Vaping-associated constrictive bronchiolitis.

A woman in her 40s who vaped reported rapid onset of shortness of breath and cough. Pulmonary function testing showed severe obstruction and no substantial response to an inhaled bronchodilator, and chest computed tomography revealed extensive air trapping. A lung cryobiopsy was done after a comprehensive and unrevealing evaluation, which showed characteristics of airway inflammation and prominent bronchial-associated lymphoid tissue. With this knowledge and her vaping history, we diagnosed vaping-associated constrictive bronchiolitis. This phenomenon has not been well described. Clinicians should know to consider vaping when a patient with a vaping history presents with severe airway obstruction.

Imaging of Small Airways Disease.

Bronchiolitis refers to a small airways disease and may be classified by etiology and histologic features. In cellular bronchiolitis inflammatory cells involve the small airway wall and peribronchiolar alveoli and manifest on CT as centrilobular nodules of solid or ground glass attenuation. Constrictive bronchiolitis refers to luminal narrowing by concentric fibrosis. Direct CT signs of small airway disease include centrilobular nodules and branching tree-in-bud opacities. An indirect sign is mosaic attenuation that may be exaggerated on expiratory CT and represent air trapping. Imaging findings can be combined with clinical and pathologic data to facilitate a more accurate diagnosis.

Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome.

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than nondeployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the subjects in this cohort reported exposure to sulfur dioxide (SO2), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease. Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO2-exposed mice. SO2 exposure led to increased formation of isolevuglandins (isoLGs) adducts and superoxide dismutase 2 (SOD2) acetylation in endothelial cells, which were attenuated by treatment with the isoLG scavenger 2-hydroxybenzylamine acetate (2-HOBA). In addition, 2-HOBA treatment or Siruin-3 overexpression in a transgenic mouse model prevented vascular remodeling following SO2 exposure. In summary, our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress appears to mediate PV remodeling in this model. Together, these findings provide new insights regarding the critical mechanisms underlying PDRS.NEW & NOTEWORTHY We developed a mice model of "post-deployment respiratory syndrome" (PDRS), a condition in Veterans with unexplained exertional dyspnea. Our model successfully recapitulates many of the pathological and physiological features of the syndrome, revealing involvement of the ROS-isoLGs-Sirt3-SOD2 pathway in pulmonary vasculature pathology. Our study provides additional knowledge about effects and long-term consequences of sulfur dioxide exposure on the respiratory system, serving as a valuable tool for future PDRS research.

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.

Severe cryptogenic bronchiolitis: Case report.

Bronchiolitis obliterans (BO) is a progressive fibrotic process that predominantly affects the small airways and is identified as constrictive bronchiolitis by pathologists. It is commonly associated with allogeneic hematopoietic stem cell transplant (HSCT), lung transplant, exposure to inhaled toxins, post-infectious processes, autoimmune diseases, and sometimes, no known cause. In the latter case, it is referred to as cryptogenic bronchiolitis obliterans. A 52-year-old Hispanic man with a medical history of hypertension, diabetes mellitus, and coronary artery disease was referred to the pulmonary department due to experiencing dyspnea on exertion, intermittent dry cough, and progressive limitation of activities of daily living. Spirometry revealed severe obstructive changes, and chest high-resolution computed tomography showed ground-glass opacities with nodular infiltrates in the upper lobes, leading to a presumptive diagnosis of hypersensitivity pneumonitis. The patient underwent a lung surgical biopsy of the right upper and lower lobes, which revealed extensive constrictive bronchiolitis. Due to the patient's worsening general condition, bilateral lung transplantation succeeded without any further complications. Following the transplantation, the patient showed good recovery and functional improvement. Bronchiolitis obliterans, or constrictive bronchiolitis, has a variable natural history. It is associated with a higher risk of mortality in allogenic HSCT. When BO is secondary to inhalation of toxic gases, it is usually nonprogressive and limited to toxin exposure. Autoimmune diseases or cryptogenic bronchiolitis are rare and have a heterogeneous clinical course. To make a proper diagnosis, clinical history, radiologic and histologic findings must be considered.

Environmental and occupational bronchiolitis obliterans: new reality.

