Yasunari Miyazaki

Clinical Predictors and Histologic Appearance of Acute Exacerbations in Chronic Hypersensitivity Pneumonitis

BACKGROUND Acute exacerbations (AEs) in idiopathic pulmonary fibrosis (IPF) are critical factors for its clinical course and prognosis. We have seen AEs and poor prognosis consequent to AE in patients with chronic hypersensitivity pneumonitis (HP), as has been seen in patients with IPF. The aim of this study was to evaluate the clinical features of the patients with AE in those with chronic HP. METHODS We reviewed 100 consecutive patients with chronic bird fancier lung (BFL) from 1993 to 2006, and analyzed the clinical characteristics, including history, and laboratory and immunologic, imaging, BAL, and histologic findings. RESULTS AE developed in 14 patients during this observation period (AE group), whereas 86 patients remained stable (non-AE [NAE] group). The 2-year frequency of AE among patients with chronic BFL having usual interstitial pneumonia (UIP)-like lesions seen on surgical lung specimens was 11.5%. Patients with AE were more likely to be smokers (p = 0.003). In pulmonary function test results, the mean total lung capacity (TLC) and diffusing capacity of the lung for carbon monoxide (Dlco) were lower in patients with AEs (TLC: AE patients, 63.0 +/- 16.8%; NAE patients, 81.6 +/- 20.0%; Dlco: AE patients, 41.9 +/- 19.0%; NAE patients, 60.0 +/- 19.4%). The mean number of lymphocytes in BAL fluid were lower (AE patients, 13.7 +/- 7.5 lymphocytes; NAE patients, 37.2 +/- 29.7 lymphocytes), while the number of neutrophils were greater in AE patients (AE patients, 10.7 +/- 17.6 neutrophils; NAE patients, 3.6 +/- 4.4 neutrophils). Histologic and/or radiologic findings revealed that all AE patients had UIP-like lesions. Diffuse alveolar damage was observed in six cases, whereas organizing pneumonia superimposed on preexistent fibrotic lesions was observed in two cases. CONCLUSIONS The present study showed several predictive factors for AE at the time of diagnosis. Low TLC and Dlco, low lymphocyte levels in BAL fluid, and a UIP-like pattern in histology at the time of diagnosis may be the risk factors for AE.

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.

Th1 and Th17 immune responses to viable Propionibacterium acnes in patients with sarcoidosis

BACKGROUND Propionibacterium acnes and Mycobacterium tuberculosis have emerged as probable candidates responsible for sarcoidosis. This study was conducted to investigate the Th1/Th17 responses elicited by these pathogens in sarcoidosis and to clarify the causative role of these pathogens. METHODS Peripheral blood mononuclear cells (PBMCs) obtained from patients with sarcoidosis and from healthy volunteers were, respectively, co-cultured with viable P. acnes, with Bacille de Calmette et Guérin (BCG) as a viable M. tuberculosis complex, and with the early secretory antigenic target (ESAT)-6. Th1 cytokine production was measured using RT-PCR and enzyme-linked immunospot (ELISPOT) assays, and interleukin (IL)-17 mRNA expression was measured by RT-PCR. RESULTS IL-2 secretion from PBMCs after stimulation with P. acnes was significantly higher in patients with sarcoidosis than in the controls. Similarly, IL-2 and IL-12 mRNA expression after stimulation with P. acnes was significantly higher in PBMCs from patients with sarcoidosis than in PBMCs from controls. In contrast, IL-17 mRNA expression was significantly lower in PBMCs from patients with sarcoidosis than in PBMCs from controls. No significant differences between the groups were observed in the responses to stimulation with BCG or ESAT-6. CONCLUSION Sarcoidosis may arise from an imbalance of Th1/Th17 immune responses against viable P. acnes, but not M. tuberculosis complex.

