High serum concentrations of autoantibodies to HSP47 in nonspecific interstitial pneumonia compared with idiopathic pulmonary fibrosis.

BACKGROUND: The pathological diagnosis of idiopathic interstitial pneumonias (IIP) by surgical lung biopsy is important for clinical decision-making. However, there is a need to use less invasive biomarkers to differentiate nonspecific interstitial pneumonia (NSIP) from other IIP such as usual interstitial pneumonia (UIP). Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. HSP47 is increased in various fibrotic diseases. We investigated the autoantibodies to HSP47 in IIPs. METHODS: We measured the serum levels of the autoantibodies to HSP47 in 38 patients with various forms of IIP [16 with idiopathic pulmonary fibrosis (IPF), 15 with idiopathic NSIP, 7 with cryptogenic organizing pneumonia (COP)] and 18 healthy volunteers. RESULTS: The serum levels of autoantibodies to HSP47 in patients with idiopathic NSIP were significantly higher than in patients with IPF (P < 0.01), COP (P < 0.05), and healthy volunteers (P < 0.05). In addition, those in fibrosing NSIP were significantly higher than those of cellular and fibrosing NSIP (p < 0.05). CONCLUSION: We found high levels of anti-HSP47 autoantibody titers in sera of patients with idiopathic fibrosing NSIP compared with other IIPs and healthy volunteers.

The expression of pro- and anti-apoptotic Bcl-2 family proteins in peribronchiolar lymphocytes from patients with diffuse panbronchiolitis.

Diffuse panbronchiolitis (DPB) is a distinctive form of small airway disease, which is characterized by chronic inflammation with lymphocyte infiltration around bronchioles. The aim of this study was to evaluate the importance of factors related to apoptosis in peribronchiolar lymphocytes of DPB. We employed immunohistochemical methods for the localization of Bax (a promoter of apoptosis), Bcl-2 (an inhibitor of apoptosis), and caspase-3 (a key executioner molecule of apoptosis) in lung tissues of five patients with DPB. In all patients, immunostaining for Bax was almost completely absent in accumulated lymphocytes around the bronchioles and in lymphocytes of the parafollicular area that correspond to a zone populated by T cells. In contrast to the reaction for Bax, Bcl-2 immunoreactivity was uniformly strong in all of the patients. The pattern of staining for caspase-3 was similar to that for Bax in all of the patients. In normal lung tissue, a few lymphocytes showed negative immunostaining for Bcl-2 and a positive reaction for caspase-3. Our results suggest that Bcl-2 protein may provide T-lymphocyte survival and hypercellularity in the bronchioles, thereby contributing to the progression of DPB.

Antibiotic-induced apoptosis in human activated peripheral lymphocytes.

Long-term administration of macrolide antibiotics reduced the number of lymphocytes in bronchoalveolar lavage fluid in patients with chronic airway inflammatory disease. To evaluate the inflammatory activity of macrolides, their effect on apoptosis of activated lymphocytes isolated from human peripheral blood was compared with that of other antibiotics. Macrolides, including clarithromycin and azithromycin, at a final concentration of 100 microg/ml accelerated apoptosis of activated lymphocytes, while other antibiotics such as fosfomycin sodium, beta-lactams--ceftazidime, piperacillin sodium and biapenem, and a quinolone, ofloxacin, did not cause significant induction of apoptosis. Our results suggest that 14- or 15-membered ring macrolides are specifically involved in the augmentation of apoptosis of activated lymphocytes, and this may be of value therapeutically for chronic airway diseases.

Long-term macrolide antibiotic therapy in the treatment of chronic small airway disease clinically mimicking diffuse panbronchiolitis.

OBJECTIVE: In the current studies, we investigated the clinical effects of long-term macrolide antibiotic therapy for patients with chronic small airway disease (CAD) that clinically and radiologically mimics but is pathologically distinct from diffuse panbronchiolitis (DPB). PATIENTS AND METHODS: Twenty-one Japanese patients were selected on the basis of clinical criteria for DPB and were categorized as DPB or CAD following histological evaluation of surgical lung biopsies. All patients received long-term macrolide therapy, and therapeutic results were compared for the DPB and CAD groups. RESULTS: Clinical, laboratory, radiological, and bacterial features, as well as neutrophilia in bronchoalveolar lavage fluid were strikingly similar in both groups. Long-term treatment with macrolides improved the clinical symptoms and PaO(2) in both groups. There was a significant improvement in forced expiratory volume in one second (FEV(1)), vital capacity (VC), and %VC in patients with DPB but not in patients with CAD. Neutrophilia in bronchoalveolar lavage fluid was also reduced following therapy in DPB patients but was refractory in CAD patients. CONCLUSION: Based on the different responses to macrolides, CAD might be associated with conditions distinct from those of DPB. Nevertheless, low-dose macrolide therapy may be applied in CAD to achieve clinical improvement, such as in respiratory symptoms and PaO(2).

Antimicrobial susceptibilities and analysis of genes related to penicillin or macrolide resistance in Streptococcus pneumoniae.

