Search

A 63-year-old man employed in a hard metal manufacturing company for 40 years presented with a chronic dry cough and exertional dyspnea 20 years after the onset of recurrent exanthemas. A chest radiograph revealed bilateral reticular shadows in the upper lung field. Pathological specimens in which tungsten was detected were obtained via a transbronchial lung biopsy. Patch tests were positive for cobalt and other metals. The patient was diagnosed with hard metal lung disease (HMLD) concurrent with contact dermatitis and treated with corticosteroids. This case suggests that allergies to metal may play a role in the onset of HMLD.

Pulmonary Mycobacterium abscessus infection is resistant to many antibiotics and is difficult to treat. We retrospectively analyzed the clinical characteristics of pulmonary infection due to M. abscessus. Eleven cases diagnosed as having pulmonary M. abscessus infection at Osaka Red Cross Hospital from January. 2008, to June, 2012 were enrolled in this study. The average age of the 11 cases was 63 years (all were females). Nine cases showed underlying diseases, comprising 5 cases with Mycobacterium avium complex lung infection, 3 with old pulmonary tuberculosis, and 3 with bronchiectasis. The radiological examination revealed that 10 cases showed the small nodular type, 7 showed the bronchiectatic type, 4 showed a cavity lesion and 4 showed infiltrative shadows. A microbiological definite diagnosis was made from sputum in 10 cases and bronchial lavage fluid in one. As treatment for M. abscessus pulmonary infection, combined multi-drug chemotherapy was carried out in 7 of the 11 cases. No patients were successfully treated with antibiotics alone, whereas 4 patients had no exacerbation of radiological findings without any treatment. One patient received antibiotics including clarithromycin, amikacin and levofloxacin for 2 to 12 months following surgical excision and her sputum cultures have been maintained as negative over the long-term. During the study, none of the 11 patients were known to have died. In this study, we found that M. abscessus pulmonary infection is more common among females, and is found frequently in patients with M. avium complex lung infection. We also found that the clinical course of M. abscessus pulmonary infection was different among patients. We think this is because M. abscessus was shown to comprise three closely related species. M. abscessus is extremely difficult to eradicate, and surgical resection of localized disease or the main lesion or cavity may be significantly effective in preventing the progression of disease.

Aspergillosis has been the prevailing deep-seated mycosis in Japan since the 1990s. Although micafungin (MCFG) has been approved in Japan for the management of patients with such infections caused by Candida and Aspergillus species, there are relatively few reports on its use in patients with chronic pulmonary aspergillosis (CPA). Therefore, we conducted a prospective observational study to evaluate the efficacy and safety of the use of MCFG in Japanese patients with CPA. The efficacy of the antifungal was assessed on the basis of improvements in clinical symptoms and radiological findings. In addition, adverse events, including abnormal laboratory findings were determined. The overall clinical efficacy rate was 68.4% (26/38 patients), which is comparable to the results obtained in clinical trials for marketing approval conducted in Japan. Although adverse drug reactions were observed in six patients (15.8%), they were not serious. The most common of these reactions was abnormal liver functions. No relationship between the incidence of adverse drug reactions and age of the patients, MCFG dose, or duration of treatment was observed. Consequently, MCFG has favorable efficacy and safety profiles in Japanese CPA patients with various backgrounds., Medical Mycology, 49(7), pp.688-693; 2011

Sensitization to Trichophyton, a major dermatophyte, has been associated with asthma. Whether such sensitization is generally associated with the severity of asthma, like other molds such as Alternaria, is unknown.We compared 258 patients with asthma, which was classified by severity as mild (n = 123), moderate (101), or severe (34), and 114 healthy control subjects, with regard to specific IgE titers against Trichophyton rubrum and other common allergens such as mixed molds, house-dust mite, cat dander, dog dander, Japanese cedar pollen, mixed Graminea pollens and mixed weed pollens.Positive rate of Trichophyton-specific IgE was higher in the patients with moderate asthma (15.8%) than in the control subjects (7.0%, p = 0.04) and patients with mild asthma (4.9%, p0.006), and it was also higher in the patients with severe asthma (32.4%) than in control subjects (p = 0.0001), and patients with mild asthma (p0.0001) and moderate asthma (p = 0.04), but it did not differ between the control subjects and patients with mild asthma. The positive rates of mixed molds, cat dander, and dog dander were almost invariably higher in patients in all asthma subgroups than in the control subjects but did not differ among patients in the three asthma subgroups. The positive rates of other allergens were not different in all groups. Reanalysis of positive rate of Trichophyton-specific IgE after excluding 52 subjects with positive results for mixed molds showed a similar statistical trend to that of the original cohort. This may negate the potential effect of cross-reactivity to these molds. Multivariate analysis of asthma subgroups identified positive IgE results for Trichophyton as an independent determinant of asthma severity.Specific IgE response to Trichophyton may be associated with more severe asthma.

非結核性抗酸菌症とりわけ中高年女性に好発するM. avium complex症の近年の増加が著しく,結核専門病院のみならず一般総合病院の呼吸器外来でも日常的に経験する感染症の一つになっている.結核菌とは異なりヒト・ヒト感染は起こさないため社会生活には何ら制約を生じないものの, M. kmsasoii症など一部を除いてM. avium complex症をはじめとする多くの非結核性抗酸菌症は難治性である.従来からの抗結核薬に加えて新たなマクロライドやニューキノロンの併用が行われているが,さらに新たな有効薬剤の開発が切望されている.

Background: Chronic eosinophilic pneumonia (CEP) is highly sensitive to systemic corticosteroids, but frequently relapses if the dose is tapered or treatment discontinued. Long-term usage of systemic corticosteroids may cause side effects. Alternative treatments are therefore desired. Objectives: We evaluated the response of CEP to monotherapy with inhaled corticosteroids (ICS). Methods: Four patients who had CEP without spontaneous resolution were studied. Patients received inhaled beclomethasone dipropionate (BDP) at a dose of 0.8 mg/day in 1 patient and 1.6 mg/day in 3 patients for 2 weeks. Treatment was continued if a patient showed improvement in at least 1 of the following indices: radiological findings, symptoms, and blood eosinophilia. Results: After the initial 2 weeks of treatment with BDP, the blood eosinophil count increased in 2 patients and decreased in 2. Symptoms worsened in 2 and improved in 2. Infiltrates on chest radiography increased in 3 and showed little change in 1. In the 2 patients with worsening of all 3 outcome indices, oral prednisolone was started; the indices improved. In the remaining 2 patients, BDP alone was continued. One patient had worsening of CEP after 2 months of treatment, and another had relapse of CEP at 3.5 years while receiving 1.6 mg/day of BDP. All patients thus finally had worsening or relapse of CEP during treatment with BDP. Conclusions: ICS may not be effective when given as monotherapy in patients with CEP.

