Objectives: To relate ASM hypertrophy, ASM hyperplasia, and deposition of ECM to the severity and duration of asthma.
Methods: Airways from control subjects (n = 51) and from cases of nonfatal (n = 49) and fatal (n = 55) asthma were examined postmortem. Mean ASM cell volume (VC), the number of ASM cells per length of airway (NL), and the volume fraction of extracellular matrix (fECM) within the ASM layer were estimated. Comparisons between subject groups were made on the basis of general linear regression models.
Measurements and Main Results: Mean VC was increased in the large airways of cases of nonfatal asthma (P = 0.015) and fatal asthma (P < 0.001) compared with control subjects. NL was similar in nonfatal cases and control subjects but increased in large (P < 0.001), medium (P < 0.001), and small (P = 0.034) airways of cases of fatal asthma compared with control subjects and with nonfatal cases (large and medium airways, P ≤ 0.003). The fECM was similar in cases of asthma and control subjects. Duration of asthma was associated with a small increase in NL.
Conclusions: Hypertrophy of ASM cells occurs in the large airways in both nonfatal and fatal cases of asthma, but hyperplasia of ASM cells is present in the large and small airways in fatal asthma cases only. Both are associated with an absolute increase in ECM. Duration of asthma has little or no effect on ASM hypertrophy or hyperplasia or fECM.
]]>Objectives: Because chronic obstructive pulmonary disease is characterized by low-grade systemic inflammation, we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy.
Methods: A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years. Kaplan-Meier curves, log-rank analysis, and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables, while C statistics assessed the added discriminative power offered by addition of biomarkers.
Measurements and Main Results: At recruitment we measured anthropometrics, spirometry, 6-minute walk distance, dyspnea, BODE index, history of hospitalization, comorbidities, and computed tomography scan emphysema. White blood cell and neutrophil counts, serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reactive protein, Clara cell secretory protein-16, IL-6 and -8, and tumor necrosis factor-α were determined at recruitment and subsequent visits. A total of 168 of the 1,843 patients (9.1%) died. Nonsurvivors were older and had more severe airflow limitation, increased dyspnea, higher BODE score, more emphysema, and higher rates of comorbidities and history of hospitalizations. The best predictive model for mortality using clinical variables included age, BODE, and hospitalization history (C statistic of 0.686; P < 0.001). One single biomarker (IL-6) significantly improved the C statistic to 0.708, but this was further improved to 0.726 (P = 0.003) by the addition of all biomarkers.
Conclusions: The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease.
Clinical trial registered with www.clinicaltrials.gov (NCT00292552).
]]>Objectives: To extend these findings to human lung tissue samples.
Methods: DNA from lung tissue samples was obtained from nonsmokers (n = 8); smokers without COPD (n = 8); patients with very severe COPD (Global Initiative for COPD [GOLD] 4) (n = 8); and patients with cystic fibrosis (CF) (n = 8). The latter served as a positive control, with sterile water as a negative control. All bacterial community analyses were based on polymerase chain reaction amplifying 16S rRNA gene fragments. Total bacterial populations were measured by quantitative polymerase chain reaction and bacterial community composition was assessed by terminal restriction fragment length polymorphism analysis and pyrotag sequencing.
Measurement and Main Results: Total bacterial populations within lung tissue were small (20–1,252 bacterial cells per 1,000 human cells) but greater in all four sample groups versus the negative control group (P < 0.001). Terminal restriction fragment length polymorphism analysis and sequencing distinguished three distinct bacterial community compositions: one common to the nonsmoker and smoker groups, a second to the GOLD 4 group, and the third to the CF-positive control group. Pyrotag sequencing identified greater than 1,400 unique bacterial sequences and showed an increase in the Firmicutes phylum in GOLD 4 patients versus all other groups (P < 0.003) attributable to an increase in the Lactobacillus genus (P < 0.0007).
Conclusions: There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD.
]]>Objective: To compare mortality after first ICU referral in admitted patients and in patients denied admission because the unit was full.
Methods: Prospective observational multicenter cohort study of consecutive patients referred for ICU admission during two 45-day periods, conducted in 10 ICUs.
Measurements and Main Results: Of 1,762 patients, 430 were excluded from the study, 116 with previously denied admission to another ICU and 270 because they were deemed too sick or too well to benefit from ICU admission. Of the remaining 1,332 patients, 1,139 were admitted, and 193 were denied admission because the unit was full (65 were never admitted, 39 were admitted after bumping of another patient, and 89 were admitted on subsequent referral). Crude Day 28 and Day 60 mortality rates in the nonadmitted and admitted groups were 30.1 versus 24.3% (P = 0.07) and 33.3 versus 27.2% (P = 0.06), respectively. Day 28 mortality adjusted on age, previous disease, Glasgow scale score less than or equal to 8, shock, creatinine level greater than or equal to 250 μmol/L, and prothrombin time greater than or equal to 30 seconds was nonsignificantly higher in patients refused ICU admission only because of a full unit compared with patients admitted immediately. Patients admitted after subsequent referral had higher mortality rates on Day 28 (P = 0.05) and Day 60 (P = 0.04) compared with directly admitted patients.
Conclusions: Delayed ICU admission due to a full unit at first referral is associated with increased mortality.
]]>Objectives: To determine whether fever control by external cooling diminishes vasopressor requirements in septic shock.