One hundred and seventy-seven strains of Streptococcus pneumoniae derived from respiratory specimens between 1987 and 2001 were evaluated for their antimicrobial susceptibilities and distribution of genes related to penicillin and macrolide resistance. Resistance rates tended to be higher for the 1996-2001 isolates than for the 1987-1995 isolates for all beta-lactams tested. For benzylpenicillin the MIC(90) value of the isolates derived between 1996 and 2001 was 1.56 mg/L, while that of strains isolated between 1987 and 1990 was 0.05 mg/L. Furthermore, the number of strains susceptible to macrolides also decreased, but only two strains isolated in 1993 were resistant to levofloxacin of the 177 S. pneumoniae strains tested. When of genes relating to penicillin resistance were analysed using PCR with primers specific to susceptible alleles, although more than 50% of strains from 1987 to 1990 and 1991 to 1995 revealed no mutations in the pbp 1a, 2x and 2b genes, only 30.0% of strains derived between 1996 and 2001 showed no mutations in the pbp gene. Strains having mutations in all three pbp genes (1a, 2x and 2b) by the PCR method increased from only 2.2% in the 1987-1990 derived strains to 27.5% in the 1996-2001 strains. Furthermore, 64.1 and 60.0% of the isolates from 1987 to 1990 and 1991 to 1995, respectively, did not possess either the mefA or ermB by PCR analysis. Conversely, 75.0% of isolates from 1996 to 2001 possessed mefA and/or ermB. These genetic changes may explain the increase in the number of penicillin and macrolide resistant strains. We believe that it is important to evaluate changes in MIC as well as genetic mutations in order to select the most appropriate therapy for S. pneumoniae infections.

Clarithromycin and azithromycin induce apoptosis of activated lymphocytes via down-regulation of Bcl-xL.

To evaluate the anti-inflammatory action of macrolide antibiotics, we examined whether macrolide antibiotics could induce apoptosis of activated lymphocytes. The proportion of apoptotic cells was augmented by clarithromycin (CLR) and azithromycin (AZM) compared with control. There was no significant difference in Fas and Fas-ligand expression between the control and macrolide-treated groups. CLR and AZM inhibited the expression of Bcl-xL compared with that of control. Our results suggest that CLR and AZM enhance apoptosis of activated lymphocytes by down-regulation of Bcl-xL.

[A case of Pseudomans aeruginosa pneumonia complicated with multiple pustular skin lesions].

Pseudomonas aeruginosa is a common causative agent of septicemia in compromised host and the entry site of organism is most commonly the respiratory and genitourinary tract. P. aeruginosa septicemia is often associated with vesicular or pustular skin lesions, subcutaneous nodules, deep abscess, cellulites and bullae. We report a case of P. aeruginosa pneumonia with multiple pustular skin lesions on the chest and leg. A 77-year-old male was admitted to our hospital complaining of fever, productive cough and eruptions. Laboratory findings revealed a leucocytosis (14,830/microliter) and an elevated CRP (21.72 mg/dl). The chest radiograph and computed tomography revealed a fluid level in preexisting bullae and a consolidation shadow with multiple cavities in the right upper lobe and nodular shadow with cavity in the left lower lobe. P. aeruginosa strain was isolated from the bronchial lavage and pustule. Blood cultures were negative. Skin biopsy specimens showed histologically a dense infiltrate of neutrophils in the horny cell layer. He was diagnosed as Pseudomonas aeruginosa pneumonia complicated with multiple pustular skin lesions. He was treated with antimicrobial agents for 24 days and his clinical condition improved.

[A case of suspected lung metastasis of pancreatic carcinoma with bronchorrhea similar to bronchioloalveolar carcinoma].

There have been only a few reports of bronchorrhea in patients with metastatic pulmonary carcinoma. We report a case of suspected lung metastasis of pancreatic carcinoma with bronchorrhea, which was radiologically similar to bronchioloalveolar carcinoma. A 67-year-old man who had previously undergone surgical resection of pancreatic carcinoma was admitted because of a progressive cough producing copious amounts of serous sputum. A chest radiograph on admission revealed an infiltrative shadow with air bronchograms and ground glass opacities in the left middle and lower lung fields. A chest CT scan revealed a consolidative shadow with air bronchograms and bubble-like lucencies similar to bronchioloalveolar carcinoma in the left lower lobe. The histopathological features of the specimen obtained by transbronchial biopsy revealed adenocarcinoma with a pattern identical to that of the pancreatic carcinoma. Immunohistochemical staining with anti-SP-A antibody was entirely negative but those with anti-CA 19-9, Dupan 2 and CA 50 were positive in both lung and pancreatic tumors. These results strongly suggest that the pulmonary carcinoma was a metastasis of cystic adenocarcinoma of the pancreas. In summary, for a definitive diagnosis of bronchioloalveolar carcinoma, extrapulmonary adenocarcinoma as a primary site should first be ruled out.

[A case of adult-onset Still's disease complicated with acute respiratory distress syndrome].

