Toshio Ichiwata

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.

Cancer-associated retinopathy with presumed vasculitis.

PURPOSE To treat a 63-year-old woman who experienced fairly rapid vision loss in association with small-cell carcinoma of the lung. METHODS She underwent a full ophthalmologic examination, including fluorescein angiography and an immunologic study by Western blot analysis. RESULTS Fluorescein angiography demonstrated diffuse staining of the retinal vessels. She had 62-kd antiretinal antibody in her serum. Cancer-associated retinopathy was diagnosed. CONCLUSION The staining seen on the angiogram appears to indicate vasculitis, which would cause the characteristic attenuation of retinal vessels in this disease.

Clinical features of secondary pulmonary alveolar proteinosis: pre-mortem cases in Japan

To the Editors: Pulmonary alveolar proteinosis (PAP) is a rare syndrome that predominantly affects the lungs, and is characterised by the accumulation of surfactant lipids and proteins in the alveoli and terminal airways 1. In 1999, we published findings that high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralising autoantibodies were detected specifically in patients with idiopathic PAP 2. Recently, as a result of the excellent sensitivity and specificity of GM-CSF autoantibody assays in identifying this form of PAP 3, it has been proposed that the nomenclature for this condition should be changed to “autoimmune PAP” rather than “idiopathic PAP” 4. Secondary or hereditary PAP is not associated with GM-CSF autoantibodies but develops as a consequence of a separate underlying disorder or genetic background 5. Recently, we demonstrated that the characteristic high-resolution computed tomography (HRCT) findings in secondary PAP are distinct from those in autoimmune PAP 6. However, physicians may not suspect secondary PAP, even when encountering unexplained pulmonary opacities on chest radiograph or computed tomography in patients with pre-existing haematological or infectious diseases, since there is little information available on the clinical features. Here, we outline the clinical features of adult-onset secondary PAP based on our database of 40 pre-mortem cases in which serum GM-CSF autoantibodies were negative, and compare them with other cases in the literature. A total of 404 patients with pre-mortem cytologically or pathologically proven PAP were registered in our study group between 1999 and 2009. We obtained consent from all treating physicians for each identified case according to the guidelines for epidemiological studies from the Ministry of Health, Labour and Welfare 7, and all clinical data were de-identified. 360 (89%) cases were positive for serum GM-CSF autoantibody. The clinical features of 223 of the cases were previously published as …

Duration of Benefit in Patients With Autoimmune Pulmonary Alveolar Proteinosis After Inhaled Granulocyte-Macrophage Colony-Stimulating Factor Therapy

BACKGROUND Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized. METHODS To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy. RESULTS During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P<.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC≥80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P<.0005). CONCLUSIONS These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence. TRIAL REGISTRY ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp.

Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan

BackgroundSecondary pulmonary alveolar proteinosis (sPAP) is a very rare lung disorder comprising approximately 10% of cases of acquired PAP. Hematological disorders are the most common underlying conditions of sPAP, of which 74% of cases demonstrate myelodysplastic syndrome (MDS). However, the impact of sPAP on the prognosis of underlying MDS remains unknown. The purpose of this study was to evaluate whether development of sPAP worsens the prognosis of MDS.MethodsThirty-one cases of sPAP and underlying MDS were retrospectively classified into mild and severe cases consisting of very low-/low-risk groups and intermediate-/high-/very high-risk groups at the time of diagnosis of MDS, according to the prognostic scoring system based on the World Health Organization classification. Next, we compared the characteristics, disease duration, cumulative survival, and prognostic factors of the groups.ResultsIn contrast to previous reports on the prognosis of MDS, we found that the cumulative survival probability for mild MDS patients was similar to that in severe MDS patients. This is likely due to the poor prognosis of patients with mild MDS, whose 2-year survival rate was 46.2%. Notably, 75% and 62.5% of patients who died developed fatal infectious diseases and exacerbation of PAP, respectively, suggesting that the progression of PAP per se and/or PAP-associated infection contributed to poor prognosis. The use of corticosteroid therapy and a diffusing capacity of the lung for carbon monoxide of less than 44% were predictive of poor prognosis.ConclusionDevelopment of sPAP during the course of MDS may be an important adverse risk factor in prognosis of patients with mild MDS.

