Shuji Miyake

Clinical features of recurrent and insidious chronic bird fancier's lung

BACKGROUND Chronic bird fanciers lung (BFL) can be subgrouped into two types. One subgroup of patients develops interstitial pulmonary fibrosis after recurrent acute episodes (recurrent BFL), and the other subgroup of patients has no history of acute episodes but has slowly progressive chronic respiratory disease (insidious BFL). OBJECTIVE To define the clinical characteristics of both types of BFL and to provide clues for diagnosis. METHODS We performed a retrospective review of the medical records of patients with chronic BFL who were evaluated between October 1992 and March 2001 at the Tokyo Medical and Dental University Hospital in Japan. Patients were evaluated for their clinical characteristics, including history, laboratory, and immunologic findings; imaging; bronchoalveolar lavage; and histologic findings. RESULTS Thirty-two patients with chronic BFL were included in this study; 15 patients had recurrent BFL and 17 had insidious BFL. The patients with recurrent BFL tended to breed dozens of pigeons in a loft, whereas the patients with insidious BFL were likely to be exposed to smaller birds kept indoors. Specific antibodies against pigeon dropping extracts or budgerigar dropping extracts were positive in 87% of the recurrent BFL cases and 35% of the insidious BFL cases. Antigen-induced lymphocyte proliferation was positive in more than 90% of both groups. The upper lung field was frequently involved in both groups as demonstrated by chest radiographic findings. In all of the patients with insidious BFL, the diagnosis was confirmed by positive laboratory-controlled inhalation test results. CONCLUSIONS Insidious BFL may be misdiagnosed as idiopathic pulmonary fibrosis if a careful history is not taken and antigen-induced lymphocyte proliferation, careful imaging evaluation, and laboratory-controlled inhalation challenge testing are not conducted. In contrast, the clinical findings of recurrent BFL are consistent with hypersensitivity pneumonitis induced by other antigens.

A follow-up study of pulmonary function tests, bronchoalveolar lavage cells, and humoral and cellular immunity in bird fancier's lung

BACKGROUND AND OBJECTIVE The long-term outcome of bird fanciers lung appears to be variable. The objective of this study is to clarify the sequelae of disease process in bird fanciers lung, with special reference to the humoral and cellular immune responses after avoidance of direct antigen exposure. METHODS Five patients with bird fanciers lung were studied for various parameters including pulmonary function tests, cellular profiles of bronchoalveolar lavage (BAL) fluids, determinations of antibodies in BAL fluids and sera, and antigen-induced proliferation of peripheral and bronchoalveolar lymphocytes during the 5 years of follow-up. RESULTS Four of five patients showed improvement in pulmonary function, and one showed marked deterioration. This patients room was close to the pigeon coop where her son was breeding pigeons, resulting in low-grade antigenic stimulation. Three patients demonstrated an increase in CD8+ cells in BAL fluid, but the remaining two showed an increase in CD4+ cells. The levels of IgA antibodies remained unchanged, whereas IgG levels started declining after the first 3 years of follow-up. Antigen-induced proliferation of BAL lymphocytes from all five patients and blood lymphocytes from four of five patients became weaker and gradually approached normal levels. One patient had pulmonary fibrosis and showed significant reduction in pulmonary functions but elevated reactivity of BAL lymphocytes to pigeon antigens. CONCLUSION This follow-up study demonstrates persistence of sensitized lymphocytes and antibody production in the respiratory tract and warrants careful evaluation of patients with bird fanciers lung, even after antigen avoidance.

A clinical study of hypersensitivity pneumonitis presumably caused by feather duvets

BACKGROUND Bird fanciers lung (BFL) is a type of hypersensitivity pneumonitis induced by the inhalation of bird-related antigens. The BFL induced by feathers is difficult to diagnose because feathers are generally unrecognized as a causative antigen. OBJECTIVE To determine the clinical features of BFL presumably induced by feather duvets (feather duvet lung) to provide clues for diagnosis. METHODS We performed a retrospective review of the medical records of patients with feather duvet lung evaluated between April 1, 2000, and June 30, 2003, at the Tokyo Medical and Dental University Hospital in Japan. RESULTS Seven patients with feather duvet lung were included in this study; 4 patients had acute disease and 3 had chronic BFL. Duration of contact with feather duvets was 1 month to 10 years. Serum KL-6 and surfactant protein D levels were elevated in all the patients. Specific antibodies against avian antigens were positive in acute BFL but negative in chronic BFL. Antigen-induced lymphocyte proliferation in peripheral blood or bronchoalveolar lavage cells was positive in all the patients. The diagnosis was confirmed by an environmental or inhalation provocation test. CONCLUSIONS Feather duvets can induce acute and chronic BFL. Physicians should be aware of feather duvets as a cause of BFL because feather duvets are becoming more prevalent.

