Integrated multidisciplinary community service for chronic obstructive pulmonary disease reduces hospitalisations.

BACKGROUND: Hospitalisations for chronic obstructive pulmonary disease (COPD) exacerbation affect patient outcomes and healthcare costs. The long-term impact of an integrated COPD disease-management approach on hospitalisation remains controversial. AIM: The aim of this study was to evaluate whether a multidisciplinary community service reduces respiratory hospitalisations for COPD patients. METHODS: A total of 346 patients was followed for a mean duration of 27.3 months. The number of admissions, total bed days for respiratory (COPD exacerbation or pneumonia) or general medical causes and length of stay (LOS) per respiratory admission was compared before and after referral with the service. A secondary multivariate analysis examined which clinical parameters best predict benefit from such service. RESULTS: The total respiratory admission and hospital bed days after referral were reduced by 31% (288 vs 417, P < 0.001) and 40.4% (1637 vs 2746, P < 0.0001) respectively, compared with the equivalent duration prior. The average LOS for each respiratory admission was also significantly reduced after referral (6.61 vs 5.70, P = 0.02). Overall, 55% patients experienced a reduction in admission frequency and hospital days. The impact on admission frequency and hospital days was the greatest in those with an at least moderate disease (GOLD ≥2, odds ratio (OR): 3.2, 95% confidence interval (CI): 1.2, 8.9; P = 0.019) and those who completed pulmonary rehabilitation (PR) (OR: 1.7, 95% CI: 1.1, 2.8; P = 0.04). In contrast, general medical admissions increased, one-third attributable to a cardiovascular cause both before and after referral. CONCLUSIONS: The implementation of COPD multidisciplinary community service was associated with reduced respiratory hospitalisations in the long term. Patients with moderate or severe disease and who are able to complete PR are much more likely to benefit.

Characterisation of TNF block haplotypes affecting the production of TNF and LTA.

Polymorphisms in the central major histocompatibility complex (MHC) (particularly TNF and adjacent genes) associate with several immunopathological diseases and with susceptibility to pneumonia. The MHC is characterised by strong linkage disequilibrium (LD), so identification of loci affecting disease must be based on haplotypes. We have defined 31 tumour necrosis factor (TNF) block haplotypes (denoted FV1-31) in Caucasians, Asians and Australian Aboriginals. This study correlates the carriage of TNF block haplotypes with TNF and lymphotoxin alpha (LTA) protein production by peripheral blood mononuclear cells from 205 healthy Caucasian subjects, following in vitro stimulation with Streptococcus pneumoniae (S. pneumoniae; gram-positive bacteria), Escherichia coli (E. coli; gram-negative bacteria) or TNF over 4, 8 and 24 h. Fifteen haplotypes were present at >1%, accounting for 94.5% of the cohort. The haplotypes were grouped into five families based on common alleles. Following stimulation, cells from carriers of the FV10 haplotype (family 2) produced less LTA compared with non-FV10 carriers. Carriers of the FV18 haplotype (family 4) produced more LTA than other donors. Induction of TNF by S. pneumoniae following 24 h stimulation was also greater in donors with FV18. The FV18 haplotype associated with the 44.1 MHC ancestral haplotype (HLA-A2, -C5, -B44, -DRB1*0401 and -DQB1*0301) that has few disease associations. FV16 occurred in the 8.1 MHC haplotype (HLA-A2, B8, DR3) that is associated with multiple immunopathological diseases. FV16 did not affect TNF or LTA levels. The findings suggest that many genetic variations critical in vivo are not effectively modelled by short-term cultures.

Pharmacogenetics of ß2 adrenergic receptor gene polymorphisms, long-acting ß-agonists and asthma.