A nationwide epidemiological survey of chronic hypersensitivity pneumonitis in Japan

BACKGROUND In 1999, a Japanese epidemiological survey of chronic hypersensitivity pneumonitis (HP) showed that summer-type HP was the most prevalent variant of the disease. The number of reported cases of chronic HP has recently been increasing, and the clinical features of the disease seem to have changed. We conducted another nationwide epidemiological survey of chronic HP in Japan to determine better estimates of the frequency and clinical features of the disease. METHODS A questionnaire was sent to qualified hospitals throughout Japan, and data on cases of chronic HP diagnosed between 2000 and 2009 were collected. RESULTS In total, 222 cases of chronic HP from 22 hospitals were studied. Disease subtypes included bird-related HP (n=134), summer-type HP (n=33), home-related HP (n=25), farmers lung (n=4), isocyanate-induced HP (n=3), and other types (n=23). The median proportion of lymphocytes in bronchoalveolar lavage fluid was high (24.5%). The primary findings of computed tomography of the chest were ground-glass attenuation and interlobular septal thickening. Centrilobular fibrosis was the major pathological finding on examination of surgical lung biopsy specimens from 93 patients. The median survival time was 83 months. CONCLUSIONS The proportion of bird-related HP was higher than that in the previous epidemiological survey, and the proportions of isocyanate-induced HP and farmers lung were lower. A crucial step in diagnosing chronic HP is to thoroughly explore the possibility of antigen exposure.

Pathogenesis of cBFL in common with IPF? Correlation of IP-10/TARC ratio with histological patterns

Background: A Th1 predominant immune response has been shown in acute hypersensitivity pneumonitis. Predominance of Th2 appears to favour the development of pulmonary fibrosis through the profibrotic process and has been described as crucial in the progression of idiopathic pulmonary fibrosis. Chronic bird fancier’s lung (cBFL) can present with a histological pattern of usual interstitial pneumonia (UIP)-like lesions. Little is known about the Th1/Th2 balance in the pathogenesis of cBFL. Methods: To evaluate the relevance of Th1-type chemokines (interferon-inducible protein, IP-10) and Th2-type chemokines (thymus- and activation-regulated chemokine, TARC) and their receptors (CXCR3 and CCR4) to the histological patterns of cBFL, 40 patients with cBFL who underwent surgical lung biopsies, 12 with acute BFL (aBFL) and 10 healthy volunteers were analysed. IP-10 and TARC levels in serum and bronchoalveolar lavage (BAL) fluid were measured by ELISA. Immunohistochemistry for CXCR3 and CCR4 was performed on surgical lung specimens. Results: The ratio of TARC to IP-10 in the serum of patients with UIP-like lesions was significantly higher than in patients with cNSIP/OP-like lesions, aBFL and healthy volunteers. The ratio of CCR4 to CXCR3 in patients with UIP-like lesions was significantly higher than in those with cNSIP/OP-like lesions and fNSIP-like lesions. The ratio of CCR4-positive to CXCR3-positive cells correlated with the ratio of TARC to IP-10 in serum. Conclusions: A Th2 predominant immune response may play an important role in the development of UIP-like lesions, as already observed in idiopathic pulmonary fibrosis. A Th1 predominance may play a role in the development of cNSIP/OP-like lesions in cBFL.

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.

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.

Proteome Analysis of Bronchoalveolar Lavage Fluid in Chronic Hypersensitivity Pneumonitis

BACKGROUND Hypersensitivity pneumonitis (HP) is an immune-mediated lung disease induced by inhalation of numerous antigens. Pathologically, chronic HP tends to show usual interstitial pneumonia (UIP) and fibrotic nonspecific interstitial pneumonia (fNSIP) patterns. Patients with UIP pattern present insidious onset and a risk for acute exacerbations. METHODS To evaluate the proteomic differences of bronchoalveolar lavage fluid (BALF) between UIP and fNSIP patterns, BALF from seven patients with UIP pattern and four patients with fNSIP pattern was examined using two-dimensional gel electrophoresis and mass spectrometry. RESULTS By individually comparing each BALF sample, we found that the protein levels of surfactant protein A (SP-A), immunoglobulin heavy chain α, α-2 heat shock glycoprotein, haptoglobin β, and immunoglobulin J chain were significantly higher in the patients with UIP pattern than those in the patients with fNSIP pattern. In contrast, the protein levels of glutathione s-transferase, vitamin D-binding protein, and β-actin were significantly higher in the patients with fNSIP pattern than those in the patients with UIP pattern. To confirm the results of SP-A in the BALF proteome, we performed enzyme-linked immunosorbent assay in a larger group. The concentrations of SP-A in BALF from the patients with UIP pattern were significantly higher than those from the patients with fNSIP pattern (2.331 ± 1.656 μg/ml vs. 1.319 ± 1.916 μg/ml, p = 0.034). CONCLUSIONS We identified several proteins that may play roles in the development of pathological differences between UIP and fNSIP patterns of chronic HP.

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.