Histological variability and consequences in chronic bird-related hypersensitivity pneumonitis.

BACKGROUND AND OBJECTIVE: Lobar and temporal histological variability in chronic bird-related hypersensitivity pneumonitis (BRHP) has not been clearly elucidated. This study was designed to evaluate the spatio-temporal histopathological variability in chronic BRHP. METHODS: Fifty-two patients with chronic BRHP who underwent a surgical lung biopsy (SLB) between 1992 and 2008 were evaluated. The histopathological characteristics of the lung biopsy specimens were classified by the 2002 American Thoracic Society/European Respiratory Society (ATS/ERS) consensus classification of idiopathic interstitial pneumonias (IIPs). Autopsy specimens from seven patients were also evaluated to examine the serial changes from SLB to autopsy. RESULTS: In a study of lobar histological variability based on the findings of SLB, 7 patients were diagnosed with cellular nonspecific interstitial pneumonia (NSIP) pattern, 16 with fibrotic NSIP pattern, 20 with fibrotic NSIP pattern and usual interstitial pneumonia (UIP) (discordant UIP) pattern and 9 with UIP (concordant UIP) pattern. In a study of sequential changes, specimens of SLBs with fibrotic NSIP pattern changed to a bronchiolocentric interstitial pneumonia (BIP) pattern or UIP pattern. CONCLUSION: Interlobar and intralobar histological variability is present in chronic BRHP. In several patients with chronic BRHP, a fibrotic NSIP pattern may be an early lesion that progresses to a UIP pattern.

Cyclosporine A combined with low-dose corticosteroid treatment in patients with idiopathic pulmonary fibrosis.

BACKGROUND: It has been reported that cyclosporine A (CYA) treatment may benefit idiopathic pulmonary fibrosis (IPF) patients. We conducted a randomized, controlled trial at 27 centers across Japan to evaluate the efficacy and safety of CYA with low-dose corticosteroids (CS) for IPF treatment. We compared these findings with others obtained using cyclophosphamide (CPA) combined with low-dose CS: the current standard therapy for IPF. METHODS: The study involved patients between 50 and 74 years of age with well-defined IPF. The primary endpoint was a change in forced vital capacity (FVC) between baseline and 48 weeks. RESULTS: We started this trial in May 2005 and ended it in December 2008. Ninety-nine patients were enrolled in the study. There was no significant difference between the CYA and CPA groups with regard to the change in FVC between baseline and 48 weeks (-0.078L and -0.087L, respectively). Neither did the two groups differ significantly with regard to the incidence rates of several adverse events. CONCLUSIONS: This clinical trial revealed no significant differences between the CYA group and the CPA group with regard to either safety data or the primary endpoint. However, the trial should be regarded as inconclusive because of its small sample size. There was a trend toward a reduction in FVC decline per year when the trial groups were compared with the placebo groups of previous studies, despite patients in this study having severely impaired lung function. Both therapies were well tolerated and lacked serious adverse effects.

Higher serum CCL17 may be a promising predictor of acute exacerbations in chronic hypersensitivity pneumonitis.

BACKGROUND: Recent research has suggested that the Th1 and Th2 chemokine/cytokine axis contributes to the development of chronic hypersensitivity pneumonitis (HP). Acute exacerbations (AE) are significant factors in the prognosis of chronic HP. Little is known, however, about these biomarkers in association with AE in chronic HP patients. METHODS: Fifty-six patients with chronic HP were evaluated, including 14 patients during episodes of AE. Th1 mediators (C-X-C chemokine ligand [CXCL]10 and interferon [IFN]-γ), Th2 mediators (C-C chemokine ligand [CCL]17, interleukin-4, and interleukin-13), and pro-fibrotic mediator (transforming growth factor [TGF]-ß) were measured to evaluate the mediators as predictors of AE. C-C chemokine receptor (CCR)4 (receptor for CCL17)-positive lymphocytes were quantified in lung specimens. RESULTS: Serum CCL17 levels at baseline independently predicted the first episode of AE (HR, 72.0; 95% CI, 5.03-1030.23; p = 0.002). AE was significantly more frequent in the higher-CCL17 group (≥285 pg/ml) than in the lower-CCL17 group (<285 pg/ml) (log-rank test, p = 0.0006; 1-year incidence: higher CCL17 vs. lower CCL17, 14.3% vs. 0.0%). Serum CCL17 levels and CCR4-positive cells during episodes of AE were increased from the baseline (p = 0.01 and 0.031). CONCLUSIONS: Higher serum concentrations of CCL17 at baseline may be predictive of AE in patients with chronic HP, and CCL17 may contribute to the pathology of AE by inducing the accumulation of CCR4-positive lymphocytes in the lungs.

