Clinical efficacy of carbapenems on hospital-acquired pneumonia in accordance with the Japanese Respiratory Society Guidelines for management of HAP.

Hospital-acquired pneumonia (HAP) is the second most common cause of hospital-acquired infection and is the leading cause of death. In 2002, the Japanese Respiratory Society (JRS) published guidelines for the diagnosis and treatment of HAP (JRS GL 2002). In these guidelines, treatment with carbapenems is recommended for all disease types of HAP, excluding cases of mild or moderate pneumonia with no risk factors, and cases with early-onset ventilation-acquired pneumonia. To evaluate the efficacy of carbapenems on HAP in accordance with JRS GL 2002, we conducted a prospective study of HAP patients treated with carbapenems based on JRS GL 2002. The results of this study were also analyzed based on the revised guidelines published in June 2008 (JRS GL 2008), and the validity of the new guidelines was examined. Of the 33 subjects, 19 were judged as responders to the treatment, corresponding to a response rate of 57.6%. There were 3 deaths, corresponding to a mortality rate of 9.1%. The efficacy of carbapenems for the treatment of HAP based on JRS GL 2002 was confirmed. The severity rating system in JRS GL 2002 has a tendency to overestimate the severity of the cases and may lead to overtreatment in some cases. On the other hand, the severity rating system by JRS GL 2008 seemed to be more accurate and closely correlated with the efficacy of the treatment. It is suggested that JRS GL 2008 is more useful in clinical practice for accurately judging the severity of the disease and initiating appropriate subsequent antibiotic therapy.

High frequency of ß-lactamase-negative, ampicillin-resistant strains of Haemophilus influenzae in patients with chronic bronchitis in Japan.

In Japan, the increasing incidence of ß-lactum-resistant Haemophilus influenzae infections is of growing concern. We retrospectively studied whether the prevalence of ß-lactamase-negative ampicillin-resistant strains of H. influenzae was influenced by chronic lung diseases. H. influenzae isolates, obtained from patients who were diagnosed with acute or chronic bronchitis, or acute exacerbation of chronic bronchitis in 2005, were studied. In addition to susceptibility testing, polymerase chain reaction (PCR) was performed for the detection of TEM-1 ß-lactamase, and Asn526-Lys and Ser385-Thr amino acid substitutions in the ftsI gene encoding penicillin-binding protein-3 (PBP-3). The minimum inhibitory concentration values of ß-lactams were found to be increased in isolates from patients with chronic bronchitis who had been repeatedly administered antibiotics. Genetic analysis using PCR suggested that this might be associated with a high frequency of ß-lactamase-negative strains with mutations in PBP-3. The presence of ß-lactum-resistant strains needs to be considered for patients with chronic bronchitis in whom H. influenzae is isolated as a causative pathogen.

[ELISPOT response to Mycobacterium tuberculosis antigens for diagnosing and monitoring tuberculosis patient therapy].

BACKGROUND: Using the ELISPOT assay, a promising immunological tool for detecting Mycobacterium tuberculosis (MTB) antigen-specific response, we monitored the clinical course of patients with tuberculosis (TB). METHODS: Blood samples were obtained from 35 patients with TB and healthy controls, numbering 52 age-matched control subjects and 43 university students. Nine of those with TB were examined twice before and after anti-tuberculosis treatment. The frequency of IFN-gamma secreting cells was determined using the ELISPOT assay in peripheral mononuclear cells (PBMC) stimulated with purified protein derivative (PPD), early secretory antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP-10). RESULTS: The frequency of PPD secreting cells correlated significantly with tuberculin skin test (TST) magnitude in BCG-vaccinated individuals. Significant responses to either ESAT-6 or CFP-10 were found in 94% of those with TB. The frequency of IFN-gamma secreting cells decreased when negative sputum tests were confirmed by successful tuberculosis treatment. CONCLUSIONS: The ELISPOT assay detecting MTB-specific immune response is promising both in diagnosing MTB and monitoring responsiveness to tuberculosis therapy.

