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Lung pathology in fatal novel human influenza A (H1N1) infection.

Am J Respir Crit Care Med. 2010 Jan 1;181(1):72-9

Authors: Mauad T, Hajjar LA, Callegari GD, da Silva LF, Schout D, Galas FR, Alves VA, Malheiros DM, Auler JO, Ferreira AF, Borsato MR, Bezerra SM, Gutierrez PS, Caldini ET, Pasqualucci CA, Dolhnikoff M, Saldiva PH

RATIONALE: There are no reports of the systemic human pathology of the novel swine H1N1 influenza (S-OIV) infection. OBJECTIVES: The autopsy findings of 21 Brazilian patients with confirmed S-OIV infection are presented. These patients died in the winter of the southern hemisphere 2009 pandemic, with acute respiratory failure. METHODS: Lung tissue was submitted to virologic and bacteriologic analysis with real-time reverse transcriptase polymerase chain reaction and electron microscopy. Expression of toll-like receptor (TLR)-3, IFN-gamma, tumor necrosis factor-alpha, CD8(+) T cells and granzyme B(+) cells in the lungs was investigated by immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: Patients were aged from 1 to 68 years (72% between 30 and 59 yr) and 12 were male. Sixteen patients had preexisting medical conditions. Diffuse alveolar damage was present in 20 individuals. In six patients, diffuse alveolar damage was associated with necrotizing bronchiolitis and in five with extensive hemorrhage. There was also a cytopathic effect in the bronchial and alveolar epithelial cells, as well as necrosis, epithelial hyperplasia, and squamous metaplasia of the large airways. There was marked expression of TLR-3 and IFN-gamma and a large number of CD8(+) T cells and granzyme B(+) cells within the lung tissue. Changes in other organs were mainly secondary to multiple organ failure. CONCLUSIONS: Autopsies have shown that the main pathological changes associated with S-OIV infection are localized to the lungs, where three distinct histological patterns can be identified. We also show evidence of ongoing pulmonary aberrant immune response. Our results reinforce the usefulness of autopsy in increasing the understanding of the novel human influenza A (H1N1) infection.

PMID: 19875682 [PubMed - indexed for MEDLINE]

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Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial.

Am J Respir Crit Care Med. 2009 Oct 1;180(7):598-602

Authors: Oborne J, Mortimer K, Hubbard RB, Tattersfield AE, Harrison TW

RATIONALE: Asthma exacerbations are unpredictable, disruptive, and frightening, and are therefore important to prevent. OBJECTIVES: We investigated whether a policy of quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate reduces asthma exacerbations requiring treatment with oral corticosteroids. METHODS: A total of 403 people with asthma were given a self-management plan and randomized to take an active or placebo corticosteroid inhaler in addition to their usual asthma treatment when their PEF fell by 15% on 2 consecutive days or by 30% on 1 day. The study inhalers provided a quadrupling or no change in corticosteroid dose. MEASUREMENTS AND MAIN RESULTS: Eighteen of 197 (9%) and 29 of 203 (14%) participants had an exacerbation of asthma requiring treatment with oral corticosteroids in the active and placebo groups, respectively, giving a risk ratio of 0.64 (95% confidence interval, 0.37-1.11, P = 0.11). Of the 94 participants who started the study inhaler far fewer required treatment with oral corticosteroids in the active compared with the placebo group: 12 of 56 (21%) in the active group and 19 of 38 (50%) in the placebo group, giving a risk ratio of 0.43 (95% confidence interval, 0.24-0.78, P = 0.004). CONCLUSIONS: Although our primary outcome did not reach statistical significance, quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate appears to reduce acute exacerbations of asthma and deserves further investigation. Clinical trial registered with www.controlled-trials.com (ISRCTN 46018181).

PMID: 19590019 [PubMed - indexed for MEDLINE]

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An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.

Am J Respir Crit Care Med. 2009 Jul 1;180(1):59-99

Authors: Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG, de Jongste JC, Kerstjens HA, Lazarus SC, Levy ML, O’Byrne PM, Partridge MR, Pavord ID, Sears MR, Sterk PJ, Stoloff SW, Sullivan SD, Szefler SJ, Thomas MD, Wenzel SE,

BACKGROUND: The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways. PURPOSE: The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older. METHODS: A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures. RESULTS: The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. CONCLUSIONS: The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.

PMID: 19535666 [PubMed - indexed for MEDLINE]

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Critical illness outcomes in specialty versus general intensive care units.

