ABSTRACT
Rationale: Small airway disease is an important pathophysiological feature of chronic obstructive pulmonary disease (COPD). Recently, "pre-COPD" has been put forward as a potential precursor stage of COPD that is defined by abnormal spirometry findings or significant emphysema on computed tomography (CT) in the absence of airflow obstruction. Objective: To determine the degree and nature of (small) airway disease in pre-COPD using microCT in a cohort of explant lobes/lungs. Methods: We collected whole lungs/lung lobes from patients with emphysematous pre-COPD (n = 10); Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I (n = 6), II (n = 6), and III/IV (n = 7) COPD; and controls (n = 10), which were analyzed using CT and microCT. The degree of emphysema and the number and morphology of small airways were compared between groups, and further correlations were investigated with physiologic measures. Airway and parenchymal pathology was also validated with histopathology. Measurements and Main Results: The numbers of transitional bronchioles and terminal bronchioles per milliliter of lung were significantly lower in pre-COPD and GOLD stages I, II, and III/IV COPD compared with controls. In addition, the number of alveolar attachments of the transitional bronchioles and terminal bronchioles was also lower in pre-COPD and all COPD groups compared with controls. We did not find any differences between the pre-COPD and COPD groups in CT or microCT measures. The percentage of emphysema on CT showed the strongest correlation with the number of small airways in the COPD groups. Histopathology showed an increase in the mean chord length and a decrease in alveolar surface density in pre-COPD and all GOLD COPD stages compared with controls. Conclusions: Lungs of patients with emphysematous pre-COPD already show fewer small airways and airway remodeling even in the absence of physiologic airway obstruction.
Subject(s)
Asthma , Emphysema , Pulmonary Disease, Chronic Obstructive , Pulmonary Emphysema , Humans , Cross-Sectional Studies , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/diagnostic imaging , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Emphysema/complications , Pulmonary Emphysema/diagnostic imaging , Pulmonary Emphysema/pathology , Lung , Asthma/pathology , X-Ray MicrotomographyABSTRACT
Background Interstitial lung abnormalities (ILAs) reflect imaging features on lung CT scans that are compatible with (early) interstitial lung disease. Despite accumulating evidence regarding the incidence, risk factors, and prognosis of ILAs, the histopathologic correlates of ILAs remain elusive. Purpose To determine the correlation between radiologic and histopathologic findings in CT-defined ILAs in human lung explants. Materials and Methods Explanted lungs or lobes from participants with radiologically documented ILAs were prospectively collected from 2010 to 2021. These specimens were air-inflated, frozen, and scanned with CT and micro-CT (spatial resolution of 0.7 mm and 90 µm, respectively). Subsequently, the lungs were cut and sampled with core biopsies. At least five samples per lung underwent micro-CT and subsequent histopathologic assessment with semiquantitative remodeling scorings. Based on area-specific radiologic scoring, the association between radiologic and histopathologic findings was assessed. Results Eight lung explants from six donors (median age at explantation, 71 years [range, 60-83 years]; four men) were included (unused donor lungs, n = 4; pre-emptive lobectomy for oncologic indications, n = 2). Ex vivo CT demonstrated ground-glass opacification, reticulation, and bronchiectasis. Micro-CT and histopathologic examination demonstrated that lung abnormalities were frequently paraseptal and associated with fibrosis and lymphocytic inflammation. The histopathologic results showed varying degrees of fibrosis in areas that appeared normal on CT scans. Regions of reticulation on CT scans generally had greater fibrosis at histopathologic analysis. Vasculopathy and bronchiectasis were also often present at histopathologic examination of lungs with ILAs. Fully developed fibroblastic foci were rarely observed. Conclusion This study demonstrated direct histologic correlates of CT-defined interstitial lung abnormalities. © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Jeudy in this issue.
