Koichiro Tatsumi

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.

Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis.

RATIONALE Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. OBJECTIVES To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. METHODS We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk). MEASUREMENTS AND MAIN RESULTS Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. CONCLUSIONS Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).

Impact of interstitial lung disease on surgical morbidity and mortality for lung cancer: analyses of short-term and long-term outcomes

BACKGROUND This study investigated postoperative morbidity, mortality, and the long-term survival for patients with lung cancer who have interstitial lung diseases. METHODS A retrospective chart review of 931 patients with lung cancer who underwent pulmonary resection at Chiba University Hospital between 1990 and 2000 was undertaken. Interstitial lung disease was defined by medical history, physical examination, and abnormalities compatible with bilateral lung fibrosis on chest computed tomography or high-resolution computed tomography (36 patients: 3.9%, interstitial lung diseases group). The remaining 895 patients (96.1%) were categorized as non-interstitial lung disease group. RESULTS The incidence of postoperative pneumonia and acute or exacerbation of interstitial pneumonia was higher in the interstitial lung disease group (all P <.05). Thirty-day mortality was statistically equivalent between the interstitial lung disease and the non-interstitial lung disease groups (P =.30). The 5-year overall survivals were 62.5% (non-interstitial lung disease) and 35.6% (interstitial lung disease). Respiratory failure was the second main cause of death after the recurrence of primary cancer in the interstitial lung disease group. The risk factors for long-term mortality were interstitial lung diseases, advanced pathologic stage, male sex, high age, and positive smoking history (all P <.05). CONCLUSIONS Interstitial lung disease was a risk factor for developing postoperative morbidity and mortality and poor long-term survival due to the occurrence of respiratory failure.

Effects of acetazolamide in patients with the sleep apnoea syndrome.

There is as yet no convincing evidence that acetazolamide, a carbonic anhydrase inhibitor, is effective in obstructive sleep apnoea. A study was therefore designed to examine the effect of acetazolamide (250 mg/day) on sleep events and ventilatory control during wakefulness in nine patients with the sleep apnoea syndrome. In eight of the nine patients the apnoea index and the total duration of apnoea were reduced by acetazolamide, and the mean (SEM) apnoea index of all patients changed from 25.0 (6.7) to 18.1 (5.8) episodes an hour. Furthermore, the total time of arterial oxygen desaturation (SaO2)--more than 4% depression in SaO2 from the baseline sleeping level--divided by total sleep time was also significantly decreased and its mean (SEM) value improved from 24.1 (7.9) to 13.6 (4.8)% of total sleep time. Five of the seven patients with varying degrees of daytime hypersomnolence had their symptoms obviously improved. There was no patient whose predominant type of apnoea was converted from the obstructive to the central type, or vice versa. In the studies of wakefulness, metabolic acidosis, an increase of arterial oxygen tension (PaO2) and a decrease of arterial carbon dioxide tension (PaCO2) were observed. The slopes of the occlusion pressure response and the ventilatory response to carbon dioxide increased, and the carbon dioxide ventilatory response line shifted to the left. It is suggested that acetazolamide cannot remove apnoea completely but has a beneficial effect in mild cases of obstructive sleep apnoea through an augmentation of central (CO2, H+) drive and a stabilising effect on ventilatory control.

VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells

Severe pulmonary hypertension (PH) is characterized by complex precapillary arteriolar lesions, which contain phenotypically altered smooth muscle (SM) and endothelial cells (EC). We have demonstrated that VEGF receptor blockade by SU5416 {3‐[(2,4‐dimethylpyrrol‐5‐yl)methylidenyl]‐indolin 2‐one} in combination with chronic hypoxia causes severe angioproliferative PH associated with arterial occlusion in rats. We postulate that endothelial‐mesenchymal transdifferentiation can take place in the occlusive lesions and that endothelium‐derived mesenchymal cells can further differentiate toward a SM phenotype. To examine this hypothesis, we incubated human pulmonary microvascular endothelial cells (HPMVEC) with SU5416 and analyzed these cells utilizing quanti‐tative‐PCR, immunofluorescent staining and flow cytometry analysis. In vitro studies in HPMVEC demonstrated that SU5416 suppressed PGI2S gene expression while potently inducing COX‐2, VEGF, and TGF‐β1 expression;and caused transdifferentiation of mature vascular endothelial cells (defined by Dil‐ac‐LDL, Lectin and Factor VIII) to SM‐like (as defined by expression of α‐SM actin) “transitional” cells, coexpressing both endothelial and SM markers. SU5416 expanded the number of CD34 and/or c‐kit positive cells and caused transdifferentiation of CD34 positive cells but not negative cells. In conclusion, our data show that SU5416 generated a selection pressure that killed some EC and expanded progenitor‐like cells to transdiffer‐entiate to SM‐like and neuronal‐like cells.—Sakao, S., Taraseviciene‐Stewart, L., Cool, C. D., Tada, Y., Kasahara, Y., Kurosu, K., Tanabe, N., Takiguchi, Y., Tatsumi, K., Kuriyama, T., and Voelkel, N. F. VEGF‐R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle‐like and neuronal‐like cells. FASEB J. 21, 3640–3652 (2007)

Identification of Annexin 1 as a Novel Autoantigen in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Consistent with the hypothesis that pulmonary epithelial apoptosis is the key to the acute exacerbation of idiopathic pulmonary fibrosis (IPF), we conducted serological identification of Ags by recombinant expression cloning (SEREX) analysis using type II alveolar cell carcinoma (A549) cell lines to identify disease-related Abs. In a survey of Abs to the recombinant autoantigens identified by SEREX analysis, five Abs were identified as novel candidates for the acute exacerbation of IPF. Abs to annexin 1 were detected in 47 and 53% of the sera and bronchoalveolar lavage materials from patients with acute exacerbation of IPF. Some identical TCR Vβ genes were identified in sequential materials obtained at 1–3 mo in all 10 acute exacerbation IPF cases, suggesting that some infiltrating CD4-positive T cells sharing limited epitopes expand by Ag-driven stimulation during disease extension. The CDR3 region of these identical TCR Vβ genes showed high homology with the N-terminal portion of annexin 1, including in the HLA-DR ligand epitopes predicted by TEPITOPE analysis. By Western blotting analysis and observation of the CD4-positive T cell responses in bronchoalveolar lavage samples, the N-terminal portion of annexin 1 was cleaved and found to induce marked proliferative responses of CD4-positive T cells in three patients. Our study demonstrates that annexin 1 is an autoantigen that raises both Ab production and T cell response in patients with acute exacerbation of IPF, and that the N-terminal portion of annexin 1 plays some role in the pathogenesis of acute exacerbation in IPF patients.

Indigenous Pulmonary Propionibacterium acnes Primes the Host in the Development of Sarcoid-Like Pulmonary Granulomatosis in Mice

Although many cases of sarcoidosis are self-limiting with spontaneous remission, uncontrolled pulmonary granulomatosis with fibrosis produces intolerable long-term respiratory symptoms in a minority of patients. Individuals with chronic pulmonary sarcoidosis require an alternative therapy to corticosteroidal treatment because of its insufficient effectiveness. Although many researchers have considered infection as the triggering factor for this disease, the mechanisms by which the candidate causative organisms induce this disorder remain unclear. We report here that extrapulmonary sensitization to Propionibacterium acnes, which is one of the candidates to date, induced pulmonary Th-1 granulomas mainly in the subpleural and peribronchovascular regions often observed in sarcoidosis. These granulomas appear to be caused by indigenous P. acnes pre-existing in the lower respiratory tract of the normal lung, which is believed to be germ-free, and by an influx of P. acnes-sensitized CD4(+) T cells from the circulation. Importantly, the eradication of indigenous P. acnes with antibiotics alleviated the granulomatous lung disease. This is the first report to present clear evidence of the contribution of an indigenous pulmonary bacterium to the formation of granulomatous lesions in the lung. We propose that treatment targeting indigenous P. acnes in the lung may be a possible remedy for pulmonary sarcoidosis.