Am J Respir Crit Care Med. 2009 Apr 15;179(8):676-83

Authors: Lott JP, Iwashyna TJ, Christie JD, Asch DA, Kramer AA, Kahn JM

RATIONALE: General intensive care units (ICUs) provide care across a wide range of diagnoses, whereas specialty ICUs provide diagnosis-specific care. Risk-adjusted outcome differences across such units are unknown. OBJECTIVES: To determine the association between specialty ICU care and the outcome of critical illness. METHODS: We conducted a retrospective cohort study design analyzing patients admitted to 124 ICUs participating in the Acute Physiology and Chronic Health Evaluation IV from January 2002 to December 2005. We examined 84,182 patients admitted to specialty and general ICUs with an admitting diagnosis or procedure of acute coronary syndrome, ischemic stroke, intracranial hemorrhage, pneumonia, abdominal surgery, or coronary-artery bypass graft surgery. ICU type was determined by a local data coordinator at each site. Patients were classified by admission to a general ICU, a diagnosis-appropriate (”ideal”) specialty ICU, or a diagnosis-inappropriate (”non-ideal”) specialty ICU. The primary outcomes were in-hospital mortality and ICU length of stay. MEASUREMENTS AND MAIN RESULTS: After adjusting for important confounders, there were no significant differences in risk-adjusted mortality between general versus ideal specialty ICUs for all conditions other than pneumonia. Risk-adjusted mortality was significantly greater for patients admitted to non-ideal specialty ICUs. There was no consistent effect of specialization on length of stay for all patients or for ICU survivors. CONCLUSIONS: Ideal specialty ICU care appears to offer no survival benefit over general ICU care for select common diagnoses. Non-ideal specialty ICU care (i.e., “boarding”) is associated with increased risk-adjusted mortality.

PMID: 19201923 [PubMed - indexed for MEDLINE]

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Randomized clinical trial of activated protein C for the treatment of acute lung injury.

Am J Respir Crit Care Med. 2008 Sep 15;178(6):618-23

Authors: Liu KD, Levitt J, Zhuo H, Kallet RH, Brady S, Steingrub J, Tidswell M, Siegel MD, Soto G, Peterson MW, Chesnutt MS, Phillips C, Weinacker A, Thompson BT, Eisner MD, Matthay MA

RATIONALE: Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days. OBJECTIVES: To test the efficacy of activated protein C (APC) as a therapy for patients with ALI. METHODS: Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days. MEASUREMENTS AND MAIN RESULTS: APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups. CONCLUSIONS: APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

PMID: 18565951 [PubMed - indexed for MEDLINE]

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Pneumonia in HIV-infected persons: increased risk with cigarette smoking and treatment interruption.

Am J Respir Crit Care Med. 2008 Sep 15;178(6):630-6

Authors: Gordin FM, Roediger MP, Girard PM, Lundgren JD, Miro JM, Palfreeman A, Rodriguez-Barradas MC, Wolff MJ, Easterbrook PJ, Clezy K, Slater LN

RATIONALE: Bacterial pneumonia is a major cause of morbidity for HIV-infected persons and contributes to excess mortality in this population. OBJECTIVES: To evaluate the frequency and risk factors for occurrence of bacterial pneumonia in the present era of potent antiretroviral therapy. METHODS: We evaluated data from a randomized trial of episodic antiretroviral therapy. The study, Strategies for Management of Antiretroviral Therapy, enrolled 5,472 participants at 318 sites in 33 countries. Study patients had more than 350 CD4 cells at baseline. Diagnosis of bacterial pneumonia was confirmed by a blinded clinical-events committee. MEASUREMENTS AND MAIN RESULTS: During a mean follow-up of 16 months, 116 participants (2.2%) developed at least one episode of bacterial pneumonia. Patients randomized to receive episodic antiretroviral therapy were significantly more likely to develop pneumonia than patients randomized to receive continuous antiretroviral therapy (hazard ratio, 1.55; 95% confidence interval, 1.07-2.25; P = 0.02). Cigarette smoking was a major risk factor: Current-smokers had more than an 80% higher risk of pneumonia compared with never-smokers (hazard ratio, 1.82; 95% confidence interval, 1.09-3.04; P = 0.02). Participants who were on continuous HIV treatment and were current smokers were three times more likely to develop bacterial pneumonia than nonsmokers. Current smoking status was significant, but a past history of smoking was not. CONCLUSIONS: Bacterial pneumonia is a major source of morbidity, even for persons on potent antiretroviral therapy, including those with high CD4 cells. Efforts to reduce this illness should stress the importance of uninterrupted antiretroviral therapy and attainment and/or maintenance of nonsmoking status.

PMID: 18617640 [PubMed - indexed for MEDLINE]

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Simple and accurate prediction of the clinical probability of pulmonary embolism.