Pulmonary Mycobacterium abscessus infection is resistant to many antibiotics and is difficult to treat. We retrospectively analyzed the clinical characteristics of pulmonary infection due to M. abscessus. Eleven cases diagnosed as having pulmonary M. abscessus infection at Osaka Red Cross Hospital from January. 2008, to June, 2012 were enrolled in this study. The average age of the 11 cases was 63 years (all were females). Nine cases showed underlying diseases, comprising 5 cases with Mycobacterium avium complex lung infection, 3 with old pulmonary tuberculosis, and 3 with bronchiectasis. The radiological examination revealed that 10 cases showed the small nodular type, 7 showed the bronchiectatic type, 4 showed a cavity lesion and 4 showed infiltrative shadows. A microbiological definite diagnosis was made from sputum in 10 cases and bronchial lavage fluid in one. As treatment for M. abscessus pulmonary infection, combined multi-drug chemotherapy was carried out in 7 of the 11 cases. No patients were successfully treated with antibiotics alone, whereas 4 patients had no exacerbation of radiological findings without any treatment. One patient received antibiotics including clarithromycin, amikacin and levofloxacin for 2 to 12 months following surgical excision and her sputum cultures have been maintained as negative over the long-term. During the study, none of the 11 patients were known to have died. In this study, we found that M. abscessus pulmonary infection is more common among females, and is found frequently in patients with M. avium complex lung infection. We also found that the clinical course of M. abscessus pulmonary infection was different among patients. We think this is because M. abscessus was shown to comprise three closely related species. M. abscessus is extremely difficult to eradicate, and surgical resection of localized disease or the main lesion or cavity may be significantly effective in preventing the progression of disease.

SummaryThe purpose of the present study was to elucidate the role of oestrogen in the pathogenesis of Mycobacterium avium complex (MAC) pulmonary disease, which occurs most frequently in postmenopausal women. The study was carried out in a murine infectious model using ovariectomized DBA/2 female mice. Infection with MAC was established by intratracheal administration of bacilli. In some experiments, ovariectomized mice were treated with exogenous 17β-estradiol (E2). The number of bacilli in the lungs of infected mice which received ovariectomy was significantly larger than that in the lungs of sham-operated control mice, and treatment of ovariectomized mice with exogenous E2 restored the burden of bacilli to the same level as that in the sham-operated control mice. We next examined the effect of E2 in vitro using bone marrow-derived macrophages obtained from DBA/2 female mice. The macrophages showed bacteriostatic activity against MAC after treatment with interferon-gamma (IFN-γ) and this activity was further enhanced by the exogenous addition of E2 to the culture medium. In parallel with these findings, E2 augmented the production of reactive nitrogen intermediates (RNI) by macrophages pretreated with IFN-γ and stimulated with MAC, as shown by evaluating nitrite production and inducible nitric oxide synthase mRNA expression. These findings taken together suggest that absence of endogenous oestrogen appears to be responsible for the development of MAC pulmonary disease in this mouse model and that the enhancement by E2 of anti-MAC activity of murine macrophages induced through increased RNI production may play some role in resistance to MAC infection.

We have investigated the efficacy of a clarithromycin-containing four-drug regimen for Mycobacterium avium complex (MAC) pulmonary disease in 46 patients without acquired immunodeficiency syndrome (AIDS). The patients were 14 males and 32 females with a mean age of 60.9 +/- 11.5 yr. Patients received 10 mg/kg/d of clarithromycin plus ethambutol, rifampin, and initial kanamycin and subsequent quinolone for 24 mo. Seven patients (15.2%) were dropped in the first 6 mo. Among 39 patients who received more than 6 mo of therapy, 28 patients (71.8%) converted their sputa to negative: 26 of 31 patients (83.9%) infected with clarithromycin-susceptible strains and two of eight patients (25.0%) with resistant or intermediate strains. The timing of sputum conversion was 3.6 +/- 1.9 mo, with a range of 2 to 9 mo. The conversion rate was significantly lower in patients who were infected with clarithromycin-resistant or intermediate strains, who had had prior therapy (55.0% versus 89.5%), or who were acid-fast bacilli (AFB) smear-positive at entry (60.7% versus 100%). The age and sex of patients, the species of pathogen (M. avium or M. intracellulare), type and extent of the disease, and the use of kanamycin did not significantly affect the conversion rate. Although the regimen was efficacious for newly treated patients, frequent adverse reactions and a low conversion rate of sputum in retreated patients are problems that remain to be solved.

BACKGROUND—Aspergillus fumigatus can colonise the airways and the lungs with localised underlying conditions and occasionally invade the surrounding lung tissues even in subjects without systemic predisposing factors, presumably by escaping the local host defences. The aim of this study was to investigate the effects of A fumigatus culture filtrate (ACF) on the activities of human phagocytes—inhibition of germination of A fumigatus spores by alveolar macrophages (AMs) and hyphal damage by polymorphonuclear leucocytes (PMNs)—which are the critical host defences against A fumigatus. METHODS—Spores were incubated with AMs at a ratio of 1:1 in a medium containing different concentrations of ACF for 10 hours at 37°C. Spore germination was visualised with light microscopy and the inhibition rate was calculated. The percentage of hyphal damage caused by PMNs pretreated with various concentrations of ACF was measured by a colorimetric tetrazolium metabolic assay. RESULTS—The inhibition rate of spore germination by AMs cultured with medium alone (control) was 90 (0.8)% whereas that by AMs cultured with the medium containing 10% ACF was significantly (p