Adrenergic ß2 receptor (ADRß2) agonists are widely used in asthma. Approximately 10% of patients have severe, poorly controlled disease despite extensive use of ADRß2 agonists. Variations in responses to ADRß2 agonists can, in part, be attributed to genetic variation, with 49 different polymorphisms having been identified for the ADRß2 gene. Although clear associations exist between ADRß2 gene polymorphisms, such as +46G>A, and patient response, the importance of these polymorphisms remains controversial. Patient selection, the number of polymorphisms analysed, differences in the type/dose of ADRß2 agonist, use of inhaled corticosteroids and population sizes have all varied. Most studies were limited to mild or moderate asthmatics using ADRß2 agonists sparingly. It is difficult to extrapolate from these studies to individual patients who have severe asthma, use a variety of ADRß2 agonists and do so frequently. The extent to which ADRß2 gene polymorphisms are relevant to asthma management needs further review, both clinically and at the molecular level. In vitro studies have helped to define the functional changes induced by specific ADRß2 gene polymorphisms, including 3'-untranslated region poly-C repeat. The resulting ADRß2 gene haplotypes (rather than genotypes), the interactions among ADRß2 gene haplotypes and variations in the chemistry of different agonists deserve more detailed assessment. Responses to ADRß2 agonists depend on effective downstream signalling following ADRß2 activation and also on receptor regulation. Studies on other regulators of ADRß2 receptor signalling and trafficking may be equally important in understanding the functional role of ADRß2 gene polymorphisms. The role of ADRß2 gene polymorphisms in the pathogenesis and management of severe asthma cannot be clearly defined until more specific and targeted research studies are performed.

Posttransplant bronchiolitis obliterans syndrome is associated with bronchial epithelial to mesenchymal transition.

Bronchiolitis obliterans syndrome (BOS) compromises lung transplant outcomes and is characterised by airway epithelial damage and fibrosis. The process whereby the normal epithelial configuration is replaced by fibroblastic scar tissue is poorly understood, but recent studies have implicated epithelial mesenchymal transition (EMT). The primary aim of this study was to assess the utility of flow cytometry in detecting and quantifying EMT in bronchial epithelial cells. Large airway brushings were obtained at 33 bronchoscopies in 16 BOS-free and 6 BOS grade 1-3 patients at 2-120 months posttransplant. Flow cytometry was used to assess expression of the mesenchymal markers alphaSMA, S100A4 and ED-A FN and HLA-DR. TGF beta 1 and HGF were measured in Bronchoalveolar lavage (BAL). Expression of all three mesenchymal markers was increased in BOS, as was HLA-DR. BAL HGF, but not TGF beta 1 was increased in BOS. Longitudinal investigation of one patient revealed a 100% increase in EMT markers concurrent with a 6-fold increase in BAL TGF beta 1 and the diagnosis of BOS at 17 months posttransplant. Flow cytometric evaluation of bronchial epithelium may provide a novel and rapid means to assess lung allografts at risk of BOS.

Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia.

Recent studies suggest that macrolides may have beneficial effects for patients at risk for certain infections. The current authors examined the effect of macrolide therapy on 30- and 90-day mortality for patients with severe sepsis caused by pneumonia. A retrospective cohort study was conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had chest radiography consistent with, and had a discharge diagnosis of pneumonia and clinical criteria of severe sepsis. Subjects were considered to be on macrolides if they received at least one dose within 48 h of admission. Severe sepsis was present in 237 (30.1%) subjects, out of whom 104 (43.9%) received macrolides. Mortality was 20.3% at 30 days and 24.5% at 90 days. In the multivariable analysis, the use of macrolide was associated with decreased mortality at 30 days (hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.2-0.7) and at 90 days (HR 0.3, 95% CI 0.2-0.6) in patients with severe sepsis and in patients with macrolide-resistant pathogens (HR 0.1, 95% CI 0.02-0.5). Macrolide use was associated with decreased mortality in patients with severe sepsis due to pneumonia and macrolide-resistant pathogens. Confirmatory studies are needed to determine whether macrolide therapy may be protective for patients with sepsis.

The microsatellite, macrophage migration inhibitory factor -794, may influence gene expression in human mononuclear cells stimulated with E. coli or S. pneumoniae.