[Trends in antibiotic susceptibility and genetic beta-lactam resistance patterns among Haemophilus influenzae cases isolated from adult patients with respiratory tract infection].

Haemophilus influenzae, a major respiratory tract pathogen, is becoming increasingly resistant to beta-lactam antibiotics. Studying annual trends in antibiotic susceptibility and genetic patterns of H. influenzae beta-lactam resistance, we isolated 122 strains from the adult respiratory tract in 2007, determined MIC for different antibiotics, and analyzed TEM-1 beta-lactamase resistant genes and ftsI encoding PBP3 mutation compared to results in 2005 and 2007. We found that ABPC-susceptible strains with MIC <1 microg/mL (BLNAS) accounted for 71.0%, ABPC-resistant strains with MIC exceeding 2 microg/mL without beta-lactamase activity (BLNAR) for 25.3%, and beta-lactamase-positive strains (BLP) for 3.7%. The BLNAS ratio showed no significant change from 2002 and 2005. The BLP ratio decreased from those in 2002 and 2005. Genetic studies of resistant genes showed that gBLNAS with no resistant genes had increased in the last five years. The ratio of all strains with PBP3 mutation (gBLNAR and gLow-BLNAR) remained constant from 2002 to 2007. The proportion of gBLNAR with two PBP3 mutations had increased, however, while gLow-BLNAR with one mutation had decreased. LVFX showed constant strong antimicrobial potency for all mutation groups. Among beta-lactam antibiotics, the lowest MIC90 was observed in parenteral CTRX and oral CDTR-PI use. Although a new MIC peak generated by gBLNAR became obvious in the ABPC and CDTR-PI MIC distribution, the MIC of the new peak was still low enough to treat with high doses of those two antibiotics.

[The preventive effect of 23-valent pneumococcal polysaccharide vaccine against drug-resistant Streptococcus pneumonia in patients with chronic respiratory disease].

OBJECTIVE: To elucidate the preventive effect of 23-valent pneumococcal polysaccharide vaccine (PV) on drug-resistant Streptococcus pneumoniae. METHODOLOGY: Participants (outpatients, over 60 years of age, and with chronic lung disease) were interviewed and divided into two groups: the PV-vaccinated group (n=722) and the non-vaccinated group (n=872). The antimicrobial susceptibility and the genotype of antibiotic-resistant genes among the isolated pneumococcal strains from sputum before and after vaccination were studied. RESULTS: The number of the isolated strains was as follows: prior to the vaccination, 24 isolates in the vaccinated group, 18 isolates in the non-vaccinated group; after vaccination (within 5 years), 53 isolates in the vaccinated group, 46 isolated in the non-vaccinated group. The PV decreased the frequency of Penicillin G-resistant strains successfully (from 16.7 to 7.5%) in the vaccinated group while the frequency increased (from 5.5 to 15.2%) in the non-vaccinated group during the same period. In genetic analysis, the rates of strains with altered pbpla, pbp2x and pbp2b were decreased in the vaccinated group than the non-vaccinated group (28.6% versus 53.3%). CONCLUSIONS: The 23-valent pneumococcal polysaccharide vaccine may have a preventive effect against drug-resistant Streptococcus pneumoniae.

[A case of lymphocytic interstitial pneumonia complicated with primary Sjögren's syndrome followed by chest CT scanning for thirteen years].

We encountered a rare case of lymphocytic interstitial pneumonia (LIP) complicated with primary Sjögren's syndrome (SjS), followed by chest CT scanning for a long period of time. A 54-year-old man with hemoptysis was admitted to our hospital in December, 2001. A diagnosis of SjS was made based on elevation of anti-SS-B/La antibody titer in serum in combination with diagnosis of keratoconjunctivitis sicca and xerostomia on a Schirmer test and a lip biopsy, respectively. Subsequent histopathological diagnosis by open lung biopsy showed LIP. Chest CT in September, 1995 at previous hospital revealed ground-glassed opacity (GGO), small nodules, thickened bronchovascular bundles and cyst formation in lungs. Chest CT was performed every year until 2008, when remarkable progression from thickened bronchovascular bundles accompanied by nodular opacities to an air-space consolidation in the right lower lobe was observed. Also, appearance of cyst formation in the right middle lobe, nodular lesions and GGO in the left lower lobe were noticed. Although the nodular opacities and GGO improved after an administration of corticosteroid (PSL 0.5 mg/kg/day), little improvement in the consolidations and cyst formation was demonstrated. In conclusion, it was suggested that differences among CT findings of LIP may be important for evaluating of efficacy of treatment by steroid agents for LIP associated with SjS.