Patients diagnosed with environmental/occupational bronchiolitis obliterans (BO) over the last 2 decades often present with an indolent evolution of respiratory symptoms without a history of high-level, acute exposure to airborne toxins. Exertional dyspnea is the most common symptom and standard clinical and radiographic evaluation can be non-diagnostic. Lung biopsies often reveal pathological abnormalities affecting all distal lung compartments. These modern cases of BO typically exhibit the constrictive bronchiolitis phenotype of small airway remodeling, along with lymphocytic inflammation. In addition, hypertensive-type remodeling of intrapulmonary vasculature, diffuse fibroelastosis of alveolar tissue, and fibrous thickening of visceral pleura are frequently present. The diagnosis of environmental/occupational BO should be considered in patients who present with subacute onset of exertional dyspnea and a history compatible with prolonged or recurrent exposure to environmental toxins. Important areas for future studies include development of less invasive diagnostic approaches and testing of novel agents for disease prevention and treatment.

DIPNECH: pragmatic approach, uncertainties, notable associations, and a proposal for an improved definition.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms 'diffuse' and 'idiopathic.' We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Cutaneous Exposure to Arsenicals Is Associated with Development of Constrictive Bronchiolitis in Mice.

Organoarsenicals, such as lewisite and related chloroarsine, diphenylchloroarsine (DPCA), are chemical warfare agents developed during World War I. Stockpiles in Eastern Europe remain a threat to humans. The well-documented effects of cutaneous exposure to these organoarsenicals include skin blisters, painful burns, and life-threatening conditions such as acute respiratory distress syndrome. In survivors, long-term effects such as the development of respiratory ailments are reported for the organoarsenical sulfur mustard; however, no long-term pulmonary effects are documented for lewisite and DPCA. No animal models exist to explore the relationship between skin exposure to vesicants and constrictive bronchiolitis. We developed and characterized a mouse model to study the long-term effects of cutaneous exposure on the lungs after exposure to a sublethal dose of organoarsenicals. We exposed mice to lewisite, DPCA, or a less toxic surrogate organoarsenic chemical, phenyl arsine oxide, on the skin. The surviving mice were followed for 20 weeks after skin exposure to arsenicals. Lung microcomputed tomography, lung function, and histology demonstrated increased airway resistance, increased thickness of the smooth muscle layer, increased collagen deposition in the subepithelium, and peribronchial lymphocyte infiltration in mice exposed to arsenical on skin.

Mosaic Attenuation Pattern: A Guide to Analysis with HRCT.

Mosaic attenuation pattern is commonly encountered on high-resolution computed tomography and has myriad causes. These diseases may involve small airways, vessels, alveoli, or interstitium, with some involving compartmental combinations. Small airways disease is caused by cellular bronchiolitis, infiltrated by inflammatory cells or constrictive bronchiolitis, resulting in fibrosis of the small airways. Any acute or chronic cause of ground-glass opacity can result in a mosaic pattern. Vascular causes of mosaic attenuation include chronic thromboembolic pulmonary hypertension and rarely other causes of pulmonary arterial hypertension. Ancillary CT findings along with the clinical history help narrow the differential diangosis. Biopsy is uncommonly required for definitiive diagnosis.

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.

Improvement of constrictive bronchiolitis (bronchiolitis obliterans) after rituximab therapy in 2 patients with primary sjögren syndrome.

Constrictive bronchiolitis is one of the manifestations of small-airway involvement in primary Sjögren syndrome (SS) and is associated with fixed airflow obstruction despite treatment with bronchodilators, macrolides, corticosteroids, and corticosteroid-sparing agents. Reports have shown a beneficial effect of rituximab on interstitial lung disease associated with SS, but the effect of rituximab on constrictive bronchiolitis is unknown. Herein, we present 2 cases of patients with constrictive bronchiolitis associated with SS who experienced symptomatic improvement and stabilization of pulmonary function testing (PFT) after rituximab therapy. Lung function declined in one of the patients when B cells reconstituted, with improved PFT results on re-administration of rituximab. Our case reports suggest that B cells may be involved in the pathogenesis of SS-associated constrictive bronchiolitis. Therapy targeting B cells may therefore be helpful in treating this debilitating and refractory condition. Further research is warranted.

The Usefulness of a Transbronchial Lung Cryobiopsy for Diffuse Bronchiolitis.

We herein report four cases of diffuse bronchiolitis proven by a transbronchial lung cryobiopsy (TBLC). Based on various aspects, including the pathological findings, we definitively diagnosed two patients with diffuse panbronchiolitis (DPB) and the other two with primary ciliary dyskinesia (PCD). One of the DPB patients had more severe peribronchiolar fibrosis than the other, and the disease course was refractory to macrolide therapy. One of the PCD patients was additionally diagnosed with combined constrictive bronchiolitis. This report highlights the importance of a TBLC in the differentiation of bronchiolitis, suggesting its utility for helping pulmonologists formulate a treatment strategy.