BACKGROUND—Diffuse panbronchiolitis (DPB), characterised by progressive sinobronchial sepsis, is well characterised in Japanese subjects but not in other ethnic groups. The experience with DPB in seven Chinese patients is described and the clinical profiles compared with those of Japanese subjects. METHODS—Seven Chinese patients (three women; mean (SD) age 48(18.6) years, all never smokers) who attended a teaching hospital centre and fulfilled the diagnostic criteria for DPB were assessed prospectively for clinical, radiological, lung function, microbiological, and other "characteristic" laboratory parameters. RESULTS—Lung function assessment showed a typical obstructive pattern (n = 5) and air trapping (n = 7). Typical bronchiolar infiltration by lymphocytes and plasma cells and accumulation of foamy macrophages in the intraluminal tissue were detected in open lung biopsy specimens (n = 2). Chest radiographs and high resolution computed tomographic scans revealed hyperinflation, diffuse nodules, bronchial thickening and dilatation, peripheral hypoattenuation, and bronchiolectasis. Radiological improvement, manifest as a reduction in nodular density and bronchial thickening, and persistence of other abnormalities such as air trapping were not accurately depicted by the classical Nakata or Akira classifications. The other "characteristic" features such as HLA-B54, IgG subclass deficiency, raised CD4/CD8 T lymphocyte ratio, cold haemagglutinaemia, raised IgA, IgG, and rheumatoid factor were not present. Treatment with erythromycin led to excellent responses in symptoms, lung function indices, and the radiological picture. A review of the non-Japanese cases in the literature reveals that this absence of typical "additional features" in DPB might also be applicable to non-Japanese patients. CONCLUSIONS—We report the only series of non-Japanese Mongoloid patients with well characterised DPB who had uncharacteristic investigation profiles. This experience should help other clinicians in the investigation and management of DPB in non-Japanese patients.

During the 7 years from 1990, thirty-two patients (20 in male and 12 in female, mean age; 53 years old) were diagnosed as having pulmonary cryptococcosis. To clarify the essential points for early diagnosis of pulmonary cryptococcosis, we reviewed the clinical records and chest images. Three patients had a past history of pulmonary tuberculosis and eleven patients had underlying disorders such as malignancy, chronic pulmonary diseases and so on, but no HIV infection, which would affect this disease. Eighteen patients did not have any past history nor complications. The symptoms such as cough, sputum, chest pain and fever were generally of low-grade, 14 patients had no symptom at diagnosis. Except of some patients with severe infections and severe underlying disorders, laboratory findings such as inflamatory and nutritious markers were almost within near the normal range. On plain chest X-ray films the distribution of lesions was almost in proprtion to the volume of the lobes. The multifocal nudular and/or infitrative shadows wer observed in about 2/3 cases and single lesion in about 1/3. The width of lesions were minimal except of one case with interstitial pneumonia and two cases with multifocal segmental pneumonia. The cavity lesions were observed in 7 cases and hilar lymphadenopathy in 3 cases. On CT images, the lesions were almost located in the outer zone, the lesions which were adjacent to the pleura were observed in 15 cases. Cavitary lesions were almost smooth in edge and ubiquitous, the walls were also thick. The peripheral air-bronchogram in the nodular/infitrative shadows were observed in three cases. Pulmonary cryptococcosis is air-borne and almost a chronic infection except in AIDS patients, so careful planning for examination is essential with considerations of the characteristics of clinical and imaging features of this infection.

Macrophage-stimulating protein (MSP) is an 80-kD serum protein with homology to hepatocyte growth factor (HGF). Its receptor, RON tyrosine kinase, is a new member of the HGF receptor family. The MSP-RON signaling pathway has been implicated in the functional regulation of mononuclear phagocytes. However, the function of this pathway in other types of cells has not been elucidated. Here we show that in contrast to the HGF receptor, which was expressed at the basolateral surface, RON was localized at the apical surface of ciliated epithelia in the airways and oviduct. In addition, MSP was found in the bronchoalveolar space at biologically significant concentrations. MSP bound to RON on normal human bronchial epithelial cells with a high affinity (Kd = 0.5 nM) and induced autophosphorylation of RON. Activation of RON by MSP led to a significant increase in ciliary beat frequency of human nasal cilia. These findings indicate that the ciliated epithelium of the mucociliary transport apparatus is a novel target of MSP. Ciliary motility is critical for mucociliary transport. Our findings suggest that the MSP-RON signaling pathway is a novel regulatory system of mucociliary function and might be involved in the host defense and fertilization.

肺アスペルギルス症は,全身性の抵抗減弱患者のみならず肺や気道局所にのみ基礎疾患を有する患者においてもしばしばその発症を見るが,その病原性因子については未だ明らかにされていない.Aspergillus fumigatusに対する感染防御機構に関しては貪食球がその中心的役割を果たすことから,A.fumigatusから産生されるマイコトキシンであるgliotoxin, fumagillin, helvolic acidやAsp-hemolysinを用いて貪食球機能に対する影響を検討した.貪食球の機能としては,ヒト肺胞マクロファージ(AM)の分生子発芽抑制能,多核白血球(PMN)の遊走能,PMNのO2-放出能,PMNによる菌糸傷害を検討した.検討したマイコトキシンはこれらの貪食球機能を抑制したが,中でもgliotoxinが最もその効果が強く,次いでfumagillin≧helvolic acid>>Asp-hemolysinの順であった.生体局所においては,感染防御機構がアスペルギルスを排除しようと働く一方で,先行する病変部位を足場に侵入・定着したアスペルギルスがそこでその防御機能を障害する物質を産生し,病変を引き起こしている可能性が考えられた.

Fibrosing mediastinitis is rare. One type of this disease is idiopathic fibrosing mediastinitis. It is necessary to rule out malignancy in order to accurately diagnose fibrosing mediastinitis. We herein report a case of anaplastic large cell lymphoma diagnosed three months after a preliminary diagnosis of fibrosing mediastinitis. Glucocorticoid therapy was not successful in controlling disease progression. Immediately after initiating chemotherapy for lymphoma, the patient's symptoms improved dramatically and the mediastinal lesion decreased in size. Although few similar cases have been reported, hidden malignancy may present as fibrosing mediastinitis. Therefore, physicians should consider the probability of malignancy in patients with fibrosing mediastinitis because treatments may vary accordingly.

