Epstein-Barr virus-associated pneumonia and bronchiolitis obliterans syndrome in a lung transplant recipient

We report the case of a 25-year-old lung and liver transplant recipient who developed respiratory failure. High levels of Epstein-Barr virus (EBV) genome copies were detectable in respiratory tract specimens, while the search for various other viral, bacterial or fungal pathogens remained empty. Post-transplant lymphoproliferative disease was excluded. Due to the rapid progression of respiratory insufficiency, a re-transplantation of the lung was performed. EBV-encoded small RNAs could be demonstrated by in situ hybridization within pneumocytes and lymphocytes of the explanted lung tissue. The clinical situation improved soon after re-transplantation, and the EBV load detected in the lower respiratory tract decreased significantly.     

Inflammatory myopathy, bronchiolitis obliterans/organizing pneumonia, and anti-Jo-1 antibodies--an interesting association.

We report an interesting association of inflammatory myopathy, characterized pathologically as dermatomyositis, with bronchiolitis obliterans/organizing pneumonia and anti-histidyl-tRNA synthetase (Jo-1) antibody. The relations of different types of pulmonary involvement to inflammatory myopathy and antisynthetase antibodies are discussed.     

Lung infiltrates in cancer patients: differentiating metastases from bronchiolitis obliterans organizing pneumonia

Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare condition that affects oncological patients, often during or after chemotherapy, and can easily be mistaken for lung metastases. BOOP should be taken into consideration in cases when patchy nodular infiltrates with uncertain behavior appear in the lung; these infiltrates are often unresponsive to treatment with antibiotics. We report a case in which a patient treated for transitional cell bladder carcinoma with surgery and adjuvant chemotherapy developed multiple bilateral pulmonary nodules one month after the end of treatment.     

Electron microscopic study of chronic eosinophilic pneumonia

Two cases of chronic eoslnophlllc pneumonia were examined electron mlcroscoplcally to study the role of eosinophll granulocytes. Eoslnophlls, together wlth macrophages and lymphocytes, were observed to have Infiltrated prominently in the lung tissues of the two cases. Degeneration and necrosis of pneumocytes were observed, and denuded basement membranes and destroyed alveolar structures were occasionally found. In the alveolar septa, swelling of the endothellal cells of the blood caplllarles, edema of the stroma and fibrin deposition were observed. Eosinophils, released eosinophil granules and macrophages phagocytosing eosinophll granules were found frequently near the degenerated and necrotic alveolar tissues. These findings suggest that the tissue injuries were induced by the cytotoxic effects of the eosinophil granules.     

A case of vasculitis syndrome associated with bronchiolitis obliterans organizing pneumonia (BOOP)]

In 1996 36-year-old man was admitted into our hospital because of polyarthralgia, skin eruptions followed by multiple cutaneous ulcers, dry cough and elevation of C-reactive protein level. The finding of skin biopsy from left elbow was vasculitis. Chest CT showed linear interstitial shadow at bilateral dorsalis lungs. Transbronchial lung biopsy (TBLB) revealed marked infiltration of inflammatory cells in the bronchial walls and peripheral alveoli. In addition, eosinophils were not in branchoalveolar lavage (BAL) fluid. Moreover, video-assisted thoracic surgery (VATS) revealed organizing fibroblastic polyp and bronchiolitis obliterans at terminal bronchiole. We diagnosed his pneumonia as bronchiolitis obliterans organizing pneumonia (BOOP). Administration of oral prednisolone (40 mg/day) was begun and he experienced diminished BOOP and other clinical manifestations. Three years later he developed dry cough, dyspnea and digital ulcers again. Arterial blood gas analysis revealed marked hypoxemia and laboratory studies showed LDH (377 IU/ml) and CRP (8.27 mg/dl) levels were elevated. Chest CT pointed out an exacerbation of BOOP. Treatment with intravenous pulses methylprednisolone and oral prednisolone (60 mg/day) resulted in marked improvement of the clinical manifestations. We describe a rare case of vasculitis associated with BOOP.     

A case of bronchiolitis obliterans in a young child

Bronchiolitis obliterans (BO) is an infrequent chronic obstructive pulmonary disease that follows an insult to lower respiratory tract. BO following a severe lung infectious disease is the most common form reported in children. It implies a chronic necrotizing and ultimately fibrosing process affecting the small airways which results in progressive obliteration with resultant obstructive lung disease. The characteristic symptom-complex includes dyspnea, chronic cough, sputum production and wheezing. Although histopathology remains the gold standard for diagnosis, computed tomographic scan is of great help in diagnosis. Etiological role of mechanical ventilation has not yet been studied well. We report a case of BO in a three year old child occurring after an episode of lower respiratory tract infection requiring prolonged mechanical ventilation with subsequent development of ventilator-associated pneumonia. Our patient had a protracted clinical course with good response to corticosteroids.     

