Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial.

PURPOSE: Bone marrow-derived, allogeneic, multipotent adult progenitor cells demonstrated safety and efficacy in preclinical models of acute respiratory distress syndrome (ARDS). METHODS: This phase 1/2 trial evaluated the safety and tolerability of intravenous multipotent adult progenitor cells in patients with moderate-to-severe ARDS in 12 UK and USA centres. Cohorts 1 and 2 were open-label, evaluating acute safety in three subjects receiving 300 or 900 million cells, respectively. Cohort 3 was a randomised, double-blind, placebo-controlled parallel trial infusing 900 million cells (n = 20) or placebo (n = 10) within 96 h of ARDS diagnosis. Primary outcomes were safety and tolerability. Secondary endpoints included clinical outcomes, quality of life (QoL) and plasma biomarkers. RESULTS: No allergic or serious adverse reactions were associated with cell therapy in any cohort. At baseline, the cohort 3 cell group had less severe hypoxia. For cohort 3, 28-day mortality was 25% for cell vs. 45% for placebo recipients. Median 28-day free from intensive care unit (ICU) and ventilator-free days in the cell vs. placebo group were 12.5 (IQR 0,18.5) vs. 4.5 (IQR 0,16.8) and 18.5 (IQR 0,22) vs. 6.5 (IQR 0,18.3), respectively. A prospectively defined severe ARDS subpopulation (PaO2/FiO2 < 150 mmHg (20 kPa); n = 16) showed similar trends in mortality, ICU-free days and ventilator-free days favouring cell therapy. Cell recipients showed greater recovery of QoL through Day 365. CONCLUSIONS: Multipotent adult progenitor cells were safe and well tolerated in ARDS. The clinical outcomes warrant larger trials to evaluate the therapeutic efficacy and optimal patient population.

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.

A diplotype in the lymphotoxin alpha gene is associated with differential expression of LTA mRNA induced by Gram-positive and Gram-negative bacteria.

We sequenced the lymphotoxin alpha (LTA) promoter and identified LTA10G>A in strong linkage with LTA252G>A and LTA723C>A. Stimulated cells from LTA723AA: LTA252GG:LTA10AA individuals had significantly higher LTA mRNA levels than LTA723CC:LTA252AA:LTA10GG and LTA723AA:LTA252AG:LTA10GA individuals, suggesting that this diplotype may contain a functional polymorphism explaining the observed disease associations with LTA252G>A.

[Stakes, treatment strategies and progression of MRSA nosocomial pneumonia, especially pneumonia due to mechanical ventilation]. / Enjeux, stratégies de traitement et évolution des pneumonies nosocomiales à SARM, notamment les pneumonies acquises sous ventilation mécanique.

THE IMPORTANCE OF THE INITIAL TREATMENT: Many studies have shown excess mortality during acquired pneumonia with mechanical ventilation when the initial antibiotic treatment is inappropriate, even following subsequent adaptation of the latter. EFFICACY OF TREATMENT: From a clinical point of view, since the regression of the various signs appears after varying time lapses, it is not easy to judge within the first three days the efficacy of an antibiotic. From a microbiological point of view, the bacterial concentrations observed at the time of diagnosis decrease within the first two days, when the response to treatment is favorable. PROBLEMS WITH VANCOMYCIN: Treatment of reference in the case of gram+ germ infections, vancomycin currently fails in 40% of MRSA pneumonias acquired under mechanical ventilation. The probable reason for such failure is an insufficient local concentration, which does not exceed the minimal inhibiting concentration (MIC) of the germ. BETWEEN EFFICACY AND TOLERANCE: The increase in the MIC of vancomycin in the serum and the lungs during acute MRSA acquired under mechanical ventilation may provoke problems in tolerance, notably renal.

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.

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.

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.

Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations.

Genetic factors are likely to contribute to the variable presentation of community-acquired pneumonia (CAP). The purpose of this prospective cohort study was to determine whether the LTalpha+250 (TNFbeta+250) and TNFalpha-308 gene polymorphisms are associated with different presentations of CAP. Septic shock (SS) was defined using American College of Chest Physicians/Society of Critical Care Medicine (ACCP-SCCM) criteria. Type I respiratory failure (T1RF) was defined as an O(2) saturation on room air of < 90% with a normal PCO(2). A total of 280 patients were genotyped; 31 had SS, 80 had T1RF. Genotype proportions are given in the order of AA/GA/ GG. The proportion of patients in each genotype developing SS was as follows: LTalpha+250 0.19/0.07/0.09 (p = 0.01 AA versus non-AA); TNFalpha-308 0.16/0.06/0.12 (p = NS). Carrying at least one AA (tumor necrosis factor [TNF] high secretor) genotype had an 18.0% risk of SS versus 6.8% (p = 0.006). GG homozygotes (TNF low secretors) at both loci had only a 2.9% risk of SS. Septic shock was associated with the LTalpha+250:TNFalpha-308 A:G haplotype but not the A:A haplotype, suggesting that LTalpha+250 is a marker, rather than a causative polymorphism. Carriage of the G:G haplotype had a significant protective effect against the development of septic shock (p = 0.011). T1RF was not associated with LTalpha+250 AA genotype. In the absence of septic shock, there was a significant trend to greater T1RF in patients with LTalpha+250 GG (TNFalpha hyposecretor) genotype (p = 0.03). Our finding of different genotype associations for SS and T1RF has important implications for immunotherapy in both CAP and sepsis, as well as for the definition of the systemic inflammatory response syndrome (SIRS).