Subject(s)
Bronchiectasis , Lung Diseases, Interstitial , Male , Humans , Middle Aged , Aged , Aged, 80 and over , Lung/diagnostic imaging , Lung/pathology , Lung Diseases, Interstitial/diagnostic imaging , Fibrosis , X-Ray MicrotomographyABSTRACT
AIMS AND OBJECTIVES: To explore the prevalence of psychological distress such as anxiety, depression and post-traumatic stress disorder and its associations with medication adherence in lung transplant patients. BACKGROUND: Psychological distress after lung transplantation may impact clinical outcomes by associated behaviours such as non-adherence to medication. Evidence about the relation between psychological distress and medication adherence in lung transplant patients is limited and not well explained. DESIGN AND METHODS: We conducted a single-centre study with a cross-sectional design in 73 lung transplant candidates and 116 recipients. Questionnaires were the Brief Symptom Inventory, Impact of Event Scale and Basel Assessment of Adherence to Immunosuppressive Medications Scale. The STROBE checklist was monitored. RESULTS: In candidates, 39.7% reported (sub)clinical symptoms of depression, in recipients this was 21.6%. We observed suicidal ideation in recipients (8.6%), and candidates (5.5%). The prevalence of (sub)clinical symptoms of anxiety was 38.3% in candidates and 33.7% in recipients. After lung transplantation, 12% of the recipients reported clinical symptoms of PTSD related to the transplantation. Symptoms of anxiety and medication adherence were significantly and positively related in transplant recipients. We found no association between depressive or post-traumatic stress symptoms, and medication adherence. CONCLUSIONS: In lung transplant patients, we found a high prevalence of symptoms of depression and anxiety. Recipients had high levels of post-traumatic stress symptoms related to the transplantation. The prevalence of suicidal ideation was unexpectedly high in recipients. After lung transplantation, higher levels of anxiety were related to better medication adherence. We propose that LTX recipients are very anxious to develop dyspnoea and therefore take their medication more conscientiously. RELEVANCE TO CLINICAL PRACTICE: The clinical nurse specialist can play a key role in identifying and addressing psychological and behavioural problems. More prospective research on the role of anxiety and dyspnoea in lung transplant recipients is recommended.
Subject(s)
Lung Transplantation , Psychological Distress , Cross-Sectional Studies , Humans , Lung Transplantation/adverse effects , Medication Adherence , Prospective StudiesABSTRACT
The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2 /FiO2 ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized.
Subject(s)
Lung Transplantation , Transplant Recipients , Adult , Humans , Lung , Prospective Studies , Retrospective Studies , Tissue Donors , Treatment OutcomeABSTRACT
OBJECTIVES: Endovascular aortic repair (EVAR) is associated with an increased risk of pulmonary embolism, which is often clinically silent and therefore difficult to recognise. The aim was to investigate the incidence of pulmonary embolism after EVAR using routinely performed pre- and post-operative aortic computed tomography angiography (CTA), and the association between pulmonary embolism and mortality. METHODS: This single centre retrospective cohort study included adult patients who underwent EVAR in the University Medical Centre Utrecht between January 2010 and July 2015 and who had a total aortic, thoracic aortic, or pulmonary CTA within one month post-operatively. Baseline and mortality data were obtained by reviewing hospital and general practitioner records. The primary outcome was pulmonary embolism within one month after surgery. Secondary outcomes were 30 day and six month mortality. RESULTS: During the study period, 526 EVARs were performed. Seventy-four of these procedures were included in the analysis of which there were 40 thoracic and 34 abdominal EVARs. In nine patients (12%, 95% CI 7-22) pulmonary embolism was observed of which one was central, two were segmental, and six were subsegmental. Seven were clinically silent and two were present on the pre-operative CTA. Thirty day mortality was significantly higher in patients with pulmonary embolism (relative risk 14.4, 95% CI 1.4-143, p = .037) though none of the deaths seemed directly attributable to it. CONCLUSIONS: This study, although preliminary, suggests that silent pulmonary embolism after EVAR occurs in approximately one in 10 patients, despite routine thrombo-embolism prophylaxis. Pulmonary embolism was associated with a higher 30 day mortality risk yet it was not the cause of death in any of these patients.