Ultrastructural and immunohistochemical evidence for release of eosinophilic granules in vivo: cytotoxic potential in chronic eosinophilic pneumonia

We studied a patient with relapsing idiopathic chronic eosinophilic pneumonia. Each one of four attacks observed during a 4-year period was characterized by dyspnea, wheezing, peripheral blood eosinophilia, elevated serum IgE levels, and pulmonary infiltrates. Glucocorticoid therapy caused prompt resolution of symptoms and disappearance of blood eosinophilia and pulmonary shadowing. Electron microscopy and tissue immunofluorescence studies for major basic protein documented extensive eosinophil degranulation and the presence of free granules within the pulmonary microvasculature. In addition, exfoliation of the alveolar lining cell was observed in association with a clustering of free intact and disintegrating extracellular eosinophil granules against a denuded basement membrane. These findings suggest a cytotoxic potential of the eosinophil at the level of the pulmonary parenchyma in a case of idiopathic chronic eosinophilic pneumonia.     

Respiratory reovirus 1/L induction of intraluminal fibrosis, a model of bronchiolitis obliterans organizing pneumonia, is dependent on T lymphocytes

Bronchiolitis obliterans organizing pneumonia (BOOP) is a clinical syndrome characterized by perivascular/peribronchiolar leukocyte infiltration leading to the development of intraalveolar fibrosis. We have developed an animal model of BOOP where CBA/J mice infected with 1 x 10(6) plaque-forming units (PFU) reovirus 1/L develop follicular bronchiolitis and intraalveolar fibrosis similar to human BOOP. In this report, we demonstrate a role for T cells in the development of intraluminal fibrosis associated with BOOP. Corticosteroid treatment of reovirus 1/L-infected mice both inhibited the development of fibrotic lesions when administered early in the time-course and promoted the resolution of fibrotic lesions when corticosteroid administration was delayed. Further, the depletion of either CD4(+) or CD8(+) T cells before reovirus 1/L infection also inhibited fibrotic lesion development. Both corticosteroid treatment and depletion of CD4(+) or CD8(+) T cells also resulted in decreased expression of the proinflammatory and profibrotic cytokines, interferon (IFN)-gamma and monocyte chemoattractant protein-1 (MCP-1). Further, treatment of mice with a neutralizing monoclonal antibody to IFN-gamma also significantly inhibited the development of fibrosis. Taken together, these results suggest a significant role for T cells in the development of reovirus 1/L-induced BOOP fibrotic lesions in CBA/J mice and suggests that T(H)1-derived cytokines, especially IFN-gamma, may play a key role in fibrotic lesion development.     

Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation.

Pulmonary dysfunction is a significant complication following allogeneic hematopoietic stem cell transplantation (HSCT), and is associated with significant morbidity and mortality. Effective antimicrobial prophylaxis and treatment strategies have increased the incidence of noninfectious lung injury, which can occur in the early posttransplant period or in the months and years that follow. Late-onset noninfectious pulmonary complications are frequently encountered, but diagnostic criteria and terminology for these disorders can be confusing and therapeutic approaches are suboptimal. As a consequence, inaccurate diagnosis of these conditions may hamper the appropriate data collection, enrollment into clinical trials, and appropriate patient care. The purpose of this review is to clarify the pathogenesis and diagnostic criteria of representative conditions, such as bronchiolitis obliterans syndrome and bronchiolitis obliterans organizing pneumonia, and to discuss the appropriate diagnostic strategies and treatment options.     

Self-reactive antibodies associated with bronchiolitis obliterans syndrome subtype of chronic lung allograft dysfunction

BackgroundChronic Lung Allograft Dysfunction (CLAD) remains the major limitation in long term survival after lung transplantation. Our objective is to evaluate for the presence of autoantibodies to self-antigens, which is a pathway along with complex interplay with immune as well as non-immune mechanisms that leads to a fibroproliferative process resulting in CLAD.MethodsSerum profiles of IgG autoantibodies were evaluated using customized proteomic microarray with 124 antigens. Output from microarray analyzed as antibody scores is correlated with bronchiolitis obliterans (BOS) subtype of CLAD using Mann-Whitney U test or Fisher exact test. Autoantibodies were evaluated for their predictive value for progressive BOS using a Cox proportional hazard model. BOS free survival and overall survival was analyzed using Kaplan-Meier survival analysis.ResultsForty- two patients included in the study are grouped into “stable BOS” and “progressive BOS” for comparisons. Pulmonary fibrosis is the major indication for lung transplantation in our cohort. Progressive BOS group had significantly worse survival (p < 0.005). Sixteen IgG autoantibodies are significantly elevated at baseline in progressive BOS group. Six among them correlated with worse BOS free survival (p < 0.05). In addition, these six IgG autoantibodies remain elevated at three months and one year after lung transplantation.ConclusionPre-existing IgG autoantibodies correlate with progressive BOS and survival in a single center, small cohort of lung transplant recipients. Further validation with larger sample size, external cohort and confirmation with additional tissue, bronchoalveolar lavage samples are necessary to confirm the preliminary findings in our study.     

Respiratory reovirus 1/L induction of intraluminal fibrosis. A model for the study of bronchiolitis obliterans organizing pneumonia.

