Nobuharu Ohshima

Regulation of human B cell function by sulfasalazine and its metabolites

Although sulfasalazine is a well-known disease-modifying antirheumatic drug (DMARD), the mechanisms of its action remain unclear. Indeed, it remains uncertain whether sulfasalazine itself or one of its metabolites is responsible for the antirheumatic effects of sulfasalazine. Since one of the characteristic features of rheumatoid arthritis (RA) is chronic stimulation of B cells, we compared the effects of sulfasalazine and its metabolites on the in vitro function of human B cells. Ig production was induced from highly purified B cells from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus IL-2. Sulfasalazine suppressed the production of IgM and IgG at its pharmacologically attainable concentrations (1-10 microg/ml). Of the metabolites of sulfasalazine, sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA), but not 4-acethyl SP, also significantly suppressed the production of IgM and IgG at their pharmacologically relevant concentrations. By contrast, any of sulfasalazine, SP, 5-ASA and 4-acethyl SP did not suppress the IFN-gamma production of immobilized anti-CD3 stimulated CD4+ T cells. These results indicate that sulfasalazine and its metabolites preferentially suppress the function of B cells, but not that of T cells, at their pharmacologically attainable concentrations. The data therefore suggest that not only sulfasalazine, but its metabolites, might contribute to the beneficial effects of sulfasalazine.

Sustained functional serotype-specific antibody after primary and secondary vaccinations with a pneumococcal polysaccharide vaccine in elderly patients with chronic lung disease.

An observational study was conducted to determine immunogenicity before and after primary and secondary vaccinations with 23-valent pneumococcal polysaccharide vaccine in a cohort of 40 elderly patients with chronic lung diseases. Safety of this vaccine was also compared between primary and secondary vaccination. We analyzed serotype-specific immunoglobulin G (IgG) and the opsonization index (OI) for serotypes 6B, 14, 19F, and 23F and compared adverse local and systemic reactions. The levels of serotype-specific IgG and the OIs significantly increased 1 month after primary and secondary vaccinations. Peak levels of IgG after secondary vaccination were 5-20% lower than those after primary vaccination, while serotype-specific OIs after secondary vaccination were comparable with those after primary vaccination. The levels of serotype-specific IgG required for 50% killing significantly decreased 1 month after vaccination. These values for serotypes 14, 19F, and 23F were slightly elevated immediately before secondary vaccination, but those for serotype 6B did not change. After secondary vaccination, these values declined slightly for serotypes 14, 19F, and 23F and remained low for serotype 6B. Although self-limited local and systemic reactions were more frequent after secondary vaccination compared with primary vaccination, no serious systemic reaction was found after either vaccination. Our data suggest a sustained functional serotype-specific IgG after primary and secondary vaccination and confirmed the safety of secondary vaccination among elderly individuals with chronic lung disease.

Recurrence of chronic pulmonary aspergillosis after discontinuation of maintenance treatment by antifungal triazoles.

OBJECTIVE To assess the prevalence and risk factors of recurrence of chronic pulmonary aspergillosis (CPA) after discontinuation of antifungal triazoles. METHOD We reviewed the medical records of CPA patients who achieved resolution of clinical and radiographic manifestations and stopped taking antifungal triazoles between June 2006 and June 2012 at Tokyo National Hospital. We evaluated whether there was CPA recurrence within 1 year after treatment cessation and investigated risk factors for relapse. The association of anti-Aspergillus antibody conversion with CPA recurrence was also reviewed. RESULTS A total of 39 patients were included in this study and there was CPA recurrence in 14 patients. Compared with the Non-recurrence group, the Recurrence group exhibited 1) younger age (p = 0.017), 2) more than one lung lobe affected by CPA more frequently (p = 0.008), 3) longer duration needed to remit manifestations of chest radiograph (p = 0.031), 4) longer antifungal treatment duration (p = 0.042). The present study did not reveal an association between negative conversion of serum anti-Aspergillus antibody and recurrence risk. Multivariate logistic regression analysis revealed that patients with CPA with affected area of more than one lung lobe had increased risk (odds ratio, 10.20; 95% confidence interval, 1.49-69.77; p = 0.018). CONCLUSION CPA recurrence can be seen in about one-third of cases after discontinuing azole treatment. We should make decisions about treatment duration and follow up depending on the severity of each case, particularly on the expansion of CPA-affected area.