[Clinical and pathological analysis of 10 cases of secondary pneumothorax due to angiosarcoma of the scalp].

Angiosarcoma of the scalp is a very rare disease. Secondary pneumothorax is known as a characteristic complication in this disease due to lung metastasis. In this study, 17 patients of angiosarcoma of the scalp, diagnosed at our hospital between 1996 and 2006, were analyzed. Secondary pneumothorax was observed in 10 of these patients, among which bilateral pneumothorax occurred in 5 relapse of pneumothorax occurred in 6 and pneumothorax with bloody pleural fluid occurred in 7 patients. Characteristic findings on chest CT were multiple thin-wall cavities and ground-glass attenuation around the cavity, located in bilateral subpleural lung fields. It is suggested that the subpleural thin-wall cavities cause pneumothorax. Although pleurosclerosis were performed in 5 patients and one of them had a subsequent partial resection of the lung, pneumothorax reocurred within a short period of time in all patients. The average survival time from the first pneumothorax episode was only 4.1 months. Secondary pneumothorax caused by this disease was intractable, resulting in an unfavorable outcome. It is necessary to develop a proper treatment strategy for secondary pneumothorax to create a favorable prognosis in this disease.

Metastatic brain mass caused by slow-growing small-cell lung cancer: differential vascular endothelial growth factor expression in primary and metastatic tumor.

Brain metastasis is a critical complication of small-cell lung cancer (SCLC), resulting in rare long-time survival. We report a case of a 72-year-old man who displayed a very unique clinical appearance, with a large metastatic brain tumor that grew much faster than primary SCLC. The brain tumor expressed high levels of vascular endothelial growth factor (VEGF) that was negative in primary lung tumor. The patient, who underwent brain surgery and chemotherapy against SCLC, has survived for > 2 years with a good performance status since initial brain symptoms occurred. Weak expression of VEGF in primary tumor might be associated with good prognosis. However, VEGF upregulation could occur after metastasis, resulting in aggressive tumor growth.

[Familial occurrence of bronchiolitis obliterans associated with pulmonary aspergillosis].

We report the familial occurrence of bronchiolitis obliterans (BO) associated with pulmonary aspergillosis. A mother and daughter admitted for dyspnea after taking Sauropus androgynus both had overfiltration of both lungs in chest X-ray and severe obstructive impairment in lung function tests. They were initially diagnosed with severe asthma and treated with high-dose prednisolone (0.5mg/kg/day) for 1 month to no effects. They did not show reversibility in lung function test. They were difinitively diagnosed with BO associated with Sauropus androgynus. Six months later, the mother's symptoms worsened with productive sputum and severe dyspnea, and her chest X-ray showed patty shadow in both upper lung fields. Precipitating antibodies to aspergillus antigen were positive and aspergillus fumigatus was detected from her sputum culture. She was diagnosed with aspergillosis and treatment with Micafungin (MCFG) and Itraconazole (ITCZ) was started. The daughter's symptoms also worsened and her chest tomography showed multiple cavities in both lung fields. Precipitating antibodies to aspergillus were positive. She was diagnosed with Invasive aspergillosis. She was treated unsuccessfully with MCFG and Amphotericin B (AMPH) and ITCZ. Few reports cover BO with aspergillus infection without organ impairment. In these 2 cases, treatment with steroids' or immune suppression of the lung with BO may a trigger aspergillus infection.

[Outcome of patients with acute exacerbation of idiopathic interstitial fibrosis (IPF) treated with sivelestat and the prognostic value of serum KL-6 and surfactant protein D].