Bronchiolitis obliterans organizing pneumonia (BOOP) is a term that was first applied in 1985 to describe a long-observed but unclassified pattern of acute lung injury. BOOP lesions are characterized by fibrous extensions into the alveolar spaces in association with a peribronchiolar organizing pneumonia. Since 1985, an increasing number of reports of BOOP have appeared in the clinical literature, and it is now accepted that BOOP is a significant pulmonary syndrome. Although BOOP can be associated with a number of documented pulmonary insults, many cases are not associated with known causes and are thus classified as idiopathic. The lack of an appropriate small animal model that closely mimics the generation of BOOP lesions has been an impediment to basic studies of the pathogenic mechanisms responsible for the generation of BOOP in humans. In this report, we describe an animal model for BOOP in which CBA/J mice infected with reovirus serotype 1/strain Lang develop BOOP lesions. These lesions closely resemble those seen in humans and occur in a well defined temporal sequence that proceeds from initial peribronchiolar inflammatory lesions to characteristic, fibrotic cellular BOOP lesions over a 3-week time course.     

Alzheimer's disease: a 'cobalaminergic' hypothesis.

An association between Alzheimer's Disease (AD) and low CSF and serum vitamin B12 (B12) has recently been described (1, 2, 3). This is apparently independent of nutritional intake (4). It has been suggested that such patients may exhibit an atypical form of cobalamin deficiency (3, 4). It is therefore proposed that these deficiencies may be aetiologically important, at least in sub-groups of AD, and a mechanism is described whereby B12 deficiency may result in the characteristic neurotransmitter changes of the disease. The hypothesis generates predictions regarding biochemical evaluation of such patients and suggests associations between the neurochemical disturbances and structural abnormalities of AD.     

Bronchiolitis interstitial pneumonitis: a pathologic study of 31 lung biopsies with features intermediate between bronchiolitis obliterans organizing pneumonia and usual interstitial pneumonitis, with clinical correlation

Bronchiolitis combined with interstitial pneumonitis generally has been equated with bronchiolitis obliterans organizing pneumonia (BOOP). We describe our experience with lung biopsies that had both bronchiolar and interstitial diseases. We studied 31 patients who had respiratory difficulty leading to open lung biopsy, which showed a combination of both prominent bronchiolitis and prominent interstitial pneumonitis. We compared these cases clinically and pathologically with 6 other pulmonary diseases, namely, bronchiolitis obliterans, BOOP, nonspecific interstitial pneumonitis, usual interstitial pneumonitis, airway-centered interstitial fibrosis, and idiopathic bronchiolocentric interstitial pneumonia, and with 10 cases of cystic fibrosis, an unrelated disease with both bronchiolar and interstitial pathology. The commonality of our cases was a combination of bronchiolitis and interstitial inflammation and fibrosis but little or no intra-alveolar organizing pneumonia. Bronchiolitis obliterans with organizing pneumonia involved less area than the interstitial pneumonitis in each case. All 19 patients for whom we had follow-up received corticosteroids for their pulmonary diseases. Seven patients had improvement in symptoms and pulmonary function test results and radiographic findings, 5 patients experienced subjective improvement with unchanged results of pulmonary function tests or chest x-ray, 1 patient's condition was unchanged, 6 patients' disease worsened, and 4 of these 6 died. The natural history of these cases, which we have designated bronchiolitis interstitial pneumonitis, seems more sanguine than usual interstitial pneumonitis and worse than BOOP at least in the short term. On the one hand, response to corticosteroids was not as frequent as generally accepted for BOOP. On the other hand, disease did not progress in most patients on corticosteroids.     

Constrictive bronchiolitis obliterans. Characterisation of fibrogenesis and lysyl oxidase expression patterns

The process leading to irreversible fibrotic constriction of the bronchioles was studied in two cases of bronchiolitis obliterans (BO) after bone marrow transplantation. Because lysyl oxidase (LOX) is the main collagen cross-linking enzyme that might account for irreversible fibrosis, its expression was studied together with expression of extracellular matrix (ECM) proteins. Characteristic types of lesions could be distinguished on the basis of histological and immunohistological criteria. An inflammatory stage was characterised by infiltration restricted to the bronchioles by lymphocytes and dendritic cells. A fibro-inflammatory stage was characterised by the coexistence of a persistent immune cellular lesion pattern with further focal modelling of a sub-epithelial neo-synthesised connective matrix. LOX expression was observed at the tips of intra-luminal fibrotic protrusions, together with tenascin and cellular fibronectin. A fibrotic stage was characterised by dense ECM deposits spreading throughout the peri-bronchiolar connective tissue, resulting in bronchiole obliteration and final disappearance. In contrast to reversible cases of fibrosis, persistence of long-term LOX expression reflecting continuing fibrosing activity might account for the irreversible status of BO. Our two cases illustrated that, at inflammatory and fibro-inflammatory stages, BO may be stabilised by immunosuppressive treatment, while the persistence of LOX expression in the fibrotic stage might correspond to a disease that becomes irreversible and fatal.