Aspergillus fumigatus感染におけるAsp-hemolysinの関与を推定する目的からA.fumigatus臨床分離株でのAsp-hemolysinタンパク質,およびそのmRNA発現の有無をウエスタンブロット法ならびにノーザンブロット法により検討した.ウエスタンブロット解析の結果,サブロー培地培養株16株中5株に,199培地培養株16株中12株にそれぞれ抗Asp-hemolysinウサギ抗血清に対し反応陽性を示すバンドが認められた.また,ノーザンブロット解析では,サブロー培地培養株16株中6株に,199培地培養株16株中13株にAsp-hemolysin cDNAとハイブリダイズした約0.7kb mRNAの単一シグナルが認められた.以上の結果から,Asp-hemolysinはA.fumigatus臨床分離株の遺伝子にもコードされていることが明らかとなった.

A case of nocardiosis with associated endobronchial excavated lesions is reported. A 79-year-old woman was diagnosed as having dermatomyositis in March, 2010. She was started on prednisolone (50mg/day) and was then switched to betamethasone due to lower limb edema and tapered to a dose of 2.5mg/day. A periodic chest X-ray examination in July, 2010, incidentally revealed nodular densities and associated cavities in the upper right lung field. On thoracoabdominal computed tomography (CT), bilateral pulmonary nodular shadows with various-sized cavities and multiple, new, intrahepatic, low-density regions were also identified. On bronchoscopy, a white, excavated lesion resembling an ulcerous lesion was observed in the left upper lobe bronchus, and a small exophytic lesion was observed in the right B6 bronchus. Nocardia asteroides complex was isolated from cultures of bronchial lavage fluid and sputum. The patient was treated with 4 weeks of intravenous imipenem (1.5g/day), followed by oral minocycline therapy (200mg/day) for 6 months, after which lesion resolution was confirmed on CT and treatment was discontinued. No recurrence has been reported in the roughly 18 months of follow-up to date. Nocardiosis results from infection with bacteria of the zoonotic, aerobic, Actinomyces genus and presents with disseminated lesions. Reported cases of human infection are increasing due to greater numbers of immunocompromised patients and improved diagnostic techniques. However, nocardiosis involving endobronchial lesions is extremely rare, and, to the best of our knowledge, the present case is the first report of endobronchial excavated lesions caused by nocardiosis.

抗酸菌感染症は,臨床的に結核と非定型抗酸菌症(AM症)に大別されている.結核は,既感染者が初感染で獲得した結核免疫の何らかの破綻を基礎に発症すると考えられ,この機序はopportunisticで,コンプロマイズドホストの発症と捉えることが出来る.またAM症は,局所的あるいは全身的感染抵抗力減弱宿主が高率に罹患することが明らかになっており,本症については,いわゆる「一次感染型」と「二次感染型」の概念について概説した.

Congenital velopharyngeal insufficiency (CVPI) is characterized by a disorder of the velopharynx similar to that observed in cleft palate without an overt or submucous cleft. We investigated nasal disease in 62 patients with congenital velopharyngeal insufficiency and compared the findings with those in cleft palate patients and normal subjects.The incidence of sinusitis in CVPI patients (46.8%) was similar to that in cleft palate patients (44.4%)-markedly higher than in normal subjects (

Chronic pulmonary aspergillosis (CPA) is slowly progressive inflammatory pulmonary syndrome due to Aspergillus spp. The evidence regarding CPA treatment is limited. We conducted a randomized, multicenter, open-label trial comparing intravenous micafungin (MCFG) of 150-300mg once daily with intravenous voriconazole (VRCZ) of 6mg/kg twice on Day 1 followed by 4mg/kg twice daily for the treatment of 107 in patients with CPA to compare the efficacy and safety of both drugs as initial treatment in Japan. Treatment effectiveness was defined by clinical, mycological, radiological and serological responses 2 weeks after the initial administration and at the end of therapy. The total of 50 and 47 patients were assigned to the MCFG and VRCZ groups, respectively. The difference in efficacy rates between MCFG and VRCZ was not significant, either after 2 weeks [68.0% vs. 58.7%; the absolute difference, 9.3% with a 95% confidence interval (CI), -9.97 to 28.58, P=0.344] or at the end of therapy (60.0% vs. 53.2%; the absolute difference, 6.8% with a 95% CI, -12.92 to 26.54, P=0.499). In the safety evaluation, fewer adverse events occurred in the MCFG than VRCZ group (26.4% vs. 61.1%, P=0.0004). MCFG was as effective as VRCZ and significantly safer than as an initial treatment of CPA. (UMIN Clinical Trials Registry number, UMIN000001786.)., The Journal of infection, 61(5), pp.410-418; 2010

We examined the records of sixty-one patients (17 males and 44 females) with endobronchial tuberculosis (EBTB). Smear tests of acid-fast bacilli were positive in 42 cases ad cultures of tubercle bacilli (TB) were positive in 57. The main findings of chest roentgenogram on admission were as follows : no abnormal findings in 8, atelectasis in 30, infiltration in 25, and cavitary lesions in 6. The localization and cross-sectional extension of lesions confirmed bronchoscopically were as follows : trachea in 15, with 3 circular lesions (CLs). Right (R-) main bronchus in 19 with 11 CLs, left (L-) main bronchus in 18 with 11 of CLs, R-truncus intermedius in 14 with 6 of CLs, R-upper lolar bronchus (UB) in 17 with 12 CLs, R-middle lobar bronchus in 14 with 11 of CLs, R-lower lobar bronchus (LB) in 6 with 2 CLs, L-UB in 10 with 7 CLs and L-LB in 3 with 2 CLs. All cases were treated by combination chemotherapy with isoniazid, refampicin, streptomycin and/or ethambutol and the rate of negative conversion of TB was good, but most of circular lesions resulted in severe bronchial stenosis or complete obstruction during and after chemotherapy, and no improvement was seen in any of the atelectasis cases at the cessation of chemotherapy. We discuss the points of early diagnosis and management of EBTB.(Internal Medicine 31 : 593-598, 1992)

We describe a case of Churg-Strauss syndrome (CSS) associated with allergic bronchopulmonary candidiasis (ABPC). A 61-year-old man who had been given a diagnosis of ABPC based on serologic and radiographic findings experienced pain and purpuric rash on the left leg accompanied with motor weakness. The diagnosis of CSS was made from skin, nerve and muscle biopsies. Although immunosuppressant and prednisolone were administered and resulted in transient improvement, candidal pneumonia was suspected to have developed 60 days after the administration and the patient finally died of respiratory failure. To our knowledge, this is the first case of CSS associated with ABPC.