Subject(s)
Aortic Aneurysm, Abdominal/surgery , Aortic Aneurysm, Thoracic/surgery , Endovascular Procedures/adverse effects , Pulmonary Embolism/etiology , Aged , Aged, 80 and over , Aortic Aneurysm, Abdominal/mortality , Aortic Aneurysm, Thoracic/mortality , Cause of Death , Computed Tomography Angiography , Female , Follow-Up Studies , Humans , Male , Postoperative Complications/diagnostic imaging , Pulmonary Embolism/diagnostic imaging , Retrospective Studies , Risk FactorsABSTRACT
Both Eurotransplant (ET) and the US use the lung allocation score (LAS) to allocate donor lungs. In 2015, the US implemented a new algorithm for calculating the score while ET has fine-tuned the original model using business rules. A comparison of both models in a contemporary patient cohort was performed. The rank positions and the correlation between both scores were calculated for all patients on the active waiting list in ET. On February 6th 2017, 581 patients were actively listed on the lung transplant waiting list. The median LAS values were 32.56 and 32.70 in ET and the US, respectively. The overall correlation coefficient between both scores was 0.71. Forty-three per cent of the patients had a < 2 point change in their LAS. US LAS was more than two points lower for 41% and more than two points higher for 16% of the patients. Median ranks and the 90th percentiles for all diagnosis groups did not differ between both scores. Implementing the 2015 US LAS model would not significantly alter the current waiting list in ET.
Subject(s)
Lung Transplantation , Patient Selection , Algorithms , Cross-Sectional Studies , Europe , Humans , Middle Aged , United StatesABSTRACT
Air pollution from road traffic is a serious health risk, especially for susceptible individuals. Single-centre studies showed an association with chronic lung allograft dysfunction (CLAD) and survival after lung transplantation, but there are no large studies.13 lung transplant centres in 10 European countries created a cohort of 5707 patients. For each patient, we quantified residential particulate matter with aerodynamic diameter ≤10â µm (PM10) by land use regression models, and the traffic exposure by quantifying total road length within buffer zones around the home addresses of patients and distance to a major road or freeway.After correction for macrolide use, we found associations between air pollution variables and CLAD/mortality. Given the important interaction with macrolides, we stratified according to macrolide use. No associations were observed in 2151 patients taking macrolides. However, in 3556 patients not taking macrolides, mortality was associated with PM10 (hazard ratio 1.081, 95% CI 1.000-1.167); similarly, CLAD and mortality were associated with road lengths in buffers of 200-1000 and 100-500â m, respectively (hazard ratio 1.085- 1.130). Sensitivity analyses for various possible confounders confirmed the robustness of these associations.Long-term residential air pollution and traffic exposure were associated with CLAD and survival after lung transplantation, but only in patients not taking macrolides.
Subject(s)
Air Pollution/adverse effects , Environmental Exposure/adverse effects , Lung Transplantation/mortality , Primary Graft Dysfunction/physiopathology , Adult , Air Pollutants/analysis , Cohort Studies , Europe/epidemiology , Female , Graft Survival , Humans , Macrolides/therapeutic use , Male , Middle Aged , Particulate Matter/analysis , Proportional Hazards Models , Regression AnalysisABSTRACT
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal fibrosing lung disease with a median survival of approximately 3 years after diagnosis. The only medical option to improve survival in IPF is lung transplantation (LTX). The purpose of this study was to evaluate trajectory data of IPF patients listed for LTX and to investigate the survival after LTX. METHODS AND RESULTS: Data were retrospectively collected from September 1989 until July 2011 of all IPF patients registered for LTX in the Netherlands. Patients were included after revision of the diagnosis based on the criteria set by the ATS/ERS/JRS/ALAT. Trajectory data, clinical data at time of screening, and donor data were collected. In total, 98 IPF patients were listed for LTX. During the waiting list period, 30 % of the patients died. Mean pulmonary artery pressure, 6-min walking distance, and the use of supplemental oxygen were significant predictors of mortality on the waiting list. Fifty-two patients received LTX with a median overall survival after transplantation of 10 years. CONCLUSIONS: This study demonstrated a 10-year survival time after LTX in IPF. Furthermore, our study demonstrated a significantly better survival after bilateral LTX in IPF compared to single LTX although bilateral LTX patients were significantly younger.