Increasing threat of Gram-negative bacteria.

The widespread use of broad-spectrum antibiotics has led to emergence of antibiotic-resistant strains of many Gram-negative organisms. This problem is particularly serious in critically ill patients, especially those with ventilator-associated pneumonia. Extensive antibiotic resistance has developed in Gram-negative bacteria, due both to innate resistance in some species and the fact that they are highly adept at acquiring antibiotic-resistant determinants from each other. Antibiotic resistance develops through the following three basic mechanisms: alteration of the drug target, prevention of drug access to the target (including actively removing the drug from the bacteria), and drug inactivation. Certain Gram-negative microorganisms are particular problems in the intensive care unit, including Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, and the Enterobacteriaceae. The combination of an increasing population at risk, and the natural virulence and adaptability of Gram-negative bacteria guarantees that critical care physicians will face a persistent and increasing challenge from these pathogens.

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.

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.

Effect of clopidogrel on bleeding after coronary artery bypass surgery.

OBJECTIVE: Platelet dysfunction is a common cause of bleeding after coronary artery bypass graft surgery. This study explores the effects of clopidogrel on bleeding complications after coronary artery bypass graft surgery. DESIGN: Prospective observational study of patients undergoing coronary artery bypass graft. SETTING: Tertiary care center. PATIENTS: A total of 247 patients undergoing coronary artery bypass graft surgery. INTERVENTIONS: None. MEASUREMENTS: Primary end point was need for reexploration secondary to bleeding. Secondary end points included need for transfusion of blood products and chest tube output. MAIN RESULTS: Eight (3.3%) of 247 patients required reexploration secondary to bleeding. Clopidogrel recipients had higher incidence of reexploration for bleeding (9.8 vs. 1.6, p =.01) with an odds ratio of 6.9 (95% confidence interval, 1.6-30). Clopidogrel also increased the percentage of patients receiving packed red blood cell transfusion (72.6 vs. 51.6%, p =.007), the number of packed red blood cell units (3 vs. 1.6, p =0.0004), and the number of cryoprecipitate units (2.4 vs. 1.2, p =.04) transfused after coronary artery bypass graft surgery. Among clopidogrel recipients, a trend for increased transfusion of platelet units (4.3 vs. 1.7, p =.05) and fresh frozen plasma units (1.1 vs. 0.6, p =.08) also was found. CONCLUSIONS: Preoperative use of clopidogrel in combination with aspirin is associated with increased need for surgical reexploration as well as risk of packed red blood cell and cryoprecipitate transfusions after coronary artery bypass graft surgery.

Bronchostenosis due to childhood tuberculosis and manifested as an asymptomatic mass.

We report a case of bronchostenosis manifested as an asymptomatic mass on preoperative chest roentgenogram. Bronchoscopic biopsy inadvertently led to drainage of the obstructed bronchus. The various pathogenic origins of bronchostenosis are discussed, with the most likely cause in this case being previous tuberculosis.

Pharmacoeconomics of pneumonia.

Because diagnosis and treatment are so intimately linked, the pharmacoeconomics of treatment of ventilator-associated pneumonia (VAP) is impossible to discuss without discussing the cost-effectiveness of VAP diagnosis. The cost of VAP treatment is more complex than simply drug acquisition and administration costs. The critical factor in cost-effective therapy is the avoidance of inappropriate or ineffective therapy. The second most important benefit of a more accurate diagnostic strategy, such as the use of quantitative cultures, is the ability either to stop or to withhold antibiotics if the quantitative culture is negative. Therefore, the benefit of any diagnostic strategy must be evaluated principally from the aspect of these resultant changes in management. Reassurance or concern about an alternative site of infection or cause of fever will also add to the benefit or cost of more accurate diagnosis of VAP. The baseline antibiotic treatment strategy of the specific intensive care unit (ICU) will determine, to a large degree, the cost of antibiotics and the efficacy of empiric regimens. In the final analysis, pharmacy costs and cost of diagnostic testing for VAP must be based on outcome analysis, including comparison of the more expensive aspects of care, such as mortality, length of mechanical ventilation, and length of ICU stay.