Pentoxifylline prevents tumor necrosis factor-induced suppression of endothelial cell surface thrombomodulin

Thrombomodulin (TM) expression has been reported to be down-regulated by cytokines (endotoxin, interleukin-1, and tumor necrosis factor). We report, in the present study, up-regulation of surface TM antigen of human umbilical vein endothelial cells (HUVECs) by pentoxifylline (PTX) which is one of the agents that can increase intracellular cyclic AMP in HUVECs at therapeutic concentrations. Surface TM antigen was measured by an enzyme immunoassay. PTX increased surface TM antigen and intracellular cAMP in HUVECs in a dose dependent manner. Upregulation of TM by PTX was due to de novo synthesis of TM protein resulting from increased TM mRNA levels. PTX counterbalanced the TNF-induced suppression of TM expression. These results suggest that protein kinase A may be involved in cellular regulatory mechanism for TM expression and PTX may protect partially against TNF-induced endothelial cell injury and restore anticoagulant state of endothelium.

Immune responsiveness to inhaled antigens: local antibody production in the respiratory tract in health and lung diseases

The pulmonary defence mechanism in summer type hypersensitivity pneumonitis induced by Trichosporon cutaneum was investigated. We have studied the antibody response to fungal antigens in sera and bronchoalveolar lavage (BAL) fluids from patients with summer type hypersensitivity pneumonitis, bird fanciers lung, interstitial pneumonia associated with collagen vascular disease (INT‐PNE), and from normal volunteers. Antigens extracted from fungi frequently isolated from home environments were used in ELISA to detect IgG and IgA antibodies in sera and BAL fluids. The results of the present study show that antibody titre in the respiratory tract to a variety of fungi from home environments is modulated by ongoing pulmonary inflammation, and that antibody production against inhaled antigens is altered by pulmonary inflammation resulting from diverse pathogenesis. This study concludes that the preexisting pulmonary inflammatory disease alters antibody production in the respiratory tract in response to inhaled fungi, and that the type of alteration depends in part on the etiology of the preexisting disease.

Th2-Biased Immune Responses Are Important in a Murine Model of Chronic Hypersensitivity Pneumonitis

Background: Chronic hypersensitivity pneumonitis (HP) can lead to irreversible pulmonary fibrosis. A good animal model is essential to elucidate the mechanisms of this disease. We previously reported that a Th2 predominance may play an important role in the fibrogenesis in chronic HP patients. A study was undertaken to evaluate whether Th2-biased immune responses were crucial during the processes of lung fibrosis in a murine model of chronic HP. Methods: Instillation of pigeon dropping extracts (PDE) was conducted 3 days a week for 6 or 12 weeks in C57BL/6, BALB/c and A/J mice to establish models of chronic HP. We evaluated the histopathological features, immunohistochemistry, collagen content, bronchoalveolar lavage fluid (BALF) profiles and Th1/Th2 cytokines in BALF or lung tissue with RT-PCR and ELISA. Results: Thickening of the alveolar walls and structural alterations were observed only in the A/J mice after 12 weeks of exposure to PDE. The fibrosis scores were significantly increased in 12-week A/J mice compared to those in the other strains. Immunohistochemistry evaluation showed that PDE was engulfed by alveolar macrophages that were incorporated into the alveolar septa of 12-week A/J mice. Interleukin (IL)-4 mRNA increased significantly in 6- and 12-week A/J mice. IL-13 mRNA showed a significant increase in 12-week A/J mice compared with 6-week A/J mice. TGF-β1 mRNA at 12 weeks was significantly increased in A/J mice compared with the other groups. Conclusion: Th2-biased genetic backgrounds may play an important role in fibrosing processes in the present chronic HP model.

Purification of the antigenic components of pigeon dropping extract, the responsible agent for cellular immunity in pigeon breeder's disease

BACKGROUND Pigeon breeders disease (PBD) is a lung disease caused by inhalation of antigens derived from pigeons. OBJECTIVE This study was undertaken to characterize the responsible component of pigeon dropping extract (PDE) for PBD. METHODS First, crude PDE was applied to SDS-PAGE followed by immunoblotting by using antibodies in bronchoalveolar lavage (BAL) fluid. Second, 9 bands of PDE were separated by SDS-PAGE and used for antigen-induced PBMCs. Finally, amino-terminal sequencing was conducted on an isolated 21-kd protein by 2-dimensional electrophoresis. RESULTS Immunoblots with BAL fluid from patients with PBD identified 9 bands. Similar patterns were observed by using BAL fluid from 10 control patients (9 with summer-type hypersensitivity pneumonitis or idiopathic pulmonary fibrosis and 1 asymptomatic breeder), except for the 21-kd protein, which was detected in 10 patients with PBD and 1 asymptomatic breeder. The stimulation indices of PBMCs determined by using proteins electroeluted from the 9 bands were higher in patients with PBD than in the 10 control patients. The 21-kd protein was separated into 5 spots by 2-dimensional electrophoresis; these spots were all reactive with BAL fluid from patients with PBD as determined by immunoblotting. The sequence of the 21-kd protein had 57% identity to a Saccharomyces cerevisiae chromosome X reading frame. A synthetic peptide, derived from the amino acid sequence of the N-terminal of the native protein, induced significant proliferation of PBMCs obtained from 5 patients with PBD, but not with PBMCs obtained from control patients. CONCLUSION The 21-kd protein is the only protein that identified individuals exposed to pigeons by immunoblotting. Only PBMCs from patients with PBD showed significant proliferation to the 21-kd protein and to the synthetic peptide on the basis of the N-terminal sequence of the native peptide. The 21-kd protein will be an important antigen for studies on the epidemiology, diagnosis, and pathogenesis of PBD.