[Measurement of bird specific antibody in bird-related hypersensitivity pneumonitis].

Since the avian antigen is one of the important causative antigens in hypersensitivity pneumonitis, measurement of bird-specific antibody should be readily available. We measured IgG and IgA antibodies against pigeons and budgerigars by the ImmunoCap system in bird-related hypersensitivity pneumonitis (BRHP) to evaluate their diagnostic utility. In acute BRHP, antibodies markedly increased and showed high sensitivity and specificity ranging from 75-100% based on the cut-off values determined by ROC analysis. In chronic BRHP, antibody reactivity slightly increased, showing a sensitivity of 27-73% and specificity of 45-100%. Pigeon antibodies evaluated by the ImmunoCap system showed a good correlation with anti-pigeon dropping extract antibodies measured by ELISA. In conclusion, measurement of antibodies against pigeons and budgerigars are helpful for the diagnosis of BRHP.

Pulmonary Artery Leiomyosarcoma Diagnosed without Delay.

A 63-year-old female presented with abnormal lung shadows but had, apart from this, few symptoms. Computed tomography (CT) revealed multiple nodules and blockage of the pulmonary artery. She was immediately diagnosed with pulmonary artery sarcoma based on a careful differential diagnosis and underwent surgery. Her tumor was pathologically diagnosed as leiomyosarcoma (i.e. intimal sarcoma). Pulmonary artery sarcoma can be easily confounded with thromboembolism in a clinical setting and some cases are diagnosed post mortem only. In our case, clinical prediction scores (Wells score, Geneva score, and revised Geneva score) for the pulmonary embolism showed low probability. Moreover, chest CT showed uncommon findings for pulmonary thromboembolism, as the nodules were too big for thrombi. Because surgical resection can provide the only hope of long-term survival in cases of pulmonary artery sarcoma, clinicians should consider this possibility in the differential diagnosis of pulmonary embolism. Clinical prediction scores and CT findings might help to reach the correct diagnosis of pulmonary artery sarcoma.

Serial high-resolution computed tomography findings of acute and chronic hypersensitivity pneumonitis induced by avian antigen.

PURPOSE: The purpose of this study was to evaluate serial changes and the prognostic value of high-resolution computed tomographic (HRCT) findings in hypersensitivity pneumonitis (HP). METHOD: The medical records of 112 patients with bird-related HP (17 acute, 33 recurrent, and 62 insidious) were retrospectively reviewed. High-resolution computed tomographic findings at the time of diagnosis and at follow-up were retrospectively interpreted. RESULTS: Ground-glass opacities and centrilobular nodules were predominant findings in acute and recurrent HP, whereas honeycombing was the outstanding feature in insidious HP. Areas of ground-glass opacities and centrilobular nodules decreased in all groups over a long-term follow-up. Areas of honeycombing, on the other hand, increased in chronic HP, especially in the insidious cases. Cox regression models revealed a higher mortality risk in cases with airspace consolidation and honeycombing on HRCT. CONCLUSION: Acute, recurrent, and insidious HP all have characteristic features on CT. Characteristic HRCT findings can predict the prognosis of chronic HP.

Developments for a growing Japanese patient population: facilitating new technologies for future health care.

Lung cancer, COPD and cardiovascular diseases are highlighted as some of the most common disease that cause mortality, and for that reason are the most active areas for drug development. This perspective paper overviews the urgent need to develop a health care system for a rapidly growing patient population in Japan, including forthcoming demands on clinical care, expecting outcomes, and economics. There is an increasing requirement to build on the strengths of the current health care system, thereby delivering urgent solutions for the future. There is also a declaration from the Ministry of Health, Labour and Welfare (MHLW), to develop new biomarker diagnostics, which is intended for patient stratification, aiding in diagnostic phenotype selection for responders to drug treatment of Japanese patients. This perspective was written by the panel in order to introduce novel technologies and diagnostic capabilities with successful implementation. The next generation of personalized drugs for targeted and stratified patient treatment will soon be available in major disease areas such as, lifestyle-related cancers, especially lung cancers with the highest mortality including a predisposing disorder chronic obstructive pulmonary disease, cardiovascular disease, and other diseases. Mass spectrometric technologies can provide the "phenotypic fingerprint" required for the concept of Personalized Medicine. Mass spectrometry-driven target biomarker diagnoses in combination with high resolution computed tomography can provide a critical pathway initiative facilitated by a fully integrated e-Health infrastructure system. We strongly recommend integrating validated biomarkers based on clinical proteomics, medical imaging with clinical care supported by e-Health model to support personalized treatment paradigms to reduce mortality and healthcare costs of chronic and co-morbid diseases in the elderly population of Japan.