Viral Infection in Asthma

In bronchial asthma, respiratory virus infection involves several issues: 1) respiratory virus infection in infancy is a risk factor for, and may predispose to, the development of asthma later in life; 2) respiratory virus infection is associated with the acute exacerbation of bronchial asthma; and, 3) glucocorticosteroids (GC) are not adequate for controlling asthma-related symptoms upon respiratory virus infection. Various cells, inflammatory mediators and cytokines participate in the production of airway inflammation upon respiratory virus infection. Bronchial epithelial cells are a site of infection and replication of respiratory virus. They actively participate in the production of airway inflammation: 1) they produce various proinflammatory cytokines, chemokines and mediators; and, 2) they undergo apoptosis, thereby impairing the repair process. It is therefore important to understand the role of bronchial epithelial cells in the pathophysiology of bronchial asthma. In this review, the interaction between viral infection and asthma is discussed to elucidate the role of bronchial epithelial cells in viral infection.

Analysis of gene expression in human bronchial epithelial cells upon influenza virus infection and regulation by p38 mitogen-activated protein kinase and c-Jun-N-terminal kinase

Background and objective:  Airway epithelial cells, which are the initial site of influenza virus (IV) infection, participate in the inflammatory process through the expression of various genes. In this process, mitogen‐activated protein kinase (MAPK) may be associated with the expression of many genes, but its precise role remains unknown.

Pulmonary alveolar proteinosis in a patient with Behcet's disease

Secondary pulmonary alveolar proteinosis (PAP) has been described in several clinical settings that can be grouped into three main categories: infections of the lung; haematological malignancies and other conditions that alter the patients immune status; and exposure to inhaled chemicals and minerals. Recent studies reported that anti‐granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) antibody was present in the serum of patients with idiopathic PAP but not in patients with secondary PAP or in normal subjects. The present report describes the interesting case of a patient with Behcets disease and PAP. The absence of anti‐GM‐CSF antibodies in this patient suggested a diagnosis of secondary PAP.

Bench study of auto-CPAP devices using a collapsible upper airway model with upstream resistance.

The aim of this study was to investigate the response of auto-CPAP devices to respiratory events (apnea, hypopnea, flow-limitation and snoring) on the same condition using a physiological upper airway model. The hypothesis of this study is that collapsibility of the flow-limiting collapsible segment of the airway is influenced by the upstream airway resistance. Five auto-CPAP devices, AutoSet T, AutoSet Spirit, Goodnight 420E, PV10i and REMstar Auto were evaluated. Apnea: all the devices increased the auto-CPAP level, while AutoSet T and AutoSet Spirit did not respond to apnea for 30s. Hypopnea: all the devices except the AutoSet T and Goodnight 420E increased pressure. Flow-limitation: all the devices except the PV10i and REMstar Auto increased pressure. Snoring: the snoring sounds disappeared when REMstar Auto and PV10i were used, and the Goodnight 420E lowered the level of snoring. In conclusion, the response of auto-CPAP devices to respiratory events differed. Collapsible upper airway model with upstream resistance is useful for the first-step assessment of auto-CPAP devices.

IgM-type GM-CSF autoantibody is etiologically a bystander but associated with IgG-type autoantibody production in autoimmune pulmonary alveolar proteinosis

The granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody (GMAb) is the causative agent underlying autoimmune pulmonary alveolar proteinosis (aPAP). It consists primarily of the IgG isotype. At present, information on other isotypes of the autoantibody is limited. We detected serum the IgM isotype of GMAb (IgM-GMAb) in more than 80% of patients with aPAP and 22% of healthy subjects, suggesting that a continuous antigen pressure may be present in most patients. Levels of the IgM isotype were weakly correlated with IgG-GMAb levels but not IgA-GMAb, suggesting that its production may be associated with that of IgG-GMAb. The mean binding avidity to GM-CSF of the IgM isotype was 100-fold lower than the IgG-GMAb isotype, whereas the IC(50) value for neutralizing capacity was 20,000-fold higher than that of IgG-GMAb, indicating that IgM-GMAb is only a very weak neutralizer of GM-CSF. In bronchoalveolar lavage fluid from nine patients, IgG-GMAb was consistently detected, but IgM-GMAb was under the detection limit in most patients, confirming that IgM-GMAb is functionally a bystander in the pathogenesis of aPAP. It rather may be involved in the mechanism for development of IgG-GMAb in vivo.