Heterogeneity of the efficacy of the 23-valent pneumococcal polysaccharide vaccine caused by various underlying conditions of chronic pulmonary disease in older patients: prospective cohort study.

OBJECTIVE: To determine the ideal conditions for use of the 23-valent pneumococcal polysaccharide vaccine (PPV23) in older outpatients with chronic pulmonary diseases. DESIGN: Prospective cohort study. PARTICIPANTS: 1378 outpatients with chronic pulmonary diseases ≥ 60 years of age. INTERVENTION: Participants were educated about PPV23, and those who responded affirmatively were vaccinated between August and November 2002. The participants who chose no intervention served as controls. The prevaccine period was defined as August 2001 to August 2002. Participants were followed for 2 years from December 2002 or until death. MAIN OUTCOME MEASURES: Events of interest included the first episode of bacterial (including pneumococcal) pulmonary infection (primary endpoint) and death of any cause (secondary endpoint). RESULTS: Frequent episodes of pulmonary infection during the prevaccine period significantly decreased event-free survival during the 2-year observation period (p<0.001). Chronic respiratory failure was associated with a decreased event-free survival only when the pulmonary infection episode did not occur in the prevaccine period (p<0.001). No significant differences in event-free survival were observed between the vaccinated and unvaccinated group during analysis of the entire cohort. In the Cox proportional hazards regression model, event-free survival decreased significantly when pulmonary infection occurred in the prevaccine period. In the subgroup analysis, the first episode of bacterial pulmonary infection (but not death of any cause) was reduced significantly by PPV23 only in patients with chronic respiratory failure who had no episodes of pulmonary infection during the prevaccine period (p=0.019). CONCLUSION: The efficacy of PPV23 against pulmonary infection and death of any cause might be unachievable if pulmonary infection occurs during the prevaccine period. PPV23 needs to be given to older patients with chronic pulmonary disease at an earlier time in which infectious complications in the lung have not yet occurred.

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.

[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.

[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.

Grade I lymphomatoid granulomatosis with increased uptake of [18F] fluorodeoxyglucose in positron emission tomography: a case report.

There are several reports describing [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) findings in patients with lymphomatoid granulomatosis (LYG). We report a case of grade I LYG that showed increased uptake of FDG. The patient was a 63-year-old Japanese male who underwent an FDG-PET/computed tomography (CT) scan in screening for a malignant lesion. Increased uptake of FDG [maximum standard uptake value (SUV(max)), 3.7] was observed in the right hilar region in FDG-PET and enhanced CT revealed a round, abnormal mass that also showed increased FDG uptake. The patient had no previous symptoms. A tumor biopsy was performed and the histological diagnosis was grade I LYG. Therefore, increased SUV(max) in FDG-PET might be useful for diagnosing of LYG.

The efficacy of high-dose penicillin for community-acquired pneumonia diagnosed by pneumococcal urine antigen test.

We analyzed the efficacy of both the Streptococcus pneumoniae urine antigen test as a quick diagnostic tool and the administration of high-dose penicillin in response to a positive S. pneumoniae urine antigen test. We conducted a retrospective analysis of 48 cases of pneumococcal pneumonia, in which the patients were treated with high-dose penicillin. All the cases were diagnosed by a positive urine antigen test. Treatment with high-dose penicillin was effective in 43 of the 48 patients. This treatment was also effective in 12 of 16 culture-confirmed cases with low susceptibility to penicillin. Eleven patients who were positive for the S. pneumoniae urine antigen test but culture-negative showed clinical improvement with high-dose penicillin. Pneumonia caused by S. pneumoniae appeared to be treated safely and effectively with high-dose penicillin based on positive results of the urine antigen test, as penicillin resistance was unlikely to be a problem.

Potential clinical benefit of the in situ hybridization method for the diagnosis of sepsis.

Despite the significant development of antibiotics, sepsis is still associated with high morbidity and mortality rates. The identification of pathologic organisms at an early stage of sepsis is critical to improve the outcome, but this is difficult to achieve with the conventional method of blood culture (BC). It has been demonstrated that the genes of pathogenic organisms surviving in neutrophils were detectable with in situ hybridization (ISH) and this method was useful for the accurate and rapid diagnosis of sepsis. In this study, we applied ISH to blood smears 60 patients with suspected sepsis. BC was also carried out using the same blood samples to investigate the diagnostic value of ISH. The number of positive results obtained by ISH was approximately four times higher than that obtained by BC (ISH, 25 [41.7%]; BC, 7 [11.7%]). The positive rate in the 21 patients given antibiotics was 61.9% by ISH (13 patients) and 4.7% by BC (1 patient). The antibiotic treatments targeting the organisms detected by either procedure showed a beneficial clinical outcome. Positive results by ISH were obtained earlier than those with BC (ISH, within 1 day; BC, several days). We conclude that ISH is a useful method for the rapid diagnosis of sepsis.

[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.

Screening of tuberculosis by interferon-gamma assay before biologic therapy for rheumatoid arthritis.

Infection with Mycobacterium tuberculosis (M. tuberculosis) is a critical complication in anti-TNF therapies. In 141 BCG vaccinated healthy individuals and 71 rheumatoid arthritis (RA) patients as screening before anti-TNF therapies, M. tuberculosis specific immune responses were evaluated by tuberculin skin test (TST) and enzyme-linked immunospot assay (ELISPOT), which detected antigen specific IFN-gamma secreting cells in peripheral blood mononuclear cells simulated with either purified protein derivative (PPD), early secretory antigen target 6 (ESAT-6) or culture filtrate protein 10 (CFP-10). Induration over 5 mm in TST was found in 87.9% of controls and 21.4% of RA patients. Erythema size in TST was significantly suppressed in RA patients, especially those receiving prednisolone (PSL), whereas the PPD specific IFN-gamma secretion was less attenuated. Significant responses to either ESAT-6 or CFP-10 in ELISPOT were detected in 14.1% of RA patients including those having positive TST, while the ELISPOT assay was negative in all healthy individuals and 73.3% of RA patients having positive TST. Of ELISPOT positive RA patients, mean dosage of PSL was 4.58 mg and 1.25 mg in TST negative and positive patients, respectively. Thus, ELISPOT is useful for screening of tuberculosis in RA patients, even in those receiving corticosteroids.

[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.

[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.

[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 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.

[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.

[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.

[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.