Idiopathic interstitial fibrosis (IPF) is a chronic, usually fatal lung disease of unknown etiology. There are few specific therapies for acute exacerbation of IPF and factors predicting the onset or severity of this syndrome are not clearly understood. A neutrophil elastase inhibitor, sivelestat (ONO-5046) has been commercially available in Japan since 2002. This inhibitor has a potent effect in the treatment of ALI/ARDS. To evaluate the outcome of patients with acute exacerbation of IPF treated with sivelestat and estimate prognostic factors, we investigated 10 patients with acute exacerbation of IPF who were intubated and mechanically ventilated. We analyzed the outcome of patients with acute exacerbation of IPF until day 180 and measured the P/F ratio, PEEP levels, the values of peripheral white blood cell number, and C-reactive protein (CRP) on day 0, 3, 7 after admission. Serum KL-6 and surfactant protein D (SP-D) concentration on day 0 were also analyzed. All patients were treated with sivelestat and methylprednisolone (mPSL) pulse therapy for 3 days from day 0 and maintenance therapy with prednisone (0.5 mg/kg/day) were continued. Of the 10 patients. 4 patients had survived (40%) and 6 patients had died (60%) at day 180 from the onset of acute exacerbation of IPF. In survivors, P/F ratio, PEEP levels, and CRP values significantly improved on day 7 (p<0.05). Serum KL-6 and SP-D were lower in survivors on day 0 (p<0.05). Taken together, serum KL-6 and SP-D may prove valuable as biochemical markers of prognosis in acute exacerbation of IPF. Sivelestat may have potential in the treatment of acute exacerbation of IPF.

[Familial occurrence of bronchiolitis obliterans associated with sauropus androgynus].

We experienced familial occurrence of bronchiolitis obliterans (BO) associated with Sauropus androgynus. The cases were a mother and daughter and both were admitted to our hospital because of dyspnea after taking Sauropus androgynus. Both cases had hyperinflation of both lungs in chest x-ray and lung function test showed severe obstructive impairment. At first, they were given a diagnosis of severe asthma and treated as such. However, neither their symptoms nor lung function improved. They did not show any reversibility on lung function tests. Although we did not perform histological examination of the lung, they were given a diagnosis of BO associated with Sauropus androgynus (SABO), because of the following reasons. Cases of SABO in Taiwan have already been demonstrated in the 1990's, and there were no other reasons to explain their severe airflow obstruction. Neither bronchodilators nor steroid treatment improved airflow obstruction. BO is rare and can mimic asthma and chronic obstructive pulmonary disease (COPD). We should inquire about the intake of food or medication in cases suspected BO.

[Gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer].

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We analyzed 19 patients with advanced NSCLC retrospectively, who were treated with gefitinib as a first-line therapy. These patients were not considered for systemic chemotherapy secondary to co-morbid conditions, poor performance status (PS) or refusal of chemotherapy. RESULTS: Median age 68 years, male/female 10/9, stage III/IV 7/12, smoker/non-smoker 12/7, adenocarcinoma/non-adeno 13/6, PS 0/1/2/3/4 0/4/7/5/3. Four patients had a partial response and the overall response rate was 21.0%. The median survival time was 6.8 months and 1-year survival was 27%. Overall toxicities were mild. Grade (G) 3 diarrhea was observed in one patient and G1 interstitial pneumonia in one. CONCLUSIONS: These results demonstrate that gefitinib is active as a first-line therapy in patients with advanced NSCLC.

[Effectiveness of pneumococcal polysaccharide vaccine in older patients with chronic respiratory diseases].