Suppression of a DNA double-strand break repair gene, Ku70, increases radio- and chemosensitivity in a human lung carcinoma cell line.

Ku70 protein, cooperating with Ku80 and DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs), is involved in DNA double-strand break (DNA DSB) repair and V(D)J recombination. Recent studies have revealed increased ionizing radiosensitivity in Ku70-deficient cells. The presented study, using a human squamous cell lung carcinoma cell line, demonstrated that introduction of an antisense Ku70 nucleic acid made the cells more radio- and chemosensitive than the parental cells. Ku70 protein expression was suppressed in the cells with antisense Ku70 construct when compared to the wild-type cells. A relatively small but statistically significant increase in radiosensitivity of the cells was achieved by the introduction of the antisense Ku70. The increased radiosensitivity in vitro was accompanied by an approximately two-fold increase in alpha and alpha/beta values in a linear-quadratic model. The antisense Ku70 increased the chemosensitivity of the cells to some DNA-damaging agents such as bleomycin and methyl methanesulfonate, but not to cisplatin, mitomycin C, and paclitaxel. This system provides us with partial suppression of Ku70, and will be a useful experimental model for investigating the physiological roles of the DNA DSB repair gene.

Nasal continuous positive airway pressure improves quality of life in obesity hypoventilation syndrome.

We studied the quality of life of obesity hypoventilation syndrome (OHS) by comparing it with age- and body mass index-matched patients without hypoventilation and age-matched obstructive sleep apnea (OSA) patients with body mass index (BMI) under 30, and the efficacy of nasal continuous positive airway pressure (CPAP) therapy for 3 to 6 months on the quality of life in these patients. Prospectively recruited patients from six sleep laboratories in Japan were administered assessments of the general health status by the Short-Form 36 Health Survey (SF-36) and subjective sleepiness by the Epworth Sleepiness Scale (ESS). Compared with matched healthy subjects, OHS and OSA patients not yet treated had worse results on the ESS scores and the SF-36 subscales for physical functioning, role limitations due to physical problems, general health perception, energy/vitality, role limitations due to emotional problems, and social functioning. The ESS scores of OHS patients were worse than those of the OSA groups including the age- and BMI-matched OSA patients. In the SF-36 subscales of OHS patients, only the subscale of social functioning showed worse results compared with that of BMI-matched OSA patients. After 3 to 6 months of treatment, ESS scores and these SF-36 subscales in all three patient groups improved to the normal level. These results suggested that the quality of life of OHS before nasal CPAP was significantly impaired and that nasal CPAP for OHS improved the quality of life associated with the improvement of daytime sleepiness to the level of the other OSA patients.

Consensus statement for the diagnosis and treatment of drug-induced lung injuries.

Keishi Kubo, Arata Azuma, Minoru Kanazawa, Hideto Kameda, Masahiko Kusumoto, Akihiko Genma, Yasuo Saijo, Fumikazu Sakai, Yukihiko Sugiyama, Koichiro Tatsumi, Makoto Dohi, Hitoshi Tokuda, Shu Hashimoto, Noboru Hattori, Masayuki Hanaoka, Yuh Fukuda, the Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries Nagano Prefectural Hospital Organization, Japan Division of Pulmonary Medicine, Infections Diseases, and Oncology, Department of Internal Medicine, Nippon Medical School, Japan Department of Respiratory Medicine, Saitama Medical University, Japan Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Japan Department of Diagnostic Radiology, National Cancer Center Hospital, Japan Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Japan Department of Diagnostic Radiology, Saitama International Medical Center, Saitama Medical University, Japan Division of Pulmonary Medicine, Department of Internal Medicine, Jichi Medical University, Japan Department of Respirology, Chiba University Graduate School of Medicine, Japan Department of Allergy and Rheumatology, Tokyo University Graduate School of Medicine, Japan Department of Respiratory Medicine, Social Insurance Central General Hospital, Japan Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Japan Department of Molecular and Internal Medicine, Hiroshima University Graduate School of Biomedical & Health Sciences, Japan Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Japan