Subject(s)
Idiopathic Pulmonary Fibrosis/surgery , Lung Transplantation , Cohort Studies , Exercise Test , Female , Humans , Hypertension, Pulmonary/epidemiology , Idiopathic Pulmonary Fibrosis/epidemiology , Idiopathic Pulmonary Fibrosis/mortality , Male , Middle Aged , Netherlands/epidemiology , Oxygen Inhalation Therapy/statistics & numerical data , Pulmonary Wedge Pressure , Retrospective Studies , Survival Rate , Waiting Lists/mortalityABSTRACT
Chronic lung allograft dysfunction (CLAD) remains a major hurdle impairing lung transplant outcome. Parallel to the better clinical identification and characterization of CLAD and CLAD phenotypes, there is an increasing urge to find adequate biomarkers that could assist in the earlier detection and differential diagnosis of CLAD phenotypes, as well as disease prognostication. The current status and state-of-the-art of biomarker research in CLAD will be discussed with a particular focus on radiological biomarkers or biomarkers found in peripheral tissue, bronchoalveolar lavage' and circulating blood' in which significant progress has been made over the last years. Ultimately, although a growing number of biomarkers are currently being embedded in the follow-up of lung transplant patients, it is clear that one size does not fit all. The future of biomarker research probably lies in the rigorous combination of clinical information with findings in tissue, bronchoalveolar lavage' or blood. Only by doing so, the ultimate goal of biomarker research can be achieved, which is the earlier identification of CLAD before its clinical manifestation. This is desperately needed to improve the prognosis of patients with CLAD after lung transplantation.
Subject(s)
Lung Transplantation , Lung , Humans , Bronchoalveolar Lavage Fluid , Biomarkers , Lung Transplantation/adverse effects , Allografts , Chronic Disease , Retrospective StudiesABSTRACT
Pathology and radiology are complimentary tools, and their joint application is often crucial in obtaining an accurate diagnosis in non-neoplastic pulmonary diseases. However, both come with significant limitations of their own: Computed Tomography (CT) can only visualize larger structures due to its inherent-relatively-poor resolution, while (histo) pathology is often limited due to small sample size and sampling error and only allows for a 2D investigation. An innovative approach of inflating whole lung specimens and subjecting these subsequently to CT and whole lung microCT allows for an accurate matching of CT-imaging and histopathology data of exactly the same areas. Systematic application of this approach allows for a more targeted assessment of localized disease extent and more specifically can be used to investigate early mechanisms of lung diseases on a morphological and molecular level. Therefore, this technique is suitable to selectively investigate changes in the large and small airways, as well as the pulmonary arteries, veins and capillaries in relation to the disease extent in the same lung specimen. In this perspective we provide an overview of the different strategies that are currently being used, as well as how this growing field could further evolve.
ABSTRACT
A non-invasive diagnostic tool to assess remodeling of the lung airways caused by disease is currently missing in the clinic. Measuring key features such as airway smooth muscle (ASM) thickness would increase the ability to improve diagnosis and enable treatment evaluation. In this research, polarization-sensitive optical coherence tomography (PS-OCT) has been used to image a total of 24 airways from two healthy lungs and four end-stage diseased lungs ex vivo, including fibrotic sarcoidosis, chronic obstructive pulmonary disease (COPD), fibrotic hypersensitivity pneumonitis, and cystic fibrosis. In the diseased lungs, except COPD, the amount of measured airway smooth muscle was increased. In COPD, airway smooth muscle could not be distinguished from surrounding collagen. COPD lungs showed increased alveolar size. 3D pullbacks in the same lumen provided reproducible assessment of airway smooth muscle (ASM). Image features such as thickened ASM and size/presence of alveoli were recognized in histology. The results of this study are preliminary and must be confirmed with further ex vivo and in vivo studies. PS-OCT is applicable for in vivo assessment of peribronchial and peribronchiolar lung structures and may become a valuable tool for diagnosis in pulmonology.