To evaluate effectiveness of pneumococcal polysaccharide vaccine, we recommended 1378 outpatients aged over 60 with chronic respiratory diseases to be vaccinated from August to October 2002, and 647 patients were vaccinated from August to November 2002. In the 1229 patients without respiratory failure, the incidence of antimicrobial treatment for bacterial respiratory infections in 547 vaccinated patients significantly decreased from 7.9% in the 2001/02 winter season to 5.7% in the 2002/03 winter season, although that in the 682 unvaccinated patients increased from 3.8% to 5.7%. The incidence of antimicrobial treatment for bacterial respiratory infections in 229 vaccinated patients with pneumococcal and influenza vaccines together significantly decreased from 10.5% in the 2001/02 winter season to 5.2% in 2002/03 winter season although that in 110 subjects vaccinated with influenza vaccine only increased from 2.7% to 7.2%. These findings suggest the effectiveness of the pneumococcal polysaccharide vaccine for the prevention of bacterial respiratory infections and the additive effectiveness of pneumococcal and influenza vaccines together.

[Combination chemotherapy with carboplatin and weekly Paclitaxel in patients with advanced non-small cell lung cancer].

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of carboplatin plus weekly paclitaxel as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Forty-nine patients were analyzed retrospectively. Every 4 weeks patients received 70 mg/m(2)paclitaxel on days 1, 8, and 15, and AUC 5-6 carboplatin on day 1. RESULTS: A median of four cycles (range, 1-7) was administered. Twenty-four patients had a partial response, and the overall response rate was 48.9%. The median survival time was 12.8 months and the 1-year survival was 50.7%. Overall toxicities were mild. The most common toxicity was neutropenia, grade 3/4 in 32% of the patients. Grade 3/4 hematologic toxicities included anemia (16%) and thrombocytopenia (8%). Grade 3/4 non-hematologic toxicities included febrile neutropenia (2%), pneumonia (10%) and interstitial pneumonia (2%). Grade 2 peripheral neuropathy was seen in one patient (2%). CONCLUSIONS: These results demonstrate that this regimen is an active and tolerable treatment for patients with advanced NSCLC. It is suggested that this weekly regimen should be considered as one of the standard therapies for future chemotherapy in advanced NSCLC.

[Usefulness of urinary antigen and sputum Gram stain for rapid diagnosis of pneumococcal respiratory infections].

We evaluated the usefulness of a rapid urinary antigen detection kit (Binax NOW) to detect Streptococcus pneumoniae in the early diagnosis of pneumococcal respiratory tract infections in 313 patients with presumptive respiratory tract infections. We compared results of this test with those of sputum Gram staining. Urinary antigen and sputum Gram staining were respectively positive in 37 and 36 of 57 patients with pneumococcal respiratory infections. The urinary antigen showed moderate positive rate of 64.9% and low false positive rate of 2.3%. The sputum Gram staining also showed moderate positive rate of 64.3% and low false positive rate of 3.5%. Pneumococcal antigen was more frequently detected in patients with severe pneumococcal infections (6/6) than those with mild (5/10) and moderate (26/41) infections. Of the 9 patients who had received antibiotics before testing, antigen was detected in 8 but positive results of sputum Gram stain were in 4. In conclusion, urinary antigen test is a useful test for early diagnosis of pneumococcal respiratory infections especially in adult patients with moderate or severe infections for whom demonstrative results of a sputum Gram stain is unavailable, even after commencement of antibiotic treatment.

[Understanding of pneumococcal vaccination in patients with chronic respiratory diseases].

Pneumococcal vaccination is still rare in Japan. To evaluate understanding concerning the vaccination, we employed a questionnaire answered by patients aged over 60 with chronic respiratory diseases from August to October 2002. Only 286 (18%) of the 1595 patients already knew of the existence of the vaccine, and 999 (64%) patients wanted to be vaccinated. That season, 717 (43%) patients were actually vaccinated. Patients with chronic respiratory failure, those who had contracted pulmonary infections in the previous year, those over 70 year-old, and male patients tended to be vaccinated. Although elderly and high-risk patients are recommended to be vaccinated, the pneumococcal vaccination rates in those patients was low. Campaigns for vaccination are needed.

[Eighty cases of chronic respiratory failure treated with home noninvasive positive pressure ventilation].