Hemoptysis in patients with tuberculosis is usually associated with smear-positive and cavitary lung disease. The present case describes a patient suffering from recurrent hemoptysis associated with tuberculosis who had smear-negative and non-cavitary lung disease, and who was subsequently diagnosed as having mild hemophilia A. Although mild hemophilia A sometimes escapes detection until adolescence, there has been no reported case of mild hemophilia A detected by recurrent hemoptysis due to pulmonary tuberculosis. Here, we report a rare case of recurrent hemoptysis in a patient with tuberculosis who had smear-negative and non-cavitary lung disease and who was finally shown to have hemophilia A.

Gemcitabine is an anti-cancer drug known to be safe and effective for pancreatic or biliary tract cancers, but lung injury is also known to be a rare side effect that sometimes becomes severe. Here we report seven cases of lung injury during gemcitabine treatment. Drug-induced lung injury was suspected in all cases. The male: female ratio was 5:2, and the average patient age was 71. Four had pancreatic cancers and three had biliary tract cancers. Gemcitabine had been administered an average 5.9 times at a dose of 1,141 mg. Patients showed a diffuse or patchy shadow mainly in the lower lung on computed tomography examination. Grades of adverse events were greater than 3 in all cases. Three patients died of the lung injury. Five cases had pulmonary emphysema, 2 had metastatic lung tumor as underlying pulmonary lesions, and these were assumed to have been important risk factors for drug-induced interstitial lung injury during gemcitabine treatment.

An autopsy case of primary pulmonary choriocarcinoma that manifested as diffuse alveolar hemorrhage is reported. A 44-year-old nurse presented with fever, dry cough, hemoptysis, and progressive dyspnea, and died after a downhill course of 2 weeks. Chest radiographs showed diffuse parenchymal shadows throughout the entire lung and a nodular lesion in the right lower lobe. Findings suggestive of acute renal failure were not seen. The autopsy revealed primary pure choriocarcinoma of the right lower lobe and diffuse alveolar hemorrhage throughout the entire lung. Findings of small vessel vasculitis (“pulmonary alveolar capillaritis”) were not observed, and extensive neoplastic involvement of the pulmonary vasculature was considered the cause of the diffuse alveolar hemorrhage. Small metastatic foci were found in the liver, adrenal glands, pancreas, and ovaries. This case shows that primary pulmonary neoplasms, on rare occasions, can produce the clinical and pathologic features of diffuse alveolar hemorrhage, probably through elevated pulmonary venous pressure caused by extensive destruction of the vasculature.

We report, to our knowledge, the first case of mucoid impaction of the bronchi due to a hypersensitivity reaction to the monokaryotic mycelium of Schizophyllum commune. The patient was hospitalized because of mild asthma attacks, persistent cough, peripheral eosinophilia, and "gloved finger" shadows on a chest roentgenogram. Bronchoscopic examination disclosed mucoid impactions that consisted of accumulations of eosinophils, Charcot-Leyden crystals, and nondichotomously branched hyphae in B3, B9, and B10 of the left lung. Cultures of the mucous plugs and sputum samples yielded white, felt-like mycelial colonies that were later identified as the monokaryotic mycelium of S. commune by use of mating tests with established monokaryotic and dikaryotic strains of S. commune. The results of tests for serum antibody to S. commune cytosol antigen were positive. Repeated bronchoscopies for performing bronchial toilet were effective in removing the mucous plugs and relieving the patient's symptoms. We suggest that the monokaryotic mycelium of S. commune should be considered as one of the fungi that can cause hypersensitivity-related lung diseases.

Mycobacterium abscessus accounts for 80% of rapidly growing mycobacterial pulmonary infections and can be lethal. Treatment is difficult because of the paucity of effective drugs. We describe a patient with pulmonary M. abscessus infection who was treated with a regimen that included faropenem, a novel oral penem, and clarithromycin. He showed favorable responses to the treatment for more than 12 months. In vitro, faropenem had considerable inhibitory activities against 56 strains of rapidly growing mycobacteria, including M. peregrinum, M. chelonae, M. fortuitum, and M. abscessus (stated in order of increasing minimal inhibitory concentrations). Thus, faropenem has the potential to be used as an adjunctive drug with clarithromycin for the treatment of infection with rapidly growing mycobacteria, including M. abscessus.

No report has been found comparing Chlamydia pneumoniae (C. pneumoniae) pneumonia radiographically with other atypical pneumonias, Chlamydia psittaci (C. psittaci) pneumonia and Mycoplasma pneumoniae (M. pneumoniae) pneumonia. We described the chest radiographs of three kinds of pneumonia cases: 46 cases of C. pneumoniae pneumonia, 39 cases of C. psittaci pneumonia, and 131 cases of M. pneumoniae pneumonia. Radiographic shadows were categorized into main shadows and sub-shadows. The main shadows are classified from the viewpoint of the characteristics; air space consolidation(AS), ground-glass opacity(GG), reticular shadow(RS), bronchopneumonia(BP), and small nodular shadows (SN). The size, the site, and the number of the main shadows were also analyzed. In comparison among the three pneumonias, BP was the most frequent in M. pneumoniae pneumonia (0.40/case). AS predominated in C. pneumoniae pneumonia (0.67/case), and GG in C. psittaci pneumonia (0.62/case). The number of main shadows was equal, about 1.4/case in three pneumonias. Large shadows were less frequent in M. pneumoniae pneumonia than C. pneumoniae pneumonia (p = 0.02) and C. psittaci pneumonia (p = 0.01). Main shadows were more frequent in the outer zone in M. pneumoniae pneumonia than C. psittaci pneumonia (p = 0.01), and in the middle zone in C. psittaci pneumonia than in M. pneumoniae pneumonia (p = 0.02). Cases with bilateral main shadows were less common in M. pneumoniae pneumonia (9%) than C. pneumoniae pneumonia(33%, p = 0.001) and C. psittaci pneumonia(30%, p = 0.005). Thickening of bronchovascular bundles as a sub-shadow was most frequently noted in M. pneumoniae pneumonia. Some differences among the three atypical pneumonias were seen in the chest radiograph. However, no specific findings of C. pneumoniae pneumonia were shown radiographically in this study.