ABSTRACT
OBJECTIVES: Lung transplant is a last treatment option for patients with end-stage pulmonary disease. Chronic lung allograft dysfunction, which generally manifests as bronchiolitis obliterans syndrome, is a major long-term survival limitation. Bronchiolitis obliterans syndrome is diagnosed when forced expiratory volume in 1 second declines > 20% in the absence of known causes. B cells can either contribute or restrain the development of bronchiolitis obliterans syndrome (eg, via induction of alloimmune antibodies, regulation of cellular immunity, and induction of tolerance). Here, we explored how peripheral B-cell subsets were altered in lung transplant recipients with bronchiolitis obliterans syndrome. MATERIALS AND METHODS: Fresh whole blood samples were analyzed from 42 lung transplant recipients, including 17 with bronchiolitis obliterans syndrome; samples from these groups were compared with 10 age-matched healthy control samples. B-cell subsets were analyzed using flow cytometry, and relative distributions of subsets were compared. Changes in forced expiratory volume in 1 second were also determined. RESULTS: Absolute B-cell count was significantly increased in transplant recipients with bronchiolitis obliterans syndrome. Transitional (CD24+CD38+) and naïve (CD27-IgD+) B cells were decreased in lung transplant patients, with transitional B cells almost absent in those with bronchiolitis obliterans syndrome. Double-negative (CD27-IgD-) memory B cells were significantly increased (P < .001). No differences were found for plasmablasts (CD38+CD24-) and switched (CD27+IgD-) and non-switched (CD27+IgD+) memory B cells. Correlation analyses showed positive correlations between lung function and naïve B cells in transplant recipients (P = .0245; r = -0.458). CONCLUSIONS: Peripheral B-cell count and subset distribution were altered in lung transplant recipients with and without bronchiolitis obliterans syndrome compared with healthy controls. Transitional and naïve B-cell decreases may be caused by differentiation toward double-negative B-cells, which were increased. The correlation between forced expiratory volume and naïve B cells during follow-up care may be clinically interesting to investigate.
Subject(s)
B-Lymphocyte Subsets/immunology , Bronchiolitis Obliterans/immunology , Lung Transplantation/adverse effects , Adult , Aged , B-Lymphocyte Subsets/metabolism , Biomarkers/metabolism , Bronchiolitis Obliterans/diagnosis , Bronchiolitis Obliterans/metabolism , Bronchiolitis Obliterans/physiopathology , Case-Control Studies , Cell Differentiation , Female , Flow Cytometry , Forced Expiratory Volume , Humans , Immunologic Memory , Immunophenotyping , Male , Middle Aged , Phenotype , Treatment OutcomeABSTRACT
Cystic fibrosis (CF) patients are colonized with a multitude of bacteria and fungi. From respiratory samples of two CF patients in our institute, a difficult to identify yeast was isolated repeatedly. This yeast was eventually identified as Cutaneotrichosporon (Cryptococcus) cyanovorans by internal transcribed spacer (ITS) and ribosomal large subunit (LSU) sequencing. C. cyanovorans is a basidiomycetous yeast originally reported as environmental isolate from South African soil and has not been described before as clinical isolate from CF patients.
ABSTRACT
Obstructive chronic lung allograft dysfunction (BOS) is the major limiting factor for lung transplantation (LTx) outcome. PTPN22 is described as the hallmark autoimmunity gene, and one specific single nucleotide polymorphism (SNP), rs2476601, is associated with multiple autoimmune diseases, impaired T cell regulation, and autoantibody formation. Taking into consideration the contribution of autoimmunity to LTx outcome, we hypothesized that polymorphisms in the PTPN22 gene could be associated with BOS incidence. We selected six SNPs within PTPN22 and analyzed both patient and donor genotypes on BOS development post-LTx. A total of 144 patients and matched donors were included, and individual SNPs and haplotype configurations were analyzed. We found a significant association between patients carrying the heterozygous configuration of rs2476601 and a higher risk for BOS development (p = 0.005, OR: 4.400, 95%CI: 1.563-12.390). Kaplan-Meier analysis showed that heterozygous patients exhibit a lower BOS-free survival compared to patients homozygous for rs2476601 (p = 0.0047). One haplotype, which solely contained the heterozygous risk variant, was associated with BOS development (p = 0.015, OR: 7.029, 95%CI: 1.352-36.543). Our results show that LTx patients heterozygous for rs2476601 are more susceptible for BOS development and indicate a deleterious effect of the autoimmune-related risk factor of PTPN22 in patients on LTx outcome.