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-ß1 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.

Proteome analysis of bronchoalveolar lavage fluid in lung fibrosis associated with systemic sclerosis.

BACKGROUND: Interstitial lung disease (ILD) is the major cause of mortality in collagen vascular diseases. However, its pathogenesis still needs to be elucidated. METHODS: To evaluate the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) and clarify the causative role in the processes of ILD in systemic sclerosis (SSc), we compared a BALF protein profile between 5 patients with systemic sclerosis with pulmonary fibrosis (SSc-fib+) and 4 patients with systemic sclerosis without pulmonary fibrosis (SSc-fib-) using two-dimensional gel electrophoresis (2-DE), and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). RESULTS: We analyzed spots over the range of 10.1kDa to 207.4kDa. SSc-fib+ patients showed increased 3 proteins compared to SSc-fib- including α2-macroglobulin, α1-antitrypsin, and pulmonary surfactant protein A and decreased 2 proteins including α2 heat shock protein (HSP) and glutathione S-transferase (GST) compared to SSc-fib- patients. CONCLUSIONS: In conclusion, we identified several interesting proteins that might have roles in ILD of SSc patients. Further studies are warranted to clarify the role of these proteins in the processes of pulmonary fibrosis in SSc.

The pathogenesis of chronic hypersensitivity pneumonitis in common with idiopathic pulmonary fibrosis: expression of apoptotic markers.

Previous studies showed that apoptotic epithelial cells were involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP); however, little is known about apoptosis in chronic hypersensitivity pneumonitis (HP). This study was performed to examine whether apoptosis has a role in chronic HP. We performed immunohistochemical studies for p53, p21, Fas, Fas ligand, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling methods on surgical lung specimens. The expression of Fas and Fas ligand was up-regulated in UIP-like lesions compared with nonspecific interstitial pneumonia (NSIP)-like lesions. The expression of p53 and p21 on epithelial cells increased significantly in UIP-like lesions compared with fibrotic NSIP-like lesions and in fibrotic NSIP-like lesions compared with normal lung tissues. These results confirm that apoptotic epithelial cells are present in chronic HP as seen in IPF. Augmented epithelial apoptosis may contribute much more to UIP-like lesions than to NSIP-like lesions in chronic HP.

Cytokeratin expression profiling is useful for distinguishing between primary squamous cell carcinoma of the lung and pulmonary metastases from tongue cancer.

It can be difficult to distinguish between primary and metastatic squamous cell carcinoma (SCC) in the lung. Surgical specimens were obtained from two groups of patients, 26 lung SCC patients without histories of any other cancer (the definite primary group) and 17 patients who had undergone surgical removal of SCC emerging in the lung after surgery for tongue SCC (the unknown group). From the former, 26 primary lung SCC were obtained. From the latter, 17 lung tumors and 15 primary tumors of the tongue were obtained. Eleven of the 17 lung tumors from the unknown group were metastatic lung SCC. All specimens were immunostained with cytokeratin (CK)5/6, CK7, CAM5.2, CK19 and p63 antibodies. The frequency of CAM5.2 and CK19 expression was significantly higher in the lung SCC of the definite primary group (21 of 26, 81% and 20 of 26, 78%, respectively) than in the metastatic lung SCC (1 of 11, 9% (P < 0.001) and 2 of 11, 18% (P = 0.003), respectively) or primary SCC of the tongue (5 of 15, 33% (P = 0.002) and 2 of 15, 13% (P < 0.001), respectively). CAM5.2 and CK19 are useful for distinguishing between primary SCC of the lung and metastases from tongue cancer.

Detection of indoor and outdoor avian antigen in management of bird-related hypersensitivity pneumonitis.