Polymorphisms within the gene encoding macrophage migration inhibitory factor (MIF) have been associated with susceptibility to inflammatory diseases such as rheumatoid arthritis and increased risk of developing sepsis. We investigated the effects of the MIF-173G>C polymorphism and the MIF-794 CATT microsatellite on MIF expression. These are in moderate linkage disequilibrium. Mononuclear cells from healthy donors were stimulated with bacterial pathogens associated with sepsis (Streptococcus pneumoniae or Escherichia coli ). MIF mRNA and protein levels were measured by real-time polymerase chain reaction and ELISA, respectively. Carriage of the C allele of MIF-173G>C or the 7 CATT repeat of the MIF-794 microsatellite correlated with lower basal and stimulated MIF mRNA levels. However, levels of intracellular and extracellular MIF protein were similar. This discordance between effects on MIF mRNA and protein was not explained by differential effects of genotype on stability of MIF mRNA (detected by actinomycin D mRNA chase). Gel shift assays revealed no differences in the profile of nuclear proteins from mononuclear cells bound by the G and C alleles of MIF-173G>C, but alleles at the microsatellite marker showed differential binding. Our data suggest that the MIF-794 CATT microsatellite influences transcription by differential binding of nuclear transcription factors. This may impact on inflammatory processes.

Genetic variation in heat shock protein 70 is associated with septic shock: narrowing the association to a specific haplotype.

Heat shock protein 70 (HSP70) plays a major role in immune responses. Polymorphisms within the gene have been associated with development of septic shock. This study refines the region of the HSP70 gene associated with development of septic shock and confirms its functionality. Subjects (n = 31) were grouped into one of three haplotypes based on their HSPA1B-179C>T and HSPA1B1267A>G genotypes. Mononuclear cells from these subjects were stimulated with heat-killed bacteria (10(7 )colony-forming units/mL Escherichia coli or Streptococcus pneumoniae) for 8 and 21 h. HSP70 and tumour necrosis factor (TNF) mRNA and protein levels were measured by reverse transcriptase-polymerase chain reaction and ELISA, respectively. The HSPA1B-179*C:1267*A haplotype was associated with significantly lower levels of HSPA1B mRNA and protein and higher production of TNF mRNA and protein compared to the other haplotypes. Induction of HSP70 was TNF independent. These results suggest that the HSPA1B-179C>T:1267A>G haplotype is functional and may explain the association of the HSP70 gene with development of septic shock.

Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia.

BACKGROUND: Although monotherapy for pneumococcal pneumonia is standard, a survival benefit of combination beta-lactam and macrolide therapy has been suggested. HYPOTHESIS: Initial empirical therapy with a combination of effective antibiotic agents would have a better outcome than a single effective antibiotic agent in patients with bacteremic pneumococcal pneumonia. METHODS: A review of adult bacteremic pneumococcal pneumonia within the Methodist Healthcare System, Memphis, Tenn, between January 1, 1996, and July 31, 2000. Empirical therapy was defined as all antibiotic agents received in the first 24 hours after presentation. On the basis of culture results, empirical therapy was classified as single effective therapy (SET), dual effective therapy (DET), or more than DET (MET). Acute Physiology and Chronic Health Evaluation II (APACHE II)-based predicted mortality, and Pneumonia Severity Index scores were calculated. RESULTS: Of the 225 patients identified, 99 were classified as receiving SET, 102 as receiving DET, and 24 as receiving MET. Compared with the other groups, patients who received MET had statistically significantly more severe pneumonia as measured by the Pneumonia Severity Index score (P =.04) and predicted mortality (P =.03). Mortality within the SET group was significantly higher than within the DET group (P =.02, odds ratio, 3.0 [95% confidence intervals, 1.2-7.6]), even when the DET and MET groups (P =.04) were combined. In a logistic regression model including antibiotic therapy and clinical risk factors for mortality, SET remained an independent predictor of mortality with a predicted mortality-adjusted odds ratio for death of 6.4 (95% confidence intervals, 1.9-21.7). All deaths occurred in patients with a Pneumonia Severity Index score higher than 90, and the predicted mortality-adjusted odds ratio for death with SET in this subgroup was 5.5 (95% confidence intervals, 1.7-17.5). CONCLUSIONS: We found that SET is associated with a significantly greater risk of death than DET. Therefore, monotherapy may be suboptimal for patients with severe bacteremic pneumococcal pneumonia who have Pneumonia Severity Index scores higher than 90.

