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Concept: Bronchiolitis obliterans

164

OBJECTIVESA sternal-sparing approach for bilateral lung transplantation was recently applied to reoperative lung transplant cases and is compared with the traditional clamshell approach.METHODSA retrospective analysis of 15 consecutive reoperative bilateral lung transplants performed from January 2008 to April 2011 was conducted. Outcomes were compared between the first 11 patients who underwent the traditional clamshell and the most recent 4 patients who underwent the sternal-sparing approach.RESULTSThe indication for retransplantation was obliterative bronchiolitis in all patients. Both groups were similar with regard to age, allograft ischaemic time and operative time. Cardiopulmonary bypass was more frequent in the sternal-sparing group although required for a shorter period of time. The need for postoperative extracorporeal membrane oxygenation for primary graft dysfunction was similar in both groups. The length of ICU care and total hospitalization length of stay were similar for the sternal-sparing group compared with the traditional clamshell approach. Operative mortality and overall survival also did not differ.CONCLUSIONSReoperative bilateral lung transplantation with a sternal-sparing approach is feasible and may yield outcomes similar to those in the traditional clamshell approach. Further analysis with larger numbers of patients is warranted to delineate the benefits of this approach for patients requiring reoperative lung transplantation.

Concepts: Time, Pulmonology, Pleural effusion, Organ transplant, Cardiopulmonary bypass, Lung transplantation, Bronchiolitis obliterans, Extracorporeal

113

There are over 7,000 e-cigarette flavors currently marketed. Flavoring chemicals gained notoriety in the early 2000’s when inhalation exposure of the flavoring chemical diacetyl was found to be associated with a disease that became known as “Popcorn Lung.” There has been limited research on flavoring chemicals in e-cigarettes.

Concepts: Chemical substance, Electronic cigarette, Flavor, Chemical industry, Bronchiolitis obliterans, Popcorn, Diacetyl

28

This article focuses on recent data which highlight the clinical settings in which exhaled nitric oxide (F(E)NO) is potentially helpful, or not, as a clinical tool. It is becoming clearer that, selectively applied, F(E)NO measurements can provide reliable clinical guidance, particularly when values are low. Such values are associated with high negative predictive values (>90%). Increased F(E)NO levels are associated with much more modest positive predictive values (75%-85%) and these are less reliable. These general principles apply when diagnosing steroid responsiveness in relation to asthma, chronic cough, and COPD. Although randomised trials do not support routine use of exhaled NO measurements in uncomplicated bronchial asthma, there is evidence that in patients with difficult asthma, or asthma associated with pregnancy, F(E)NO enhances overall management, and the decision to commence or increase inhaled steroid therapy (yes/no) may be made more accurately. Exhaled NO is potentially relevant in the assessment of occupational asthma (serial measurements) and also in diagnosing bronchiolitis obliterans in lung transplant patients.

Concepts: Asthma, Cough, Chronic obstructive pulmonary disease, Nitric oxide, Bronchiole, Bronchiolitis obliterans, Exhaled nitric oxide, Bronchodilator

27

Concern has been raised over the association of diacetyl with lung disease clinically resembling bronchiolitis obliterans in food manufacturing workers. This has resulted in the need for identification of alternative chemicals to be used in the manufacturing process. Structurally similar chemicals, 2,3-pentanedione 2,3-hexanedione 3,4-hexanedione and 2,3-heptanedione, used as constituents of synthetic flavoring agents have been suggested as potential alternatives for diacetyl, however, immunotoxicity data on these chemicals are limited. The present study evaluated the dermal irritation and sensitization potential of diacetyl alternatives using a murine model. None of the chemicals were identified as dermal irritants when tested at concentrations up to 50%. Similar to diacetyl (EC3=17.9%), concentration-dependent increases in lymphocyte proliferation were observed following exposure to all four chemicals, with calculated EC3 values of 15.4% (2,3-pentanedione), 18.2% (2,3-hexanedione), 15.5% (3,4-hexanedione) and 14.1% (2,3-heptanedione). No biologically significant elevations in local or total serum IgE were identified after exposure to 25-50% concentrations of these chemicals. These results demonstrate the potential for development of hypersensitivity responses to these proposed alternative butter flavorings and raise concern about the use of structurally similar replacement chemicals. Additionally, a contaminant with strong sensitization potential was found in varying concentrations in diacetyl obtained from different producers.

Concepts: Immune system, Asthma, Food, Flavor, Bronchiolitis obliterans, Diacetyl

27

Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long-term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past 20 years, numerous studies have evaluated the BAL cellular composition, cytokine profiles and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin-8, alpha defensins and MMP-9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment and standardization of the BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in-depth and mechanistic insights into the pathogenesis of this complex disease.