BACKGROUND: In the management of hypersensitivity pneumonitis (HP), antigen avoidance is crucial to prevent the progression of disease. Indirect and unrecognized exposure to the antigen may continue for a long time if persistence of the causative antigen is not recognized. To make a correct assessment of the patients' environment, we tried to establish the methods to detect indoor and outdoor avian antigens. METHODS: Sixteen patients with bird-related HP, 4 asymptomatic breeders, and 6 healthy controls were examined. We prepared anti-pigeon dropping extracts (PDE) polyclonal antibody from rabbits. Air samples and house dust samples were analyzed by an antigen-capture ELISA with signal amplification using catalyzed reporter deposition. RESULTS: In air samples, avian antigen could be detected in patients with HP (0.73 +/- 0.53 ng/m3) and asymptomatic breeders (0.63 +/- 0.23 ng/m3). In house dust samples, the amount of avian antigen was higher in patients with HP (2.4 +/- 1.8 microg/g) and asymptomatic breeders (4.1 +/- 2.3 microg/g) than in the controls (0.1 +/- 0.2 microg/g). CONCLUSIONS: Detection of indoor and outdoor avian antigen might contribute to the correct diagnosis and appropriate managements of bird-related HP.

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.

RANTES expression induced by Toll-like receptor 4 ligand in rat airway smooth muscle cells.

Airway smooth muscle cells (ASMCs) have been reported to express Toll-like receptors (TLRs) and take part in the pathogenesis of asthma exacerbation. Though TLRs were found to activate epidermal growth factor receptor (EGFR) in airway epithelial cells, little is known about the association of TLR ligands with EGFR signaling pathways in ASMCs. Using primary cultured ASMCs from Brown Norway rats, TLR4, eotaxin, and RANTES mRNA were examined by real-time quantitative RT-PCR after stimulation with the TLR4 ligand, lipopolysaccharides (LPS). The concentration of RANTES protein in culture supernatant was measured by ELISA. The effect of EGFR signaling inhibitors on RANTES expression was examined as well. Phosphorylation of EGFR after stimulation was examined by Western Blotting. Rat ASMCs expressed TLR4 and eotaxin, and LPS upregulated RANTES production. The EGFR tyrosine kinase inhibitor AG1478, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the matrix metalloproteinase (MMP) inhibitor GM6001 inhibited RANTES expression induced by LPS. LPS phosphorylated EGFR. TLR4 activation can induce RANTES expression via EGFR transactivation and PI3K/Akt pathway in rat ASMCs. MMP-induced EGFR proligand cleavage and ligand binding to EGFR seem to be involved in this pathway. These findings may be critical in the pathogenesis of asthma exacerbation by airway infection.

[The sequential changes of the serum levels of KL-6, SP-D, and DLCO were followed for a long term in a case of acute bird fancier's lung].

The sequential changes of the serum levels of KL-6, SP-D, and DLco were followed for a long term in a case of acute bird fancier's lung, A 52 years-old-male was admitted to our hospital because of cough, dyspnea on exertion and fever. He has been breeding 12 pigeons in home for the last five years. HRCT of the chest demonstrated diffuse centrilobular nodules and ground-glass opacities with mosaic pattern in bilateral lung fields. Bronchoalveolar lavage (BAL) showed an increased number of lymphocytes with a increased CD4/CD8 ratio, and transbronchial lung biopsy (TBLB) specimen revealed alveolitis with infiltration of lymphoid cells and Masson body in the air spaces. He was diagnosed as having bird fancier's lung because of the elevated antibodies against pigeon dropping extracts (PDE) in the serum and BALF. Respiratory failure continued after complete avoidance of contact with pigeons for a week. Clinical symptoms and chest X-ray findings improved markedly after administration of steroid, and he left the hospital to move into a new house. The serum levels of KL-6 and SP-D were unchanged by antigen avoidance, although those were returning to normal gradually after treatment of steroid. SP-D and KL-6 returned to normal in 8 months and 18 months respectively and DLco was also improved slowly in parallel with a decrease of these markers. These results suggest that the serum KL-6 level and DLco reflect the disease activity showing gradual recovery of alveolitis in such a long period.

[Two cases of familial summer-type hypersensitivity pneumonitis requiring differentiation from bird breeder's lung].

A 74-year-old-man (case 1) was admitted to our hospital because of dry cough, fever, and dyspnea on effort. His daughter-in-law, a 53-year-old-woman (case 2), was also admitted to our hospital on suspicion of hypersensitivity pneumonitis (HP). Their diagnoses of HP were established by radiological, serological, and histological examinations. It was necessary to differentiate between summer-type hypersensitivity pneumonitis (SHP) and bird breeder's lung due to their special environment. Several examinations, including immunological findings of BALF, returning-home provocation test, and antigen inhalation challenge test, enabled us to establish their diagnoses of SHP.