Postmortem studies have shown that airway wall thickening is present in asthmatic patients and may play a pathophysiologic role. We investigated the presence and characteristics of airway wall thickening in patients with asthma, using helical computed tomography. Eighty-one asthmatic patients and 28 healthy control subjects were studied cross-sectionally. Airway wall thickness was assessed by a validated method on the basis of wall area (WA), WA corrected by body surface area (WA/BSA), and WA%, defined as (WA/total area) x 100 at the apical bronchus of the right upper lobe. Airway luminal area (Ai) and Ai/BSA were also examined. Asthma duration and severity, pulmonary function, and serum eosinophil cationic protein levels were evaluated. Intraobserver and interobserver reproducibility of WA, WA%, and Ai measurements were good. As compared with control, WA, WA/BSA, and WA% were significantly increased in patients with mild (n = 13), moderate (39), and severe persistent (22) asthma but not in patients with intermittent asthma (7). Comparison of the four asthmatic subgroups demonstrated thicker airways in more severe disease, but no difference in Ai or Ai/BSA. When all asthmatic patients were analyzed together, WA and WA/BSA correlated with the duration, although weakly, and severity of asthma. WA and WA/BSA negatively correlated with FEV(1) (percentage of predicted), FEV(1)/FVC (%), and FEF(25-75%) (percentage of predicted), whereas WA% negatively correlated with only FEV(1). We conclude that airway wall thickening occurs in patients with asthma and is not limited to those with severe disease. The degree of airway wall thickening may relate to the duration and severity of disease and the degree of airflow obstruction.

We report two Japanese families affected by pulmonary Mycobacterium avium complex (MAC) disease, involving an older brother and younger sister in one family and two brothers in the second family. We investigated whether defects in the natural resistance-associated macrophage protein gene (NRAMP1) underlay susceptibility to MAC in these cases. All of the patients had computed tomographic findings of peripheral nodules and bronchiectasis. Pulse-field gel electrophoresis patterns of mycobacterial genomic DNA restriction fragments revealed that none of the MAC strains isolated from the patients was epidemiologically related to any of the others. Direct sequencing of the complementary DNA of the patients' NRAMP1 revealed a nonconservative missense mutation at codon 419 in one patient, which was heterozygous and was not seen in his affected sibling. No variations similar to those found in mice that show susceptibility to MAC were found. The results suggest an underlying genetic defect in host defense rather than exposure to an unusually virulent strain of MAC as the pathogenetic factor in MAC disease; however, alterations in the coding region of NRAMP1 do not appear to explain the susceptibility to MAC.

The effect of omeprazole, a clinically used proton pump inhibitor, alone or in combination with clarithromycin was evaluated against Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium tuberculosis, using a human alveolar macrophage model of infection. Omeprazole exhibited no significant effect on the growth of the two M. avium complex strains or on the mycobactericidal activity of clarithromycin against them. In contrast, omeprazole significantly promoted the growth of Mycobacterium tuberculosis and the anti-mycobacterial activity of clarithromycin against it in human alveolar macrophages. It was speculated that intracellular acidic milieu around M. tuberculosis might be one reason for the lower activity of clarithromycin in the treatment of human tuberculosis.

We report on a patient whose sputum contained both Mycobacterium tuberculosis and Mycobacterium avium complex (MAC). The MAC failed to be detected by the PCR-based AMPLICOR test. The unrecognized coexistence of MAC in the sample modified the results of drug susceptibility tests. Experiments revealed that the presence of both M. tuberculosis and MAC was not detected by the AMPLICOR test under certain conditions.

Macrophage-derived interleukin-12 (IL-12) is essential for the activation of a protective immune response against intracellular pathogens. In this study, we examined the regulation of IL-12 mRNA expression by monocyte-derived macrophages (MDM) in response to Mycobacterium bovis BCG stimulation. A reverse transcription-PCR assay detected p40 mRNA of IL-12 at 3 h and showed a peak at 6 to 12 h with a subsequent decline. Semiquantitation of mRNA levels by competitive PCR revealed that pretreatment with gamma interferon (IFN-gamma) amplified the expression approximately 100-fold, while pretreatment with tumor necrosis factor alpha (TNF-alpha) or granulocyte-macrophage colony-stimulating factor augmented this expression about 10-fold. In contrast, pretreatment with IL-10 and IL-4 inhibited IL-12 mRNA expression. These results were further confirmed by measuring the p70 bioactive protein level in each conditioned medium by an enzyme-linked immunosorbent assay. Since IL-12 mRNA expression was weak without cytokine pretreatment and IFN-gamma strongly augmented production, we speculated that IFN-gamma might have a role in BCG stimulation of IL-12 mRNA expression. Unexpectedly, the addition of three different kinds of anti-IFN-gamma antibodies and anti-IFN-gamma receptor antibody and the coaddition of anti-TNF-alpha antibody with anti-IFN-gamma receptor antibody all failed to inhibit IL-12 mRNA expression. However, the MiniMACS method used to remove NK cells from a mononuclear cell suspension inhibited the expression of p40 mRNA but not the expression of mRNA of TNF-alpha or IL-1beta. We concluded that the coexistence of NK cells was essential for the induction of IL-12 in MDM stimulated with BCG rather than through the secretion of IFN-gamma.