We studied the clinical features and efficacy of home noninvasive positive pressure ventilation (NPPV) therapy in 80 patients to ascertain its indications and problems. The causes of chronic respiratory failure were restrictive thoracic diseases of post-tuberculosis sequelae (40 cases) and kyphoscoliosis (9 cases), COPD (8 cases), bronchiectasis (7 cases), and interstitial pneumonia (4 cases). One year survival rate of the patients with post-tuberculosis sequelae was 76% and most of the patients who started NPPV at their acute exacerbation died within several months. About half of the patients of COPD improved their quality of life (QOL) through NPPV. However, their survival rate 3 months later was only 69%. More than half of the patients with bronchiectasis felt that their QOL was improved by NPPV. Most of the patients with interstitial pneumonia died within 3 months indicating that NPPV is less useful for improving QOL of interstitial pneumonia PaCO2, after home NPPV, decreased significantly in the responder group (70.0 +/- 15.4 vs. 57.6 +/- 10.7[SD]Torr, p < 0.05), while PaCO2 in the non-responder group was unchanged (65.4 +/- 12.1 vs. 64.2 - 10.4 [SD] Torr). Body Mass Index (BMI) in the responder group tended to be higher than in the non-responder group. In conclusion, the restrictive thoracic diseases with post-tuberculosis sequelae and kyphoscoliosis are a good indication for NPPV and the therapy is also useful for patients with bronchiectasis who can dispose of their sputum by themselves. Home NPPV is suitable for patients whose PaCO2 decreases through NPPV and whose BMI is relatively high. QOL of interstitial pneumonia barely improves through NPPV, because interstitial pneumonia with hypercapnia is at the terminal stage.

[Pathogenesis of beta-lactam-resistant Haemophilus influenzae isolated from sputum].

Haemophlus influenzae persists in the respiratory tract and sometimes causes respiratory tract infections. To evaluate the pathogenesis of beta-lactam-resistant Haemophilus influenzae, we classified 193 Haemophilus influenzae strains isolated from sputum of patients with respiratory tract disease in 24 beta-lactamase positive (BLP) strains, 65 beta-lactamase negative ampicillin resistant (BLNAR) strains and 104 beta-lactamase negative ampicillin sensitive (BLNAS) strains and reviewed the pathogenesis of the strains. The pathogenesis of the strains was evaluated as definite pathogen, presumptive pathogen, colonization and contamination. It was judged to be the definite pathogen that many bacteria isolated from high quality sputum of the patients with respiratory tract infections. Presumptive pathogen was considered to be the bacteria provided from the patient with respiratory infections when the quality of the sputum or quantity of bacteria did not satisfy superscription basis. We considered the bacteria to be colonization or contamination isolated from patients without infections. The breakdown of definite pathogen/presumptive pathogen/colonization/contamination in each by groups was BLP (8/4/8/4), BLNAR (26/14/15/10), BLNAS (36/20/31/17). The ratio of definite or presumptive pathogen was 50% in BLP, 62% in BLNAR and 54% in BLNAS and the significant difference was not recognized in these. Pathogenesis of beta-lactam-resistant Haemophilus influenzae is estimated to be equal with beta-lactam-sensitive Haemophilus influenzae.

[Effect of glycyrrhizin on anti-tuberculosis drug-induced hepatitis].

In cases in which hepatotoxicity developed during anti-tuberculosis chemotherapy, the rapid recovery of liver function is essential for the completion of the anti-tuberculosis chemotherapy protocol. Glycyrrhizin (Stronger Neo-Minophagen C: SNMC) is widely used in Japan for the treatment of patients with drug eruption or chronic hepatitis. However, a consensus on the clinical effects of glycyrrhizin for the treatment of anti-tuberculosis drug-induced hepatitis has not yet been reached. We studied 24 cases who showed abnormal liver function test results while undergoing anti-tuberculosis chemotherapy and who were treated with or without glycyrrhizin. We then compared recovery periods of liver function among both groups. The time required for liver function normalization in the patients who received glycyrrhizin (SNMC, 40 ml daily, intravenously) was 15.1 +/- 4.5 days and the time required for normalization in the non-glycyrrhizin group was 15.2 +/- 5.2 days. The difference was not significant and the fact indicated that glycyrrhizin is not useful for the treatment of anti-tuberculosis drug-induced hepatitis.