Legionella and community-acquired pneumonia: a review of current diagnostic tests from a clinician's viewpoint.

Many physicians are unaware of the limitations of the available tests for diagnosing infections with Legionella organisms. Geographic differences in the importance of nonpneumophila Legionella species as pathogens are underrecognized, in part because available diagnostic tests are biased toward the detection of pneumophila serogroup 1. Routine laboratory practices reduce the likelihood of culturing Legionella species from clinical isolates. Failure of seroconversion is common, particularly with nonpneumophila species; even when seroconversion occurs, it may take much longer than 4 weeks. Urinary antigen testing has insufficient sensitivity to affect clinical management in most regions of the United States, as it can reliably detect only L. pneumophila serogroup 1 infections. Polymerase chain reaction-based techniques offer hope of providing highly sensitive, rapid diagnostic tests for all Legionella species, but limitations in the current tests will make validating them difficult.

The impact of blood cultures on antibiotic therapy in pneumococcal pneumonia.

INTRODUCTION: The cost-effectiveness of blood cultures in community-acquired pneumonia (CAP) has been questioned. Although penicillin-resistant Streptococcus pneumoniae is an increasing problem, penicillin therapy, where appropriate, reduces cost and may reduce antibiotic resistance. Blood cultures, however, can only reduce cost if physicians are prepared to alter therapy based on the results. We reviewed our experience to determine how often physicians changed management based on blood culture results positive for S pneumoniae. METHODS: Retrospective chart review was performed of all CAP admissions between January 1996 and December 1998 with blood culture results positive for S pneumoniae. RESULTS: Seventy-four patients out of 1,805 patients admitted with CAP during this period had pneumococcemia. Penicillin resistance was identified in 15 cases (20.3%; high grade in 4 cases) with cephalosporin resistance in 4 of these cases (1 high grade). Fifty-one patients had initial empiric therapy with a third-generation cephalosporin, and 58 patients had empiric coverage of atypical organisms; no patient received empiric penicillin therapy. Blood culture results altered management in 31 patients (41.9%), but in only 2 cases was this due to antibiotic resistance. Fifty-one patients without penicillin allergy grew penicillin-sensitive pneumococci; only 11 patients (21.6%) were changed to penicillin therapy. Thirteen of 35 patients (37.1%) who were given an additional antibiotic for atypical coverage had this antibiotic ceased. CONCLUSION: Despite evidence of penicillin-sensitive pneumococcal CAP, physicians were reluctant to narrow antibiotic therapy, potentially adding to treatment cost and reducing the impact of blood culture results on management. The impact of penicillin resistance was reduced by the usual empiric choice of a third-generation cephalosporin. While positive blood culture results can clearly be useful in the management of patients with CAP, their cost-effectiveness needs to be assessed in prospective clinical trials.

Airflow limitation is underrecognized in well-functioning older people.