A 24-year-old woman was admitted to our hospital because of a high fever that had persisted for two weeks. She complained of a sore throat and arthralgia, and had evanescent rash, lymphadenopathy, liver dysfunction, and hyperferritinemia. Tests for RF and ANA were negative. Adult-onset Still's disease was diagnosed. On the fifth day of hospitalization, acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) developed. Treatment consisted of mechanical ventilation and administration of steroid pulse-therapy and gabexate mesilate. Analysis of fluid obtained by bronchoalveolar lavage showed increases in the total cell count, predominantly of neutrophils and lymphocytes. Bilateral pulmonary infiltration seen on chest radiographs was alleviated, and the arterial blood gas data gradually improved. After cyclosporine was given, all the above symptoms associated with adult-onset Still's disease disappeared. Plasma levels of inflammatory cytokines decreased with the improvement of the patient's clinical condition.

Association of computed tomography-detected pulmonary interstitial changes with severe radiation pneumonitis for patients treated with thoracic radiotherapy.

We evaluated associations of interstitial changes with radiation pneumonitis (RP) for patients treated with thoracic radiotherapy. Between 2005 and 2009, patients who received thoracic radiotherapy of 40 Gy or more for lung cancer or thymic tumors and were followed-up for more than 6 months were eligible for this study. Possible risk factors for RP included the presence of interstitial changes on computed tomography before radiotherapy, and elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels; these were compared with the incidences of severe RP. A total of 106 patients were included. The incidences of RP were 4 (4%), 0 (0%), and 5 (5%) for grades 3, 4, and 5, respectively. For those with interstitial changes, the incidence of RP ≥ grade 3 was significantly increased from 3% (2/79) to 26% (7/27) (p < 0.001). CRP and LDH levels were also associated with increased RP, as were pulmonary emphysema and performance status ≥ 2. Among 91 patients with RP ≥ grade 1, RP grade ≥ 3 occurred significantly earlier than grades 1 and 2. In conclusion, pulmonary interstitial changes, LDH and CRP levels, pulmonary emphysema, and performance status ≥ 2 were significantly associated with RP ≥ grade 3. RP grade ≥ 3 occurred significantly earlier than grades 1 and 2. The early appearance of interstitial changes requires careful management due to the possibility of severe RP.

A case of empyema caused by Edwardsiella tarda.

In December 2003, a 57-year-old-man was diagnosed as having a hepatic tumor for which he had a hepatectomy. On pathology, the hepatic tumor biopsy specimen was diagnosed as malignant lymphoma. In February 2005, the patient was referred to our hospital because of fever and chest pain. A right pleural effusion was seen on chest X-ray. Microscopic examination of the stained pleural fluid revealed many neutrophils and Gram-negative rods, and Edwardsiella tarda was cultured from the pleural effusion fluid. These findings were consistent with an empyema caused by E. tarda. Therefore, we treated the patient with panipenem/betamipron and thoracic drainage. In this paper, we describe this rare case of empyema caused by E. tarda infection.

Sarcoidosis associated with renal masses on computed tomography.

A 50-year-old woman was admitted to our hospital after computed tomography (CT) revealed renal masses and mediastinal lymphadenopathy. Uveitis had previously been diagnosed by a local ophthalmologist. Elevated levels of serum soluble IL2 receptor were observed. However, renal function was not compromised. Abdominal CT showed multiple low attenuation tumor-like nodules in both kidneys. As lymphoma was considered likely, CT-guided renal biopsy was performed; however, histological examination of the excised specimens revealed noncaseating granulomas. Analysis of bronchoalveolar lavage fluid demonstrated a sarcoidosis pattern. The final diagnosis was sarcoidosis with renal involvement.

Natural killer cell-type body cavity lymphoma following chronic active Epstein-Barr virus infection.

We describe a 69-year-old female who developed natural killer cell-type body cavity lymphoma following chronic active Epstein-Barr virus (CAEBV) infection. Examination of the patient's pleural effusion revealed large abnormal lymphocytes, which were CD2(+), CD7(+), CD30(+), CD56(+), CD3(-), and CD4(-). No rearrangement of T cell receptor genes was detected. Clonal proliferation of Epstein-Barr virus (EBV)-infected cells in pleural effusion was demonstrated by Southern blot hybridization analysis. Human herpesvirus type-8 (HHV-8) DNA was not detected in these cells. The patient achieved a complete remission with combination chemotherapy. Prior to the clinical onset of lymphoma, high fever of unknown origin had persisted for 21 months. IgG antibodies to EBV-viral capsid antigen and to EBV-early antigens, types D and R were not high (1:160 and less than 1:10, respectively). Two months after the onset of fever, however, retrospective quantitative PCR assay revealed a high EBV DNA load in plasma, indicating that CAEBV infection had been the cause of the patient's recurrent fever. The remarkable features of this case are (i) the development of lymphoma following CAEBV infection that demonstrated a normal pattern of EBV-specific antibodies, (ii) the development of HHV-8-negative body cavity lymphoma, and (iii) the effectiveness of combination chemotherapy.