Nonspecific interstitial pneumonia (NSIP) associated with anti-KS antibody: differentiation from idiopathic NSIP.

We report two cases of biopsy-proven nonspecific interstitial pneumonia (NSIP) with anti-KS (asparaginyl-tRNA) antibody. Anti-KS antibody is the sixth anti-aminoacyl-tRNA synthetase (ARS) antibody. They showed interstitial pneumonia without clinical symptoms, and high resolution computed tomography (HRCT) of the chest demonstrated consolidation along bronchovascular bundles and volume loss in the bilateral lower lobes, which were suggestive of connective tissue diseases (CTD). One case of cellular NSIP responded to corticosteroid, but the other case of fibrotic NSIP required corticosteroid and cyclosporin. In patients with these HRCT findings, the measurement of anti-ARS antibodies could be helpful even in the absence of clinical symptoms suggestive of CTD.

[A case of sarcoidosis with pleural involvement but with no mediastinal or hilar lymph node enlargement].

A 66-year-old woman was referred to our hospital because of right chest pain on inspiration. Chest X-ray film revealed diffuse opacities, predominantly in the lower lung field, and right pleural thickening. Serum ACE and lysozyme levels were elevated. Chest CT revealed diffuse ground-glass opacity, centrilobular granular nodules, bronchovascular bundle irregular thickening and right pleural irregular thickening over the right inferior lobe, but bilateral hilar lymph node enlargement was not present. Bronchoalveolar lavage (BAL) fluid demonstrated increased numbers of total cells and CD4 T-helper lymphocytes. The transbronchial lung biopsy specimen revealed non-caseating epithelioid cell granulomas. From these findings, we established a diagnosis of type III sarcoidosis with pleural involvement. The patient has been observed without treatment, and 10 months later the lung involvement and pleural thickening have disappeared.

Histopathologic analysis of sixteen autopsy cases of chronic hypersensitivity pneumonitis and comparison with idiopathic pulmonary fibrosis/usual interstitial pneumonia.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by the inhalation of organic substances and certain inorganic chemicals. The histopathologic features of chronic HP (CHP) have not been studied extensively. We examined the pathologic characteristics of 16 autopsy cases of clinically confirmed CHP and compared them with 11 cases of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). To clarify the exact intralobular location of the fibrotic lesions, we conducted 3-dimensional reconstruction of fibrosis of CHP and IPF/UIP. Granuloma was not detected in any CHP case. Similar to IPF/UIP, honeycombing lesions were found dominantly in the lower lobes in most CHP cases; upper lobe dominance and asymmetrical distribution of honeycomb lesions were more frequent in CHP than in IPF/UIP. In all lungs affected by CHP, centrilobular fibrosis was outstanding, often connecting to the perilobular areas in the appearance of "bridging fibrosis," which was clearly demonstrated by 3-dimensional imaging. Centrilobular and bridging fibrosis were significantly more conspicuous in CHP than IPF/UIP; however, considerable overlap was found. It is important to thoroughly explore the possibility of antigen exposure in cases of lungs with UIP with centrilobular fibrosis to discriminate CHP from IPF/UIP.

Depletion of CD8+ T cells enhances airway remodelling in a rodent model of asthma.

Airway remodelling is induced by persistent airway inflammation and may lead to severe asthma. T cells play a pivotal role in asthmatic airway inflammation but their role in remodelling is poorly understood. Although previous studies have revealed that CD8(+) T cells inhibit the late airway response and airway inflammation in a rat model of asthma, their effects on airway remodelling have not been evaluated. The aim of this study was to examine the role of CD8(+) T cells in airway remodelling. Brown Norway rats were sensitized with ovalbumin (OVA) on day 0. CD8(+) T cells in rats were depleted during the repeated challenges by treating them with a CD8alpha monoclonal antibody (OX-8). Control rats were treated with mouse ascites. Sensitized rats were challenged with OVA on days 14, 19 and 24 or were sham challenged with phosphate-buffered saline. On day 29, bronchoalveolar lavage and lung tissues were harvested. Repeated OVA inhalations evoked significant increases in the numbers of periodic acid-Schiff-positive epithelial cells and proliferating cell nuclear antigen-positive epithelial cells, and in airway smooth muscle mass compared to the control group. CD8-depleted rats had significant enhancement of these changes, principally affecting the large airways. These results suggest that endogenous CD8(+) T cells have inhibitory effects on airway remodelling in this model of asthma.