Subject(s)
Autoimmunity/genetics , Bronchiolitis Obliterans/genetics , Graft Rejection/genetics , Lung Transplantation/adverse effects , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Adult , Allografts/immunology , Allografts/pathology , Bronchiolitis Obliterans/immunology , Bronchiolitis Obliterans/mortality , Bronchiolitis Obliterans/pathology , Disease-Free Survival , Female , Follow-Up Studies , Genetic Predisposition to Disease , Graft Rejection/immunology , Graft Rejection/mortality , Graft Rejection/pathology , Heterozygote , Humans , Kaplan-Meier Estimate , Lung/immunology , Lung/pathology , Male , Middle Aged , Polymorphism, Single Nucleotide/immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 22/immunologyABSTRACT
BACKGROUND: Lung transplant recipients have an increased risk for infections in the posttransplant period due to immunosuppressive therapy. Protection against infections can be achieved through vaccination, but the optimal vaccination schedule in lung transplant recipients is unknown. Data on long-term immunological follow up and vaccination responses after lung transplantation are scarce. METHODS: Here we present long-term immunological follow up of a cohort of 55 lung transplant recipients. This includes detailed antibody responses after 23-valent pneumococcal polysaccharide vaccination (23vPPV). RESULTS: All patients were vaccinated with 23vPPV before transplantation. Median follow-up after transplantation was 6.6 years (379 patient-years). After transplantation, there is a significant decrease of all immunoglobulins, IgG subclasses and pneumococcal polysaccharide antibodies. After the first year posttransplantation, there is a gradual increase of all immunoglobulins and IgG subclasses, but values were always significantly lower than in the pretransplant period. After a median of 4.4 years posttransplantation, patients were revaccinated with 23vPPV. The pneumococcal polysaccharide antibody response was impaired in 87% of patients (ie, antibody titer above cutoff and twofold increase between pre and postvaccination values for <70% of serotypes). CONCLUSIONS: We found that impairment of humoral immunity was most outspoken in the first year after lung transplantation. Immunoglobulin levels remain decreased several years after transplantation and the response to pneumococcal polysaccharide vaccine was significantly lower posttransplantation compared to the pretransplantation response. However, most patients did show a partial response to vaccination. Based on our results, revaccination with pneumococcal vaccines after transplantation should be considered 1 year after transplantation.
Subject(s)
Graft Rejection/prevention & control , Immunity, Humoral , Lung Transplantation , Pneumococcal Vaccines/therapeutic use , Streptococcus pneumoniae/immunology , Transplant Recipients , Vaccination/methods , Adult , Antibodies, Bacterial/immunology , Female , Follow-Up Studies , Graft Rejection/immunology , Humans , Immunization Schedule , Male , Middle Aged , Retrospective Studies , Time Factors , Young AdultABSTRACT
Antibodies against HLA and non-HLA are associated with transplantation outcome. Recently, pretransplant serum IgG antibody levels against apoptotic cells were found to correlate with kidney allograft loss. We investigated the presence of these antibodies in lung transplantation (LTx) patients and evaluated the correlation of pre-LTx serum levels of IgG antibodies against apoptotic cells with LTx outcome. These cells included donor lung endothelial cells (ECs) obtained from lung perfusion fluid collected during LTx procedure. Cells were isolated, expanded in vitro, and analyzed as targets for antiapoptotic cell reactivity. Cultured cells exhibited EC morphology and were CD31+, CD13+, and vWF+. End-stage lung disease patients showed elevated serum IgG levels against apoptotic lung EC (p = 0.0018) compared to healthy controls. Interestingly, the levels of circulating antibodies directed against either apoptotic Jurkat cells or apoptotic lung ECs did not correlate, suggesting a target cell specificity. We observed no correlation between chronic or acute rejection and pre-LTx serum levels of antiapoptotic antibodies. Also, these levels did not differ between matched patients developing chronic rejection or not during follow-up or at the time of diagnosis, as they remained as high as prior to transplantation. Thus, circulating levels of antiapoptotic cell antibodies are elevated in end-stage lung disease patients, but our data do not correlate with outcome after LTx.