Am J Respir Crit Care Med. 2008 Aug 1;178(3):290-4

Authors: Miniati M, Bottai M, Monti S, Salvadori M, Serasini L, Passera M

RATIONALE: Clinical probability assessment is a fundamental step in the diagnosis of pulmonary embolism. OBJECTIVES: To develop a predictive model for pulmonary embolism based on clinical symptoms, signs, and the interpretation of the electrocardiogram. METHODS: The model was developed from a database of 1,100 patients with suspected pulmonary embolism, of whom 440 had the disease confirmed by angiography or autopsy findings. It was validated in an independent sample of 400 patients with suspected pulmonary embolism (71% were inpatients). Easy-to-use software was developed for computing the clinical probability on palm computers and mobile phones. MEASUREMENTS AND MAIN RESULTS: The model comprises 16 variables of which 10 (older age, male sex, prolonged immobilization, history of deep vein thrombosis, sudden-onset dyspnea, chest pain, syncope, hemoptysis, unilateral leg swelling, electrocardiographic signs of acute cor pulmonale) are positively associated, and 6 (prior cardiovascular or pulmonary disease, orthopnea, high fever, wheezes, or crackles on chest auscultation) are negatively associated with pulmonary embolism. In the validation sample, 165 (41%) of 400 patients had pulmonary embolism confirmed by angiography. The prevalence of pulmonary embolism was 2% when the predicted clinical probability was slight (0 to 10%), 28% when moderate (11 to 50%), 67% when substantial (51 to 80%), and 94% when high (81 to 100%). There was no significant difference between inpatients and outpatients with respect to the prevalence of pulmonary embolism in the four probability categories. CONCLUSIONS: The proposed model is simple and accurate, and it may aid physicians when assessing the clinical probability of pulmonary embolism.

PMID: 18436792 [PubMed - indexed for MEDLINE]

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Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis.

Am J Respir Crit Care Med. 2008 Aug 15;178(4):425-30

Authors: Klok FA, Mos IC, Huisman MV

RATIONALE: The potential role of elevated brain-type natriuretic peptides (BNP) in the differentiation of patients suffering from acute pulmonary embolism at risk for adverse clinical outcome has not been fully established. OBJECTIVES: We evaluated the relation between elevated BNP or N-terminal-pro-BNP (NT-pro-BNP) levels and clinical outcome in patients with pulmonary embolism. METHODS: Articles reporting on studies that evaluated the risk of adverse outcome in patients with pulmonary embolism and elevated BNP or NT-pro-BNP levels were abstracted from Medline and EMBASE. Information on study design, patient and assay characteristics, and clinical outcome was extracted. Primary endpoints were overall mortality and predefined composite outcome of adverse clinical events. MEASUREMENTS AND MAIN RESULTS: Data from 13 studies were included. In 51% (576/1,132) of the patients, BNP or NT-pro-BNP levels were increased. The different analyses were performed in subpopulations. Elevated levels of BNP or NT-pro-BNP were significantly associated with right ventricular dysfunction (P < 0.001). Patients with high BNP or NT-pro-BNP concentration were at higher risk of complicated in-hospital course (odds ratio [OR], 6.8; 95% confidence interval [CI], 4.4-10) and 30-day mortality (OR, 7.6; 95% CI, 3.4-17). Patients with a high NT-pro-BNP had a 10% risk of dying (68/671; 95% CI, 8.0-13%), whereas 23% (209/909; 95% CI, 20-26%) had an adverse clinical outcome. CONCLUSIONS: High concentrations of BNP distinguish patients with pulmonary embolism at higher risk of complicated in-hospital course and death from those with low BNP levels. Increased BNP or NT-pro-BNP concentrations alone, however, do not justify more invasive treatment regimens.

PMID: 18556626 [PubMed - indexed for MEDLINE]

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Pseudomonas aeruginosa in chronic obstructive pulmonary disease.

Am J Respir Crit Care Med. 2008 Apr 15;177(8):853-60

Authors: Murphy TF, Brauer AL, Eschberger K, Lobbins P, Grove L, Cai X, Sethi S

RATIONALE: Pseudomonas aeruginosa is isolated from adults with chronic obstructive pulmonary disease (COPD) in cross-sectional studies. However, patterns of carriage and the role of P. aeruginosa in COPD are unknown. OBJECTIVES: To elucidate carriage patterns, phenotypes of strains, clinical manifestations, and the antibody response to P. aeruginosa in COPD. METHODS: A prospective study of adults with COPD was conducted. Isolates of P. aeruginosa were subjected to genotypic and phenotypic analysis. Sputum samples were studied for P. aeruginosa DNA, and immune responses were assayed. MEASUREMENTS AND MAIN RESULTS: We analyzed longitudinal clinical data, sputum cultures, pulsed-field gel electrophoresis of bacterial DNA, polymerase chain reaction of sputum, and immunoblot assays of serum. Fifty-seven episodes of acquisition of strains of P. aeruginosa were observed in 39 of 126 patients over 10 years. Acquisition of a new strain was associated with exacerbation. Thirty-one episodes of carriage were followed by clearance of the strain; 16 were of short (<1 mo) duration. Thirteen strains demonstrated persistence, and 13 strains were of indeterminate duration. Six strains were mucoid and were more likely to persist than nonmucoid strains (P = 0.005). Antibody responses developed in 53.8% of persistent carriage and in only 9.7% of short-term carriage episodes (P = 0.003). Antibiotics did not account for clearance. CONCLUSIONS: Two distinct patterns of carriage by P. aeruginosa were observed: (1) short-term colonization followed by clearance and (2) long-term persistence. Mucoid strains showed persistence. Acquisition of P. aeruginosa is associated with the occurrence of an exacerbation. Serum antibody responses do not mediate clearance of P. aeruginosa.

PMID: 18202344 [PubMed - indexed for MEDLINE]

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