Mitsunori Sakatani

Characteristics of a Large Cohort of Patients with Autoimmune Pulmonary Alveolar Proteinosis in Japan

RATIONALE Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP). Because PAP is rare, prior reports were based on limited patient numbers or a synthesis of historical data. OBJECTIVES To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP. METHODS Over 6 years, 248 patients with PAP were enrolled in a Japanese national registry, including 223 with autoimmune PAP. MEASUREMENTS AND MAIN RESULTS Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively. The male to female ratio was 2.1:1, and the median age at diagnosis was 51 years. A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur. Dyspnea was the most common presenting symptom, occurring in 54.3%. Importantly, 31.8% of patients were asymptomatic and were identified by health screening. Intercurrent illnesses, including infections, were infrequent. A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease. CONCLUSIONS Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses. The disease severity score and biomarkers provide novel and potentially useful outcome measures in PAP.

Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis.

RATIONALE The serial computed tomography findings and prognosis of the acute exacerbation of idiopathic pulmonary fibrosis (IPF) are not yet well defined in a larger number of cases. OBJECTIVES To evaluate the parenchymal abnormalities and prognosis using high-resolution computed tomography (HRCT) in acute exacerbation of IPF. METHODS The study consisted of clinical, laboratory, and HRCT data before and at the time of acute exacerbation in 64 episodes of 58 patients with IPF. A semiquantitative analysis of overall extent of parenchymal abnormalities, extent of alveolar opacity (ground-glass attenuation and consolidation), and extent of fibrotic opacity (reticulation and honeycombing) on CT was performed by two chest radiologists. The newly appeared parenchymal abnormalities were also classified into three patterns: peripheral, multifocal, and diffuse. MEASUREMENTS AND MAIN RESULTS In all patients, HRCT scans taken at the exacerbation showed typical signs of IPF and newly developing alveolar opacity. They included 34 patients of peripheral pattern, 8 of multifocal pattern, and 16 of diffuse pattern. Twenty-five patients died and 33 survived after the initial exacerbation. Worse survival was associated with patients with diffuse type compared with patients with multifocal and peripheral type. The CT patterns and overall CT extent were associated with an increased hazard of death after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, baseline FVC, and disease extent on CT. On multivariate analysis, the strongest correlations were observed between CT patterns (combined diffuse and multifocal versus peripheral) and survival (odds ratio, 4.629; 95% confidence interval, 1.900-11.278; P = 0.001). CONCLUSIONS HRCT extent and patterns are predictive of survival in acute exacerbation of IPF.

Thin-section CT findings in rheumatoid arthritis-associated lung disease: CT patterns and their courses.

PURPOSE The purpose of this study was to describe the long-term follow-up CT evaluation in rheumatoid arthritis (RA)-associated lung disease. METHOD Thin-section CT scans from 29 patients with RA and suspected associated lung disease were reviewed. Twenty-two patients underwent sequential CT evaluation during 3 to 108 months of follow-up (mean 28 months). Histologic comfirmation of pulmonary involvement was available in 19 patients. RESULTS Three major patterns were identified: reticulation with or without honey-combing (n = 19), centrilobular branching lines with or without bronchial dilatation (n = 5), and consolidation (n = 5). Reticulation and centrilobular branching lines corresponded to usual interstitial pneumonia (n = 14) and bronchiolitis obliterans (n = 1), respectively. Consolidation corresponded to bronchiolitis obliterans organizing pneumonia (BOOP; n = 3) and coexistent chronic eosinophilic pneumonia (CEP) and BOOP (n = 1). Patients with reticulation had rapid deterioration when there was new appearance of multifocal areas of ground-glass attenuation. Centrilobular branching lines progressed to bronchiectasis in one case. There was mild progression of existing bronchiectasis associated with centrilobular branching lines in one case. Area of consolidation in two patients with BOOP and one with coexistent CEP and BOOP evolved into honeycombing at serial CT. CONCLUSION Thin-section CT is a noninvasive technique for monitoring disease morphology in RA-associated lung disease. Initial CT findings and their evolution on sequential examinations may be useful in evaluating prognosis.

Adjuvant immunotherapy of lung cancer with BCG cell wall skeleton (BCG-CWS).

Four hundred fifty‐five patients with lung cancer were treated with oil‐attached cell‐wall skeleton of bacillus Calmette‐Guérin (BCG‐CWS) as adjuvant immunotherapy following initial conventional therapy. The overall survival period of the patients was prolonged significantly as compared with that of 380 patients in a historical control group receiving initial conventional therapy alone (p < 0.0001). The prolongation of the survival period of the patients was also statistically significant when classified according to clinical stages and histological cell types. The therapeutic effect was remarkable in patients combined with malignant pleurisy. Intrapleural injection of BCG‐CWS resulted in not only prevention of accumulation of pleural effusion and abrogation of tumor cells but also in prolongation of survival period (p = 0.016). No serious side effects due to BCG‐CWS were experienced. From the previous experimental studies and clinical experiences with human tumors, it can be concluded that adjuvant immunotherapy with BCG‐CWS is a useful therapeutic modality for lung cancer, especially in cases combined with malignant pleurisy.

Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis

BACKGROUND Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of the association of angiotensin II receptor gene polymorphisms with sarcoidosis was therefore undertaken. METHODS ACE (I/D), angiotensin II type 1 receptor (AGTR1), and angiotensin II type 2 receptor (AGTR2 ) gene polymorphisms were investigated by polymerase chain reaction (PCR) and SACE levels were measured in three groups of patients: those with sarcoidosis or tuberculosis and normal controls. RESULTS There was no difference in allele frequency of AGTR1 and AGTR2 polymorphism among the three groups. Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis. SACE activity was higher in patients with sarcoidosis with the AGTR1 A/C genotype than in others. However, this tendency was not detected in patients with tuberculosis. CONCLUSIONS The AGTR1 allele C is associated with high activity of SACE in patients with sarcoidosis. It is another predisposing factor for high levels of SACE in patients with sarcoidosis and is considered to be an independent factor from the ACE D allele for high levels of SACE in sarcoidosis. This fact could be one of the explanations for the increased SACE activity in sarcoidosis.

Non-specific interstitial pneumonia: findings on sequential CT scans of nine patients.

BACKGROUND The purpose of this study was to describe findings on sequential high resolution computed tomographic (CT) scans of nine patients with non-specific interstitial pneumonia. METHODS Thin section CT scans of nine patients with pathologically proven non-specific interstitial pneumonia were evaluated retrospectively. All patients underwent sequential CT scanning (mean follow up 3.1 years (range 1–8)). RESULTS The predominant finding on the initial CT scans in seven patients was patchy areas of ground glass opacity in both the central and peripheral lung, with (n = 5) or without (n = 2) irregular areas of consolidation. In another two patients areas of consolidation in both the central and peripheral lung were seen as the predominant abnormality. The initial parenchymal abnormalities had resolved completely in four patients with predominant ground glass opacity without bronchiolectasis. Some of the bronchiectasis and bronchiolectasis resolved. In two patients bronchiectasis and bronchiolectasis occurred at one year and two years of follow up, respectively. In two patients with predominant consolidation the consolidation decreased but persisted, and in one patient the consolidation evolved into honeycombing. In the other patient bronchiectasis progressed over the course of seven years, forming varicoid bronchiectasis. CONCLUSION Patients with non-specific interstitial pneumonia may recover completely after treatment with corticosteroids, but as many as half of these patients will have persistent pulmonary abnormalities on CT scans including bronchiectasis and honeycomb lung.

Novel prophylactic and therapeutic vaccine against tuberculosis

We have developed a novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-envelope and -liposome (HSP65+IL-12/HVJ). This vaccine provided therapeutic efficacy as well as remarkable protective efficacy via CD8(+) T and CD4(+) T cells in murine models compared with the saline controls, on the basis of CFU of number of multi-drug resistant TB (MDR-TB), and survival of extremely drug resistant TB (XDR-TB) challenged mice. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This vaccine exerted therapeutic efficacy (survival and immune responses) in the TB-infected monkeys. These data indicate that our novel DNA vaccine might be useful against Mycobacterium tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical trials.

Epidemiological and clinical features of idiopathic pulmonary alveolar proteinosis in Japan

Abstract:  Idiopathic pulmonary alveolar proteinosis (IPAP) is a rare disease characterized by excessive amounts of lipoproteinaceous material in the alveolus. This report presents an interim analysis of nationwide epidemiological data from Japanese patients with pulmonary alveolar proteinosis, and the roles of serum markers for IPAP. (i) The nationwide demographic data from 166 Japanese patients with IPAP are shown. The female to male ratio was 1:2, and the average age was 51 ± 14 years old (age range: 15–79 years) at registration or diagnosis. A total of 30% of patients with IPAP have a poor clinical course. In total, 30% of patients were treated with whole lung lavage therapy (WLL). Under WLL, the patients significantly improved in the short term, but 40% of the patients who underwent WLL worsened again. A new strategy such as granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) therapy for intractable PAP is required. (ii) The correlation of serum KL‐6, carcinoembryonic antigen, surfactant proteins D and A, and LDH with disease severity suggests their potential as disease markers. In contrast, serum anti‐GM‐CSF antibody did not correlate with disease severity, but is a specific marker for the diagnosis of IPAP. The combined measurements of the serum markers may well prove very useful for both the diagnosis and the management of IPAP patients.

Inhalational Talc Pneumoconiosis: Radiographic and CT Findings in 14 Patients

OBJECTIVE The purpose of this study was to evaluate the radiographic and CT findings of inhalational talc pneumoconiosis. CONCLUSION Large opacities of talc pneumoconiosis progress more often than do small opacities. The CT findings of talc pneumoconiosis overlap those of silicosis and asbestosis.

Identification of MICA as a Susceptibility Gene for Pulmonary Mycobacterium avium Complex Infection

Host genetic susceptibility to adult pulmonary Mycobacterium avium complex disease remains unknown. To identify genetic loci for the disease, we prepared 3 sets of pooled DNA samples from 300 patients and 300 sex-matched control subjects and genotyped 19,651 microsatellite markers in a case-control manner. D6S0009i-located in the MICA (major histocompatibility complex class I chain-related A) gene, which encodes a ligand of the NKG2D receptor-had the lowest P value in pooled and individual DNA typing. The A6 allele of the microsatellite was significantly associated with female patients (P <. 001), whereas the classical HLA-B and HLA-DRB1 alleles did not show significant association. Functional analysis of allelic expression imbalance revealed that A6-derived messenger RNA was more highly expressed than non-A6-derived messenger RNA in human bronchial epithelial cells. MICA was expressed in bronchiolar epithelium, alveolar macrophages, and granulomatous lesions. These findings suggest that MICA might be one of the immune molecules affecting the pathogenesis of the disease.