ABSTRACT
CONTEXT: Previous studies have evaluated the safety of relatively complex combinations of clinical decision rules and diagnostic tests in patients with suspected pulmonary embolism. OBJECTIVE: To assess the clinical effectiveness of a simplified algorithm using a dichotomized clinical decision rule, D-dimer testing, and computed tomography (CT) in patients with suspected pulmonary embolism. DESIGN, SETTING, AND PATIENTS: Prospective cohort study of consecutive patients with clinically suspected acute pulmonary embolism, conducted in 12 centers in the Netherlands from November 2002 through December 2004. The study population of 3306 patients included 82% outpatients and 57% women. INTERVENTIONS: Patients were categorized as "pulmonary embolism unlikely" or "pulmonary embolism likely" using a dichotomized version of the Wells clinical decision rule. Patients classified as unlikely had D-dimer testing, and pulmonary embolism was considered excluded if the D-dimer test result was normal. All other patients underwent CT, and pulmonary embolism was considered present or excluded based on the results. Anticoagulants were withheld from patients classified as excluded, and all patients were followed up for 3 months. MAIN OUTCOME MEASURE: Symptomatic or fatal venous thromboembolism (VTE) during 3-month follow-up. RESULTS: Pulmonary embolism was classified as unlikely in 2206 patients (66.7%). The combination of pulmonary embolism unlikely and a normal D-dimer test result occurred in 1057 patients (32.0%), of whom 1028 were not treated with anticoagulants; subsequent nonfatal VTE occurred in 5 patients (0.5% [95% confidence interval {CI}, 0.2%-1.1%]). Computed tomography showed pulmonary embolism in 674 patients (20.4%). Computed tomography excluded pulmonary embolism in 1505 patients, of whom 1436 patients were not treated with anticoagulants; in these patients the 3-month incidence of VTE was 1.3% (95% CI, 0.7%-2.0%). Pulmonary embolism was considered a possible cause of death in 7 patients after a negative CT scan (0.5% [95% CI, 0.2%-1.0%]). The algorithm was completed and allowed a management decision in 97.9% of patients. CONCLUSIONS: A diagnostic management strategy using a simple clinical decision rule, D-dimer testing, and CT is effective in the evaluation and management of patients with clinically suspected pulmonary embolism. Its use is associated with low risk for subsequent fatal and nonfatal VTE.
Subject(s)
Algorithms , Decision Theory , Pulmonary Embolism/diagnosis , Pulmonary Embolism/drug therapy , Adult , Aged , Anticoagulants/therapeutic use , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Male , Middle Aged , Prospective Studies , Pulmonary Embolism/blood , Pulmonary Embolism/complications , Thromboembolism/complications , Thromboembolism/prevention & control , Tomography, X-Ray ComputedABSTRACT
CD59 is a complement regulatory protein that inhibits membrane attack complex formation. A soluble form of CD59 (sCD59) is present in various body fluids and is associated with cellular damage after acute myocardial infarction. Lung transplantation (LTx) is the final treatment for end-stage lung diseases, however overall survival is hampered by chronic lung allograft dysfunction development, which presents itself obstructively as the bronchiolitis obliterans syndrome (BOS). We hypothesized that, due to cellular damage and activation during chronic inflammation, sCD59 serum levels can be used as biomarker preceding BOS development. We analyzed sCD59 serum concentrations in 90 LTx patients, of whom 20 developed BOS. We observed that BOS patients exhibited higher sCD59 serum concentrations at the time of diagnosis compared to clinically matched non-BOS patients (p = 0.018). Furthermore, sCD59 titers were elevated at 6 months post-LTx (p = 0.0020), when patients had no BOS-related symptoms. Survival-analysis showed that LTx patients with sCD59 titers ≥400 pg/ml 6 months post-LTx have a significant (p < 0.0001) lower chance of BOS-free survival than patients with titers ≤400 pg/ml, 32% vs. 80% respectively, which was confirmed by multivariate analysis (hazard ratio 6.2, p < 0.0001). We propose that circulating sCD59 levels constitute a novel biomarker to identify patients at risk for BOS following LTx.
Subject(s)
Bronchiolitis Obliterans/blood , Bronchiolitis Obliterans/etiology , CD59 Antigens/blood , Lung Transplantation/adverse effects , Adolescent , Adult , Allografts , Biomarkers/blood , Bronchiolitis Obliterans/immunology , Female , Graft Rejection/blood , Graft Rejection/etiology , Graft Rejection/immunology , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Risk Factors , Solubility , Time Factors , Young AdultABSTRACT
Pulmonary arterial hypertension is a progressive life-threatening disease characterized by vascular remodeling. There is evidence that varied immune mechanism play an important role in progression of pulmonary hypertension. We describe a case of a 35-year-old woman with idiopathic pulmonary arterial hypertension (IPAH) and a novel BMPR2 mutation, who underwent a successful lung transplantation. Extensive granulomatous inflammation was seen in the resected lungs. The granulomatous inflammation found in the histology supports a sarcoid-like reaction due to pulmonary hypertension in the context of the BMPR2 mutation.