Occupational Bronchiolitis: An Update.

Occupational bronchiolitis is characterized by inflammation of the small airways, and represents a heterogeneous set of lung conditions that can occur following a range of inhalation exposures related to work. The most common clinical presentation includes insidious onset of exertional dyspnea and cough. Multiple reports in recent years have drawn attention to previously unrecognized risk factors for occupational bronchiolitis following exposures in several settings. Both current and past occupational exposures, including prior military deployment-related exposures, should be considered in patients undergoing evaluation for unexplained dyspnea. Diagnostic testing for potential bronchiolitis should include a thorough assessment of the small airways.

[A case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) syndrome]. / Un cas clinique de syndrome d'hyperplasie neuroendocrine pulmonaire diffuse idiopathique (DIPNECH).

INTRODUCTION: DIPNECH is a strictly histological entity according to the WHO 2015 classification and is considered to be at pre-neoplastic risk. It has been proposed that DIPNECH syndrome should be used to describe patients have clinical symptoms, an obstructive ventilatory disorder and compatible radiological abnormalities. The diagnosis is histological and usually based on a surgical lung biopsy. CASE REPORT: We report the case of a 58-year-old woman with a chronic cough for over 20years who had an obstructive airway pattern on spirometry. Diagnoses of asthma and COPD had been discussed. After 7years of follow-up, the DIPNECH hypothesis was evoked on the scanning aspect of mosaic attenuation, expiratory trapping and micronodules, which was subsequently confirmed by surgical pulmonary biopsy. CONCLUSION: It is necessary to consider the possibility of this rare disease in order to avoid inappropriate treatments and in the hope that future therapeutic advances (somatostatin analogs, mTOR inhibitors) improve patients' experience and the progression of respiratory function.

SP-A and TLR4 localization in lung tissue of SM-exposed patients.

INTRODUCTION: Long-term pulmonary complications are one of the major long-term consequences of sulfur mustard (SM) exposure. Toll-like receptor 4 (TLR4) involves in the pathogenesis of several pulmonary disorders. Surfactant protein-A (SP-A) regulates LPS-induced TLR4 localization and activation responses. However, the intensity and significance of TLR4 and SP-A expression by lung cells in SM-exposed patients is not clear. METHODS: The gene expression of TLR4 (through real-time PCR) and TLR4 and SP-A positive cells and alveolar type II cells, as SP-A producers, (using IHC) were assessed in formalin fixed paraffin embedded (FFPE) specimens from SM-exposed (n = 17), and non-SM exposed individuals (n = 12). RESULTS: TLR4 gene expression did not change between study groups. However, its cell surface presentation was significantly reduced in SM-exposed patients and particularly in which with constrictive bronchiolitis compared with the control group (P < 0.001 and P = 0.002, respectively). Frequency of alveolar type II cells was lower in the case group rather than the control group while the number of SP-A positive cells did not alter. CONCLUSIONS: These findings suggest that reduced TLR4 cell surface presentation may have anti-inflammatory function and SP-A may have a critical role in regulation of inflammatory responses in SM-exposed patients. Further investigation on other possible mechanisms involved in TLR4 internalization maybe help to illustrate the modulatory or inflammatory activity of TLR4 in these patients.

Respiratory Health after Military Service in Southwest Asia and Afghanistan. An Official American Thoracic Society Workshop Report.

Since 2001, more than 2.7 million U.S. military personnel have been deployed in support of operations in Southwest Asia and Afghanistan. Land-based personnel experienced elevated exposures to particulate matter and other inhalational exposures from multiple sources, including desert dust, burn pit combustion, and other industrial, mobile, or military sources. A workshop conducted at the 2018 American Thoracic Society International Conference had the goals of: 1) identifying key studies assessing postdeployment respiratory health, 2) describing emerging research, and 3) highlighting knowledge gaps. The workshop reviewed epidemiologic studies that demonstrated more frequent encounters for respiratory symptoms postdeployment compared with nondeployers and for airway disease, predominantly asthma, as well as case series describing postdeployment dyspnea, asthma, and a range of other respiratory tract findings. On the basis of particulate matter effects in other populations, it also is possible that deployers experienced reductions in pulmonary function as a result of such exposure. The workshop also gave particular attention to constrictive bronchiolitis, which has been reported in lung biopsies of selected deployers. Workshop participants had heterogeneous views regarding the definition and frequency of constrictive bronchiolitis and other small airway pathologic findings in deployed populations. The workshop concluded that the relationship of airway disease, including constrictive bronchiolitis, to exposures experienced during deployment remains to be better defined. Future clinical and epidemiologic research efforts should address better characterization of deployment exposures; carry out longitudinal assessment of potentially related adverse health conditions, including lung function and other physiologic changes; and use rigorous histologic, exposure, and clinical characterization of patients with respiratory tract abnormalities.