OBJECTIVES: Dyspnea is a common symptom in older people. A reduced forced expiratory volume in 1 second (FEV1) is associated with a higher mortality rate from cardiovascular and respiratory disease, and increased admissions to hospitals. Underrecognized or undertreated airflow limitation may exacerbate the problem. The purpose of this study was to assess the prevalence and treatment of airflow limitation in a cohort of well-functioning older people. DESIGN: Cross-sectional study. SETTING: Baseline of a clinical-epidemiological study of incident functional limitation. PARTICIPANTS: Participants attended the baseline examination of the Health, Aging, and Body Composition study, a prospective cohort study of 3,075 well-functioning subjects age 70 to 79. MEASUREMENTS: Demographic and clinical data were collected by interview. Spirometry was performed unless contraindicated and repeated until three acceptable sets of flow-volume loops were obtained. Patients on bronchodilator medications had spirometry performed posttherapy. Blinded readers assessed the flow-volume loops, and inadequate tests were omitted from analysis. Airflow limitation was defined as a reduced forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) as determined by age-, sex-, and race-normalized values. Severity of airflow limitation was defined by American Thoracic Society criteria. RESULTS: Two thousand four hundred eighty-five subjects (80.8%) had assessable spirometry and data on treatment and diagnosis (1,265 men, 1,220 women). The mean age was 73.6 years. Two hundred sixty-two subjects (10.5%) had airflow limitation; 43 (16.4%) of these never smoked. Only 37.4% of participants with airflow limitation and 55.6% of participants with severe airflow limitation reported a diagnosis of lung disease. Only 20.5% of subjects with at least moderate airflow limitation had used a bronchodilator in the previous 2 weeks. CONCLUSION: Despite their good functional status, airflow limitation was present, and underrecognized, in a considerable proportion of our older population. The low bronchodilator use suggests a significant reservoir of untreated disease. Physicians caring for older people need to be more vigilant for both the presence, and the need for treatment, of airflow limitation.

Controversies in the diagnosis of ventilator-acquired pneumonia.

The appropriate investigation of patients with suspected VAP is controversial. Because it is unlikely that any new diagnostic technique will become available in the near future with better performance characteristics than those currently available, physicians need to tailor their diagnostic approach depending on individual patients and clinical scenarios. The most crucial factor in deciding which diagnostic approach to take is the influence that any test result would have on management. If preliminary screening tests, including Gram stain, are used to determine whether to start antibiotic therapy, invasive diagnostic techniques have an advantage over ETA. Quantitative cultures of respiratory specimens have a higher specificity than qualitative cultures and should be used if there is any possibility that a negative culture result would result in the discontinuation of antibiotic therapy. Physicians are caught between the need to treat VAP promptly with appropriate antibiotics and the undeniable problems of multidrug-resistant bacteria and their association with inappropriate antibiotic use. When clinically possible, a diagnostic strategy should be chosen that maximizes the possibility of limiting broad-spectrum antibiotic use. To give physicians greater comfort in the ability to withhold or discontinue antibiotics safely, further research is needed into the appropriate diagnostic strategies in different clinical settings that make this possible. The studies by Fagon et al and Singh et al are important steps in this direction.

The influence of the severity of community-acquired pneumonia on the usefulness of blood cultures.

The value of blood cultures in community-acquired pneumonia (CAP) has been questioned. At issue is the potential for blood cultures to change management. We prospectively studied the yield and impact of blood cultures in patients admitted with CAP. Two hundred and nine subjects had at least two blood cultures prior to receiving antibiotics. The severity of CAP was graded using the Pneumonia Severity Index (PSI). Twenty-nine patients (13.9%) had a pathogen identified by blood culture. The yield of blood cultures increased with PSI grade (I--5.3%, II--10.2%, III--10.3%, IV--16.1%, V--26.7%), as did the likelihood of blood cultures changing antibiotic therapy (I to III--0%, IV--9.7%, V--20.0%). One hundred and seventy-nine (85.6%) patients received a quinolone, limiting the impact of pathogens resistant to beta-lactams. Four of 16 patients (25.0%) with a culture (blood or sputum)-guided change in antibiotic therapy died, compared to five of 31 patients (16.1%) who had an empiric change. Blood cultures are of minimal value in mild to moderate CAP, and should be limited to patients with PSI grade IV or V CAP unless a specific risk factor for pathogens resistant to the empiric therapy is present.

Empyema thoracis: new insights into an old disease.

Pleural infection is a disease of historical importance and is still a modern menace, with incidences rising in adults and children, and a significant mortality in adults. Basic research is hampered by limitations with in vivo models, and the bacteriology of empyema is complex. The role of thoracic ultrasound in guiding investigation and drainage of empyema is clear. Prompt treatment with appropriate systemic antibiotics and chest tube drainage are the key; in cases of failure of these measures, thoracic surgery is of proven efficacy in the treatment of this age-old disease.