Addition of Leukotriene Receptor Antagonists to Inhaled Corticosteroids Improved QOL of Patients with Bronchial Asthma Surveyed in Suburban Tokyo, Japan

BACKGROUND Bronchial asthma is a chronic inflammatory disease that has a severe impact on health worldwide. METHODS A survey of 10,771 patients with bronchial asthma in the Tama region, Tokyo was conducted for 5 years to examine treatment and quality of life (QOL). Subjects were patients aged ≥ 16 years and their physicians who replied to a questionnaire sent in November from 2002 to 2006. Symptoms of bronchial asthma, visits to an emergency room, use of drugs, and severity of asthma were investigated. RESULTS Asthmatic symptoms improved over the 5 years, with a reduction in the number of emergency room visits. Since inhaled corticosteroids (ICS) were used by >80% of patients in 2002, we suspected that increased use of concomitant leukotriene receptor antagonists (LTRA) and long-acting β(2) agonists (LABA) might have contributed to these findings. The effects of these drugs were compared between ICS + LTRA (n = 45) and ICS + LABA (n = 54) groups of patients. There was no significant difference in the ICS dose between these groups. In the ICS + LABA group, 18.5% and 22.2% of patients visited an emergency room before and after initiation of combination therapy, respectively, with no statistically significant difference. In contrast, the rate of emergency room visits in the ICS + LTRA group decreased from 24.4% to 6.6% after addition of LTRA. CONCLUSIONS These results suggest that the frequency of visits to an emergency room was decreased by complementing the anti-inflammatory effect of ICS with further treatment of inflammation, particularly with LTRA.

Bronchial artery embolization to control hemoptysis in patients with Mycobacterium avium complex.

BACKGROUND Hemoptysis frequently develops in patients with Mycobacterium avium complex (MAC) pulmonary disease. Bronchial artery embolization (BAE) has been established as one of the useful treatments of massive and persistent hemoptysis. We evaluated the efficacy and safety of BAE for controlling hemoptysis in MAC patients, and identified the risk factors of rebleeding after BAE. METHODS Among the 529 patients with MAC who were admitted to our institution from January 2007 to December 2012, we retrospectively reviewed the demographic data, imaging, sputum, and angiographic findings, and the clinical course of 43 patients who underwent BAE using coils, due to hemoptysis. RESULTS Among the 43 patients enrolled in the study, rebleeding developed in 13 cases (30.2%) with a mean follow-up period of 18 months. Median rebleeding-free time after BAE was 29.9 months and the cumulative hemoptysis control rates were 79.1%, 73.8%, and 63.3% in one, two, and three years, respectively. Rebleeding-free time significantly correlated with comorbid chronic pulmonary aspergillosis (CPA). When limited to 35 MAC patients without CPA, the rate increased to 88.6%, 82.1%, and 70.4%, respectively. Factors such as coexisting CPA, multiple embolized vessels at BAE, longer length of time from the diagnosis of MAC to BAE, and an administration of antibiotics for MAC at the time of hemoptysis, indicated statistically significant correlations with rebleeding. Major complications concerning BAE were not encountered. CONCLUSIONS BAE using coils is an effective and safe method for controlling hemoptysis in patients with MAC pulmonary disease. However, it is important to carefully observe patients with risk factors for rebleeding after BAE.

Clinical and Angiographic Characteristics of 35 Patients With Cryptogenic Hemoptysis

BACKGROUND: Hemoptysis can cause a life‐threatening condition and often needs to be treated urgently. Nearly 20% of hemoptysis cases are diagnosed as cryptogenic after clinical investigation. The purpose of this study was to clarify the clinical and angiographic characteristics of cryptogenic hemoptysis. METHODS: We retrospectively reviewed medical records of 35 patients admitted to our hospital with cryptogenic hemoptysis from October 2010 to September 2014. RESULTS: In the 35 cases, bronchial artery embolization was successfully performed in 33 patients (94.3%), whereas bronchoscopic hemostatic therapy was added in one patient (2.8%), and embolization was not performed in one patient (2.8%) because the bronchial artery was too narrow. In the successful embolization group, the non‐rebleeding rate was 97.0% for 20 months. The angiographic findings revealed that the diameter of the bronchial arteries was < 2 mm in 13 patients, 2 to 3 mm in 17 patients, and > 3 mm in five patients. Hypervascularization was detected in 29 patients (82.9%) and small bronchial aneurysms in eight patients (22.9%). The amount of hemoptysis was slight (< 50 mL/d) in 12, mild (50–100 mL/d) in 11, moderate (100–200 mL/d) in eight, and massive (> 200 mL/d) in four patients. No obvious relationship was found between the diameter of bronchial arteries and the amount of hemoptysis. CONCLUSIONS: BAE was highly effective for the management of cryptogenic hemoptysis. Most cases of cryptogenic hemoptysis have angiographic abnormalities, including small or microaneurysms, which were suspected as the cause in some cases.