Various Bronchiolar Lesions Accompanied by Idiopathic Pleuroparenchymal Fibroelastosis with a Usual Interstitial Pneumonia Pattern Demonstrating Acute Exacerbation.

A 63-year-old man presented with persistent cough and progressive dyspnea. Computed tomography showed irregular pleural thickening and fibrotic changes with volume loss in the upper lobes, and subtle reticulation in the lower lobes. Pleuroparenchymal fibroelastosis (PPFE) was diagnosed based on the findings of a surgical lung biopsy. Bronchiolar lesions, including proliferative bronchiolitis, constrictive bronchiolitis obliterans, and peribronchiolar metaplasia were evident on pathology. A usual interstitial pneumonia (UIP) pattern was also observed in the lower lobes. Three weeks after the biopsy, an acute exacerbation occurred. We herein describe a rare case of idiopathic PPFE with various bronchiolar lesions and a UIP pattern in which an acute exacerbation developed.

Lung histopathology of non-infectious pulmonary complications after allogeneic haematopoietic stem cell transplantation.

AIMS: Non-infectious pulmonary complications (NIPCs) occur frequently following allogeneic haematopoietic stem cell transplantation (HSCT). As there is no consensus on the description of the related pulmonary pathological lesions, pathologist reports and clinical conclusions are largely inconsistent in routine practice. The aim of our study was to provide an accurate overview of post-allogeneic HSCT NIPCs from a large number of lung biopsies. METHODS AND RESULTS: We reviewed 61 lung biopsies in patients with an NIPC, including 51 surgical lung biopsies, four post-mortem biopsies and six lung explants. We found both bronchiolar (n = 59) and alveolar/interstitial pathologies (n = 27). We describe two types of bronchiolar lesions: bronchiolectasies (n = 37) and fibrous and cellular lesions with luminal narrowing (n = 43). We found a wide spectrum of airway/interstitial pathologies that were labelled using the terminology of the 2013 American Thoracic Society and European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs), including the following: organising pneumonia (OP, n = 8), non-specific interstitial pneumonia (NSIP, n = 9), diffuse alveolar damage (DAD, n = 6), lymphoid interstitial pneumonia (LIP, n = 1) and pleuroparenchymal fibroelastosis (PPFE, n = 2), as well as one instance of associated PPFE and NSIP. CONCLUSIONS: Interstitial pathology was associated with bronchiolar lesions in 41% of the cases reviewed (n = 25). Lung airway and interstitial inflammation was still present in lung explants from patients who underwent lung transplantation for post-allogeneic HSCT end-stage respiratory insufficiency. Herein, we describe a wide spectrum of pathological lung lesions encountered in post-allogeneic HSCT NIPCs.

Histological Diagnoses of Military Personnel Undergoing Lung Biopsy After Deployment to Southwest Asia.

INTRODUCTION: The current understanding of associations between lung disease and military deployment to Southwest Asia, including Iraq and Afghanistan, is both controversial and limited. We sought to clarify the relation between military deployment and biopsy-proven lung disease. METHODS: Retrospective data were analyzed for military personnel with non-neoplastic lung biopsies evaluated at the Armed Forces Institute of Pathology or Joint Pathology Center (January 2005 to December 2012). RESULTS: Of 391 subjects, 137 (35.0%) had deployed to Southwest Asia prior to biopsy. Compared to non-deployed subjects, those deployed were younger (median age 37 vs. 51 years) with higher representation of African Americans (30.0 vs. 16.9%). Deployed patients were more likely diagnosed with non-necrotizing granulomas (OR 2.4). Non-deployed subjects had higher frequency of idiopathic interstitial pneumonias, particularly organizing pneumonia. Prevalence of small airways diseases including constrictive bronchiolitis was low. CONCLUSIONS: This study provides a broader understanding of diversity of biopsy-proven non-neoplastic lung disease as it relates to military deployment to Southwest Asia and importantly did not show an increased prevalence of small airway disease to include constrictive bronchiolitis.