Cytokine mRNA Expression in Isocyanate-Induced Hypersensitivity Pneumonitis

Background: Diisocyanate is widely used as a polymerizing agent for manufacturing many products. However, repeated inhalation exposure to diisocyanates in the workplace can cause bronchial asthma, hypersensitivity pneumonitis (HP), and neoplasia. Objectives: In the current study, immunological tests were conducted to explore the mechanisms involved in the pathogenesis of diisocyanate-induced HP. Methods: Evaluations included 4 patients with diisocyanate-induced HP, 4 volunteers with current occupational exposure to diisocyanates and 4 normal volunteers without a history of exposure to diisocyanates. IgG and IgA antibody levels to diisocyanates were determined by ELISA in sera and BAL fluids. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence or in the absence of 10 µg/ml MDI-HSA (4, 4′ diphenylmethane diisocyanate)-HSA (human serum albumin). 3H-thymidine uptake, mRNA expression by RT-PCR (beta-actin, IL-1beta, IL-2R, IL-4, IL-5, IL-6, IL-10, IFN-gamma, TNF-alpha, TGF-beta) were estimated. Results: Patients with diisocyanate-induced HP had detectable IgG and IgA antibodies to diisocyanates. In addition, PBMCs from HP patients proliferated in the presence of diisocyanates and showed enhanced expression of mRNA of proinflammatory cytokines. In contrast, normal volunteers with current occupational exposure showed elevated levels of mRNA expression of IL-10 and IL-2R, suggesting the presence of sensitized cells and protection from pathology as a result of enhanced IL-10 production. Conclusions: Patients with diisocyanate-induced HP are likely to override the protective effects of IL-10 as they express lower levels of this cytokine.

Churg-strauss syndrome versus chronic eosinophilic pneumonia on high-resolution computed tomographic findings.

Objectives: The aim of this study was to compare the high-resolution computed tomographic findings between Churg-Strauss syndrome (CSS) and chronic eosinophilic pneumonia (CEP). Methods: We retrospectively reviewed the clinical records of 16 patients with CSS and 34 patients with CEP. Results: Twelve (35%) of the 34 patients with CEP had a history of asthma. Although the subpleural distribution of ground-glass opacities (GGOs) and consolidation was common both in CSS and CEP, the midzone distribution was more frequent in CSS (44%) than in CEP (12%). Centrilobular nodules within GGOs were significantly more frequent in CSS (56%) than in CEP (18%). In contrast, traction bronchiectasis associated with volume loss was demonstrated more frequently in CEP (74%) than in CSS (25%). Conclusions: On high-resolution computed tomography, the presence of the midzone distribution and nodules within GGOs without traction bronchiectasis suggests CSS rather than CEP.

The Effect of Seratrodast on Eosinophil Cationic Protein and Symptoms in Asthmatics

Thromboxane A2 (TXA2), an arachidonate derivative, is a potent bronchoconstrictor; therefore, blocking TXA2 should attenuate airway narrowing. Seratrodast, a TXA2 receptor antagonist, is expected to be a potent antiasthmatic. It was reported that seratrodast reduced bronchial hyperresponsiveness. However, it is controversial whether it reduces airway inflammation. We studied some additional effects of oral seratrodast to inhaled corticosteroids on 10 adult asthmatics in an open-label, crossover design study. Eosinophil cationic protein (ECP) levels in serum and sputum, peak expiratory flow rate (PEF), clinical symptoms, and airway responsiveness were evaluated. Clinical symptom scores were improved by administration of seratrodast (p<0.05). The addition of seratrodast to asthmatic patients significantly improved mean PEF (p<0.05). In addition, withdrawal of seratrodast resulted in deterioration of PEF. Airway hyperresponsiveness to acetylcholine measured by Astograph was improved by administration of seratrodast (p<0.01), and returned to the level of “run-in period” after withdrawal. Administration of seratrodast decreased the concentration of ECP in sputum significantly (p<0.05), and sputum ECP significantly increased again after withdrawal of (p<0.05). These results suggest that seratrodast improves clinical symptoms and airway hyperresponsiveness by reducing airway inflammation. Seratrodast may be useful as an anti-inflammatory agent and beneficial when added to inhaled corticosteroids in the treatment of bronchial asthma.