Mycobacterium avium complex (MAC) pulmonary disease with nodules and bronchiectasis is increasing. But the usefulness of computed tomography (CT) and bronchoscopy for diagnosis and the significance of MAC isolation from respiratory secretions are still unclear. For a 4-yr period, we prospectively examined the role of bronchoscopy with bronchial washing and transbronchial lung biopsy in 26 patients who had clusters of small nodules in the periphery of the lung associated with ectatic changes of the draining bronchi on the CT scan. None of them was infected with human immunodeficiency virus. Thirteen of the 26 patients (50%) had cultures positive for MAC, six in the sputum and 13 in the bronchial washing. Epithelioid granuloma was demonstrated in eight of 13 patients with culture-positive MAC and in two of 13 patients in whom MAC was culture-negative. Rapidly growing mycobacteria were cultured in the two patients. Seven of the eight biopsy-positive patients received treatment and responded by sputum conversion and/or radiographic improvement. We found that the CT finding was a useful clue to suspect MAC pulmonary disease and that the bronchial washing was more sensitive than the routine expectorated sputum for MAC isolation. Demonstration of granuloma in more than half of the MAC-positive patients would suggest that MAC may have invaded the lung tissue rather than colonized in the airways.

OBJECTIVE: The study was designed to establish an animal model of toluene diisocyanate (TDI)–induced late respiratory response and to investigate airway inflammatory cell dynamics in this model. METHODS: Guinea pigs were exposed to 2,4-TDI dissolved in ethyl acetate by nasal application according to three schedules. Schedule 1 consisted of sensitization and multiple challenge ( n = 58): 10% TDI was applied once daily for 7 days (sensitization) followed by challenges with 5% TDI once weekly for 4 weeks. Schedule 2 consisted of sensitization only ( n = 5): 10% TDI was applied once daily for 7 days. Schedule 3 consisted of single challenge only ( n = 12): 5% TDI was applied only once. As controls, ethyl acetate was applied according to the three schedules described above. Each animal was premedicated with metyrapone before each challenge. Bronchoalveolar lavage and histologic examination were performed at various times after the last challenge. RESULTS: Schedule 1 induced immediate and late respiratory responses at a prevalence of 63% and 56%, respectively. Schedules 2 and 3 induced an immediate response in some animals but no late response. Neither immediate nor late response was observed in control animals. All of the subgroups of schedule 1 that developed late responses (examined at 2, 3, 6, 24 and 168 hours) showed a significant increase of eosinophils in bronchoalveolar lavage fluid and tissue compared with the corresponding control of each (examined at the same time points). Two of the subgroups with late responses (examined at 3 and 6 hours) were compared with their corresponding subgroups, which were given the same treatment, failed to develop late response, and were examined at the same time points; they again proved to have a significant increase of eosinophils in both samples. Subgroups of schedule 1 without late response (30 minutes, 3 and 6 hours), schedule 2 (6 hours), or schedule 3 (2 and 6 hours) did not show significant changes in lavage or tissue cell composition, except for the schedule 1 subgroup examined at 6 hours, which showed a significant increase of eosinophils only in the tissue compared with its control. CONCLUSIONS: Sensitization and multiple challenge with TDI induced immediate and/or late respiratory responses at a high prevalence in guinea pigs. Eosinophilic but not neutrophilic inflammation was involved in the late response. (J ALLERGY CLIN IMMUNOL 1996;97:1308-19.)

A polymerase chain reaction (PCR) assay for the rapid detection of Mycobacterium tuberculosis in sputum samples was studied. The target DNA was a 123-base pair (bp) fragment of IS6110, which was repeated in the M.tuberculosis genome and was specific for the M.tuberculosis complex. Glass beads (2mm diameter) and lysozyme were used to lyse the mycobacteria and DNA was extracted by the phenol-extraction method. The amplified PCR product was detected by examination of ethidium-bromide-stained agarose gel and by hybridization with an oligonucleotide alkali-phosphatase-labeled probe. A total of 70 samples were tested. PCR was positive in all 13 smear and culture-positive samples, in 5 of 8 smear-negative and culture-positive samples, and in 1 of 49 smear and culture negative samples. The overall sensitivity and specificity were 85.7% and 98%, respectively. Thus, IS6110 as a PCR target was found to be very useful for the rapid diagnosis of M.tuberculosis infection and start of anti-tuberculous chemotherapy.

A substantial proportion of patients with recurrent pneumonia do not have an apparent underlying condition, but they may have unknown defects in host defence mechanisms such as cough reflex.Capsaicin cough sensitivity was measured in seven patients with recurrent pneumonia but no underlying condition. Recurrent pneumonia was defined as at least two episodes of pneumonia in 1 year, or three or more episodes at any time. After remission of pneumonia, 10 doubling concentrations of capsaicin (1.22-625 microM) were inhaled until five or more coughs were induced (cough threshold). Mucociliary clearance was assessed on the basis of nasal ciliary beat frequency and nasal clearance time. Twenty one age and sex matched healthy subjects were studied as controls.Each patient had 2-6 episodes of pneumonia. Most episodes developed in dependent lung segments, suggesting the involvement of silent aspiration. Log transformed cough threshold was significantly higher in patients than in controls (mean 2.37 M (95% CI 1.84 to 2.90) v 1.29 microM (95% CI 1.11 to 1.47); p0.0001). The effect of pneumonia per se on cough reflex seemed unlikely since the cough threshold showed little change when re-examined after 3 months. The patients and controls did not differ with respect to the indices of mucociliary clearance.Impaired cough reflex may be involved in the pathogenesis of recurrent pneumonia.

To investigate nasal and paranasal disease in patients with congenital velopharyngeal insufficiency (CVPI).Case series.Patients with CVPI or cleft palate were investigated at Kyoto (Japan) University Hospital.Consecutive sample (60 patients with CVPI and 333 with cleft palate). No eligibility criteria or sociodemographic features. Random sample (normal subjects).The incidence of sinusitis and septal deviation, nasal airway resistance, nasal mucociliary function by saccharin test, and ciliary beating frequency were examined. These findings in patients with cleft palate and normal subjects were compared to clarify the features of nasal disease in CVPI.The incidence of sinusitis in CVPI was 46.7% and approximately equal to that in cleft palate (44.1%). The incidence of septal deviation in CVPI (26.7%) was low and nasal airway resistance was almost normal. In contrast, in patients with bilateral, unilateral, or incomplete cleft palate, the incidence of septal deviation was significantly more frequent (78.9%) than that in CVPI (P0.001), and nasal airway resistance was significantly higher than that in CVPI (P.0001). In patients with submucosal cleft, septal deviation was found in 40.8% and nasal airway resistance was significantly higher than that in CVPI (P.02). Although saccharin time was significantly prolonged (P.001) and ciliary beating frequency was significantly lower (P.005) in patients with cleft palate than in normal subjects, values for these tests in patients with CVPI were normal.The incidence of sinusitis was high in CVPI. However, the frequency of septal deviation and nasal airway resistance was almost normal. Nasal mucociliary function (saccharin time and ciliary beating frequency) was also normal.