An autopsy case of unicentric Castleman’s disease associated with bronchiolitis obliterans

A 34‐year‐old woman visited the hospital suffering from enanthema of the tongue, hair loss, and nonproductive cough. Corticosteroid administration slightly resolved the enanthema and hair loss, but not the nonproductive cough. She was transferred to another hospital for the resection of a retroperitoneal mass, which was histopathologically diagnosed as unicentric, hyaline vascular type Castlemans disease. She was then referred to our hospital due to progressive dyspnea and was diagnosed as having bronchiolitis obliterans based on computed tomography scan findings and a lung function test, while paraneoplastic pemphigus was clinically considered for her enanthema. After her death from respiratory failure in spite of corticosteroid administration, autopsy confirmed constrictive bronchiolitis in the lung. Mucocutaneous lesions, clinically considered as paraneoplastic pemphigus, were histologically different from pemphigus. The constrictive bronchiolitis and other pathological findings, including nonviral chronic hepatitis and interstitial nephritis, confirmed the diagnosis of paraneoplastic autoimmune multiorgan syndrome associated with the Castlemans disease.

Clinical Features and Prognosis of Nontuberculous Mycobacterial Pleuritis

Background: While nontuberculous mycobacterial (NTM) pleuritis rarely complicates pulmonary NTM infection, high mortality has been reported in case reports and small studies. Objectives: The purpose of this study was to clarify the clinical features and treatment outcomes of pulmonary NTM infection cases accompanied by NTM pleuritis. Methods: Medical records of 1,044 patients with pulmonary NTM disease were retrospectively reviewed to select patients complicated by NTM-proven pleuritis. We investigated clinical characteristics, pathogens, pleural effusion examinations, radiographic findings, treatments, and clinical course of the NTM pleuritis patients. Results: Among 1,044 cases with pulmonary NTM, NTM pleuritis occurred in 15 cases (1.4%). The mean age was 69 years with a performance status of mostly 2 or better (80.0%), and 6 cases (40.0%) were complicated by pneumothorax. Subpleural cavities were radiologically detected in 11 cases (73.3%), and extrapulmonary air-fluid level was detected in 14 cases (93.3%). Eleven patients were treated with combinations of 2–4 antimycobacterial drugs, including clarithromycin, and 2 patients were treated with isoniazid, rifampicin, and ethambutol. Chest tube drainage was performed in 11 cases, and surgical approach was added in 6 cases. The pleural effusion of 2 patients treated with only antimycobacterial medications gradually deteriorated. Two patients died from NTM pleuritis, and 1 patient died from pneumonitis during a mean of 1.8 years of follow-up. Conclusions: Comorbid NTM pleuritis was difficult to treat by medical therapy alone and resulted in a poor prognosis. In addition to antimycobacterial agents, chest tube drainage and surgical procedures in the early stages should be considered to treat NTM pleuritis.

An HIV-positive Case of Obstructive Jaundice Caused by Immune Reconstitution Inflammatory Syndrome of Tuberculous Lymphadenitis Successfully Treated with Corticosteroids

A 60-year-old man was admitted to our hospital because of a persistent fever with enlargement of multiple lymph nodes in the mediastinum and around the pancreatic head. He was diagnosed with tuberculosis and human immunodeficiency virus infection. We started antiretroviral therapy three weeks after the initiation of anti-tuberculous therapy. Two weeks later, jaundice appeared with dilatation of the biliary tract due to further enlargement of the lymph nodes, which seemed to be immune reconstitution inflammatory syndrome (IRIS). The administration of corticosteroids resolved the obstructive jaundice without surgical treatment or endoscopic drainage. Obstructive jaundice caused by IRIS should first be treated with corticosteroids before invasive treatment.

Sudden Death in a Patient with Pulmonary Veno-occlusive Disease (PVOD) and Severe Pulmonary Hypertension

A 58-year-old woman was referred to our hospital with a chief complaint of exertional dyspnea. Bronchoscopy failed to establish a diagnosis, and the patient subsequently died suddenly due to respiratory insufficiency because of advanced pulmonary hypertension (PH). The pathological diagnosis at autopsy was pulmonary veno-occlusive disease (PVOD). PVOD is difficult to diagnose antemortem and has a poor prognosis. Lung transplantation is the only curative treatment for PVOD.