 patients and conducted testing for 43 mo, collecting 558 analyzable paired IOS and spirometry tests, with a median of 9 tests per subject (interquartile range, 5-12) and a median testing interval of 92 d (interquartile range, 62-161). Statistically significant moderate-to-strong correlations were demonstrated between all IOS parameters and spirometry, except resistance at 20 Hz, which is a proximal airway measure. No predictive value for the early detection of BOS was found for IOS or spirometry. This study presents the first longitudinal data from IOS after lung transplantation and adds considerably to the growing literature, showing unequivocal correlations with spirometry but failing to demonstrate a predictive value for BOS.

Chest imaging classification in Mycoplasma pneumoniae pneumonia is associated with its clinical features and outcomes

BackgroundThe imaging findings of Mycoplasma pneumoniae pneumonia (MPP) vary; however, few studies have focused on the relationship of imaging classification with clinical manifestations and outcomes. ObjectiveTo prospectively investigate whether chest imaging classification in Mycoplasma pneumoniae pneumonia (MPP) is associated with its clinical features and outcomes. MethodsA total of 1,401 hospitalized children with MPP were enrolled from January 2019 to December 2021. Imaging findings were categorized as bronchopneumonia and consolidation/atelectasis according to X-ray, and bronchopneumonia, consolidation/atelectasis, bronchiolitis, and mosaic pattern according to computed tomography (CT). Clinical characteristics and outcomes of patients with different imaging classifications were prospectively analyzed based on electronic medical records. ResultsBronchopneumonia was the most common finding (59.6%), while consolidation/atelectasis was the most severe group. Clinical manifestations and laboratory indicators for the consolidation/atelectasis group included serious abnormalities. Further, outcomes of the patients were worse, including having longer total durations of fever and hospitalization, greater hospitalization expenses, and a higher likelihood of developing refractory MPP, necrotizing pneumonia, and bronchiolitis obliterans (BO) in this group. The incidence of bronchiolitis, a disease characterized by a high prevalence of fever, moist rales, and an atopic constitution, tended to increase after the coronavirus disease pandemic and predisposed patients to BO. A mosaic pattern occurred in allergic and young individuals, with wheezing as the main manifestation, with patients having relatively mild symptoms and good outcomes. ConclusionDifferent imaging classifications have different clinical features and clinical outcomes; thus, formulating an imaging-based classification system is of great clinical value.

Single Cell Transcriptomics of Bronchiolitis Obliterans Syndrome

Bronchiolitis obliterans syndrome (BOS) is a manifestation of pulmonary chronic graft versus host disease (cGVHD), a serious complication of allogeneic stem cell transplantation (ASCT). BOS also occurs following bi-orthotopic lung transplant (BOLT), where it is termed chronic lung allograft dysfunction (CLAD)-BOS and is the leading cause of long-term allograft failure. In both contexts, fibrotic obliteration of the small airways leads to progressive respiratory failure. Since the molecular mechanisms leading to fibrotic airway remodeling in humans are poorly understood, we used single cell RNA-sequencing to map intercellular interactions between immune (CD45+ve) and non-immune (CD45-ve) cells of lung explants from patients undergoing first lung transplantation for cGVHD-BOS (n=1) or second lung transplantation for CLAD-BOS (n=2) compared to normal controls (NC) (n=3). BOS patients ranged in age from 44 to 61 years old; NC were similar in age and died of cerebrovascular accidents. Lungs were surgically removed at the time of BOLT (BOS samples) or at autopsy (NC). CD45+ve and CD45-ve cells were magnetically sorted and freshly processed. Single cell libraries were prepared using the 10X Genomics Chromium Controller and sequenced on an Illumina Novaseq 6000 instrument. Quality control filtering, transcript count normalization, integration, PCA, UMAP projection, and cell clustering were performed with Seurat in R v4.2.1. CD45+ve and CD45-ve cells were annotated in Azimuth using the Human Lung Cell Atlas and LungMAP Cell Cards reference data sets, respectively. Differences in gene expression between conditions were evaluated with the Seurat FindMarkers function. Inter-cellular communications were characterized with CellChat. Interaction strength was calculated as a function of ligand/receptor pair expression, and incoming and outgoing signaling was classified using network centrality analysis. We identified 45,932 CD45+ve cells (28,241 in BOS and 17,691 in NC) and 33,428 CD45-ve cells (23,390 in BOS and 10,038 in NC) including 17 distinct cell types in the CD45+ve fractionand 24 in the CD45-ve fraction. As samples came from patients with end-stage disease, we hypothesized that CD45+ve cells would be highly activated while CD45-ve cells would exhibit strongly fibrogenic programs. To test this hypothesis, we analyzed the incoming and outgoing signal strength for each cell type. Stromal cells such as type 1 (AF1) and type 2 alveolar fibroblasts (AF2), secondary crest myofibroblasts (SCMF), and pericytes had the strongest outgoing signals in BOS ( Figure 1). Except for AF2, incoming and outgoing signaling from stromal cells was stronger in BOS than in NC. These observations support stromal cells as important drivers of BOS pathogenesis. Next, we characterized signaling directionality between stromal cells and CD45+ve cells. In general, incoming signals to stromal cells from CD45+ve cells were weaker in BOS than in NC, while outgoing signals from stromal cells to CD45+ve cells were stronger. For example, signaling from stromal cells expressing THY1, which may attenuate fibrosis in fibrotic lung disease, to integrins on monocytes and macrophages was stronger in BOS. Likewise, BOS was enriched for signaling from collagens and fibronectin on stromal cells to CD44 on CD45+ve cells. As expected, genes implicated in fibrosis and wound healing were upregulated in stromal cells in BOS patients. In AF1 ( Figure 2), these included genes encoding collagens (COL6A3, COL14A1), actins (ACTA2), matricellular proteins (POSTN, TNC, SPARC), protease inhibitors (SERPINE1, TIMP1), hyaluronic acid synthetases (HAS2), proteoglycans (LUM, VCAN), and proteases (MMP19, ADAMTS9). Interestingly, we found evidence for active anti-fibrotic programs such as MMP19, PTGS2, and THY1. To our knowledge, this is the first study employing single cell transcriptomics of lung explants from patients with cGVHD-associated BOS. Robust signaling from stromal cells to CD45+ve cells may support their role in modifying the inflammatory infiltrate in BOS. We identified outgoing, stromal derived signaling associated with fibrotic (collagen and fibronectin) and anti-fibrotic programs (THY1). Our findings illustrate an interplay between pro- and anti-fibrotic programs even in end-stage BOS lungs, raising the tantalizing possibility to intervene therapeutically in this dyshomeostatic balance.