The clinical and pathologic features of ten cases of alveolar soft-part sarcoma (ASPS) were observed in subjects aged ten to 49 years. Eight were male and two were female. The lesion involved the thigh in six cases and the adjacent bone in three. All lesions were retrospectively classified as high risk (Stage II or III of Enneking's staging system), and distant metastasis to lung or bone was noted at initial presentation in four patients. Three patients died with distant metastases at a mean time of three years seven months after diagnosis. The mean interval from initial presentation to detection of distant metastasis was nine months; and the mean interval from detection of metastasis to death was three years two months. Ultrastructural studies demonstrated typical organoid arrangement of the neoplastic cells surrounded by a basement membrane with close attachment of individual cells to the basal lamina. No local recurrence, even in cases with inadequate tumor control, and the tendency for distant metastasis demonstrated in the current series, reemphasized that management of metastasis is most important in the treatment of ASPS.

Systemic hypersensitivity vasculitis developed in a 53-year-old man during acute exacerbation of bronchiectasis infected with Pseudomonas aeruginosa . High grade fever, mononeuropathy multiplex, cutaneous vasculitis, and biopsy specimen—proved mesangioproliferative glomerulonephritis with crescent formation and leukocytoclastic vasculitis associated with circulating immune complex occurred. Corticosteroid and cyclophosphamide therapy was effective for vasculitis and bronchiectasis.

Subepithelial-layer thickening, a pathological feature of airway remodelling, is present in cough-variant asthma. In bronchial biopsy samples we found mean subepithelial-layer thickness was 7.1 (SE 0.4) microm in patients with cough-variant asthma, 8.6 (0.4) microm in patients with classic asthma with wheezing, and 5.0 (0.2) microm in healthy controls. Thickness was significantly higher in patients with asthma than in controls, and was significantly greater in those with classic asthma than in those with cough-variant asthma. Early anti-inflammatory treatment might, therefore, be beneficial in cough-variant asthma, as recommended in classic asthma.

It has been suggested that proteinase enzymes could play an important role in the pathogenesis of chronic bronchial infections including bronchiectasis and cystic fibrosis (CF). Because Pseudomonas aeruginosa frequently colonizes the respiratory tract in bronchiectasis and CF, we examined the in vitro effects of human neutrophil elastase (HNE) and proteinase enzymes produced by P. aeruginosa (elastase: PE; alkaline proteinase: PAP) on the ciliary beat frequency (CBF) and ultrastructure of human nasal ciliated respiratory epithelium. HNE (500 micrograms/ml) progressively reduced CBF and caused marked epithelial disruption; lower concentrations (100 and 20 micrograms/ml) also caused epithelial disruption but without slowing CBF. The effects of HNE (500 micrograms/ml) were completely abolished by adding alpha 1-antitrypsin (5 mg/ml). There was no synergy between HNE and pyocyanin, a product of P. aeruginosa which slows CBF. PE in phosphate-buffered saline also caused epithelial disruption without slowing CBF; however, PE in medium containing divalent metal ions caused CBF slowing as well as epithelial disruption at 100 micrograms/ml. PAP (500 micrograms/ml) had almost no effect on ciliated epithelium. The effects of HNE and PE on nasal and bronchial epithelium obtained from the same patient were similar. Light and transmission electron microscopy revealed that HNE and PE were cytotoxic and caused detachment of epithelial cells from neighboring cells and the basement membrane. There was cytoplasmic blebbing of the cell surface and mitochondrial damage; however, no increase of abnormalities in the ultrastructure of cilia on living cells was seen. These results support the hypothesis that HNE and PE contribute to the delayed mucociliary clearance and epithelial damage that is observed in patients with chronic bronchial infection.

We examined nasal mucociliary transport by the saccharin method and nasal ciliary beating frequency by the photoelectric method in cleft palate patients and normal subjects. The saccharin time was longer in cleft palate patients than that in normal subjects. Cleft palate patients were devided into two groups: group 1 with sinusitis and group 2 without sinusitis. The saccharin time was longer in group 1 than in group 2 and longer in group 2 than in normal subjects. Ciliary beating frequency of the nasal septal mucosa was lower in cleft palate patients than in normal subjects. Cleft palate patients appeared to have impaired nasal mucociliary function.

Cleft palate patients often have sinusitis, but the cause of this sinusitis is not known. To clarify the cause of sinusitis in cleft palate patients, we investigated the incidence of sinusitis with regard to the type of cleft, the degree of septal deviation, velopharyngeal function, and presence of a pharyngeal flap. We also examined the laterality of sinusitis in unilateral cleft lip and palate patients. Furthermore, we examined the development of the maxillary sinuses, nasal mucociliary transport by the saccharin method and ciliary beating frequency of ciliated cells taken from the nasal septum in cleft palate patients and normal subjects.1) The incidence of sinusitis was not related to the type of cleft, the degree of septal deviation, velopharyngeal function, or presence of a pharyngeal flap. In unilateral cleft lip and palate patients, the laterality of sinusitis was not related to the cleft side. Therefore, we considered that contamination of the nasal cavity through the cleft and incompetent velopharynx were not cause of sinusitis; neither was the stagnation of nasal secretion in the presence of a pharyngeal flap nor obstruction of the maxillary ostium by a middle turbinate secondary to a deviated septum.2) There was no difference in the size of the maxillary sinus between the control group and the cleft group. Therefore, underdevelopment of the maxillary sinus did not appear to be a cause of sinusitis in cleft palate patients.3) Nasal mucociliary transport was impaired in cleft palate patients, and this impairment was thought to be a cause of the high incidence of sinusitis in cleft palate patients.The frequency of ciliary beating was lower in the cleft group than in the control group, but further investigation is necessary to determine whether the lowered ciliary beating frequency is a factor in the impairment of nasal mucociliary transport.