Concepts: Scientific method, Pulmonology, Evaluation, Cystic fibrosis, Assessment, Organ transplant, Bronchoalveolar lavage, Bronchiolitis obliterans

27

We present the case of a 25-year-old Afro-Caribbean man with a longstanding history of ulcerative colitis and primary sclerosing cholangitis. The patient presented to clinic and reported pleuritic-type chest pain. A routine chest radiograph requested from the clinic revealed an incidental right middle zone opacity in the right lung. A subsequent high-resolution CT showed multiple lung nodules. The patient also had a positive cytoplamic anti-neutrophil cytoplasmic antibody (cANCA) and proteinase 3 antibodies. Bronchoscopy was inconclusive. A video-assisted thoracoscopic surgery biopsy was then taken. The histology revealed changes suggestive of bronchiolitis obliterans organising pneumonia. The pulmonary manifestations of inflammatory bowel disease are poorly characterised. Our literature search has revealed cases hypothesising that immune system dysregulation could display pulmonary complications of ulcerative colitis. The aetiology is thought to be related to the treatment with mesalazine. However, our patient also had a positive vasculitic screen. Previous cases have resolved with supportive management or steroid therapy.

Concepts: Immune system, Ulcerative colitis, Crohn's disease, Gastroenterology, Inflammatory bowel disease, Autoimmune diseases, Primary sclerosing cholangitis, Bronchiolitis obliterans

15

Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunological pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within MHC class-II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class-II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Treg after BMT also induced cGVHD, while adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class-II that is induced by aGVHD.

Concepts: Immune system, Chemotherapy, Graft-versus-host disease, Major histocompatibility complex, Dendritic cell, Hematopoietic stem cell transplantation, Transplantation medicine, Bronchiolitis obliterans

13

Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and β-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear β-catenin expression that was dependent on autocrine ATX secretion and LPA signaling. We found that NFAT1 upstream of ATX regulated expression of ATX as well as β-catenin. Silencing NFAT1 in BOS MCs suppressed ATX expression, and sustained overexpression of NFAT1 increased ATX expression and activity in non-fibrotic MCs. LPA signaling induced NFAT1 nuclear translocation, suggesting that autocrine LPA synthesis promotes NFAT1 transcriptional activation and ATX secretion in a positive feedback loop. In an in vivo mouse orthotopic lung transplant model of BOS, antagonism of the LPA receptor (LPA1) or ATX inhibition decreased allograft fibrosis and was associated with lower active β-catenin and dephosphorylated NFAT1 expression. Lung allografts from β-catenin reporter mice demonstrated reduced β-catenin transcriptional activation in the presence of LPA1 antagonist, confirming an in vivo role for LPA signaling in β-catenin activation.

Concepts: Gene expression, Pulmonology, Cystic fibrosis, Organ transplant, Feedback, Transplantation medicine, Bronchiolitis obliterans, Positive feedback

6

Bronchiolitis obliterans, an irreversible lung disease, was first associated with inhalation of butter flavorings (diacetyl) in workers at a microwave popcorn company. Excess rates of lung-function abnormalities were related to cumulative diacetyl exposure. Because information on potential excess mortality would support development of permissible exposure limits for diacetyl, we investigated respiratory-associated mortality during 2000-2011 among current and former workers at this company who had exposure to flavorings and participated in cross-sectional surveys conducted between 2000-2003.

Concepts: Epidemiology, Diseases and disorders, Respiratory disease, Pulmonology, Bronchiolitis obliterans, Permissible exposure limit, Popcorn, Diacetyl

4

Diacetyl and 2,3-pentanedione inhalation have been suggested as causes of severe respiratory disease, including bronchiolitis obliterans, in food/flavoring manufacturing workers. Both compounds are present in many food items, tobacco, and other consumer products, but estimates of exposures associated with the use of these goods are scant. A study was conducted to characterize exposures to diacetyl and 2,3-pentanedione associated with cigarette smoking. The yields (μg/cigarette) of diacetyl and 2,3-pentanedione in mainstream (MS) cigarette smoke were evaluated for six tobacco products under three smoking regimens (ISO, Massachusetts Department of Public Health, and Health Canada Intense) using a standard smoking machine. Mean diacetyl concentrations in MS smoke ranged from 250 to 361 ppm for all tobacco products and smoking regimens, and mean cumulative exposures associated with 1 pack-year ranged from 1.1 to 1.9 ppm-years. Mean 2,3-pentanedione concentrations in MS smoke ranged from 32.2 to 50.1 ppm, and mean cumulative exposures associated with 1 pack-year ranged from 0.14 to 0.26 ppm-years. We found that diacetyl and 2,3-pentanedione exposures from cigarette smoking far exceed occupational exposures for most food/flavoring workers who smoke. This suggests that previous claims of a significant exposure-response relationship between diacetyl inhalation and respiratory disease in food/flavoring workers were confounded, because none of the investigations considered or quantified the non-occupational diacetyl exposure from cigarette smoke, yet all of the cohorts evaluated had considerable smoking histories. Further, because smoking has not been shown to be a risk factor for bronchiolitis obliterans, our findings are inconsistent with claims that diacetyl and/or 2,3-pentanedione exposure are risk factors for this disease.

Concepts: Epidemiology, Risk, Smoking, Tobacco, Tobacco smoking, Cigarette, Nicotine, Bronchiolitis obliterans