Methods: In a multicenter randomized controlled trial, febrile patients with septic shock requiring vasopressors, mechanical ventilation, and sedation were allocated to external cooling (n = 101) to achieve normothermia (36.5–37°C) for 48 hours or no external cooling (n = 99). Vasopressors were tapered to maintain the same blood pressure target in the two groups. The primary endpoint was the number of patients with a 50% decrease in baseline vasopressor dose after 48 hours.
Measurements and Main Results: Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval [95% CI], –46 to –21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, –23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, –16%; 95% CI, –28 to –4; P = 0.013).
Conclusions: In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.
]]>Objectives: This study investigated the association between CT and survival in patients with CF screened for LTX.
Methods: Clinical data and chest CTs of 411 patients with CF screened for LTX between 1990 and 2005 were collected from 17 centers. CTs were scored with the Severe Advanced Lung Disease (SALD) four-category scoring system, including the components infection/inflammation (INF), air trapping/hypoperfusion (AT), normal/hyperperfusion (NOR), and bulla/cysts (BUL). The volume of each component was computed using semiautomated software. Survival analysis included Kaplan-Meier curves and Cox regression models.
Measurements and Main Results: Three hundred and sixty-six (186 males) of 411 patients entered the waiting list (median age, 23 yr; range, 5–58 yr). Subsequently, 67 of 366 (18%) died while waiting, 263 of 366 (72%) underwent LTX, and 36 of 366 (10%) were awaiting LTX at the census date. INF and LAS were significantly associated with waiting list mortality in univariate analyses. The multivariate Cox model including INF and LAS grouped in tertiles, and comparing tertiles 2 and 3 with tertile 1, showed waiting list mortality hazard ratios of 1.62 (95% confidence interval [95% CI], 0.78–3.36; P = 0.19) and 2.65 (95% CI, 1.35–5.20; P = 0.005) for INF, and 1.42 (95% CI, 0.63–3.24; P = 0.40), and 2.32 (95% CI, 1.17–4.60; P = 0.016) for LAS, respectively. These results indicated that INF and LAS had significant, independent predictive value for survival.
Conclusions: CT score INF correlates with survival, and adds to the predictive value of LAS.
]]>Objectives: We sought to quantify the efficacy of surgical face masks when worn by patients with multidrug-resistant TB (MDR-TB).
Methods: Over 3 months, 17 patients with pulmonary MDR-TB occupied an MDR-TB ward in South Africa and wore face masks on alternate days. Ward air was exhausted to two identical chambers, each housing 90 pathogen-free guinea pigs that breathed ward air either when patients wore surgical face masks (intervention group) or when patients did not wear masks (control group). Efficacy was based on differences in guinea pig infections in each chamber.
Measurements and Main Results: Sixty-nine of 90 control guinea pigs (76.6%; 95% confidence interval [CI], 68–85%) became infected, compared with 36 of 90 intervention guinea pigs (40%; 95% CI, 31–51%), representing a 56% (95% CI, 33–70.5%) decreased risk of TB transmission when patients used masks.
Conclusions: Surgical face masks on patients with MDR-TB significantly reduced transmission and offer an adjunct measure for reducing TB transmission from infectious patients.
]]>Objectives: Improved case-finding approaches for TB and HIV are needed to reduce mortality and prevent transmission.
Methods: We identified newly diagnosed index TB cases in a rural district and enrolled their households in a TB-HIV contact-tracing study. A group of randomly selected control households were enrolled to determine community prevalence of undetected TB and HIV. Field teams screened participants for TB symptoms, collected sputum specimens for smear microscopy and culture, provided HIV counseling and testing, and collected blood for CD4 testing. Participants were referred to public clinics for TB treatment and antiretroviral therapy.
Measurements and Main Results: We evaluated 2,843 household contacts of 727 index patients with TB and 983 randomly selected control household members. The prevalence of TB in household contacts was 6,075 per 100,000 (95% confidence interval, 5,789–6,360 per 100,000), whereas the prevalence detected in randomly selected households was 407 per 100,000 (95% confidence interval, 0–912 per 100,000; prevalence difference, 5,668 per 100,000; P < 0.001). TB detected among contacts was less likely to be smear-positive than in the index patients (6% vs. 22%; P < 0.001). Most contacts with culture-confirmed TB were asymptomatic. At least one case of undiagnosed TB was found in 141 (19%) of 727 contact versus 4 (1%) of 312 control households. HIV testing was positive in 166 (11%) of 1,568 contacts tested versus 76 (14%) of 521 control participants tested (odds ratio, 1.48; P = 0.02).
Conclusions: Active case finding in TB contact households should be considered to improve TB and HIV case detection in high-prevalence settings, but sensitive diagnostic tools are necessary.
]]>Methods: The leadership of three large professional societies representing critical care practitioners convened a diverse group representing a wide variety of views regarding the role of clinical research results in clinical practice to develop a document to serve as a basis for agreement and a framework for ongoing discussion.
Results: Consensus was reached on several issues. While the results of rigorous clinical research are important in arriving at the best course of action for an individual critically ill patient, other forms of medical knowledge, including clinical experience and pathophysiologic reasoning, remain essential. No single source of knowledge is sufficient to guide clinical decisions, nor does one kind of knowledge always take precedence over others. Clinicians will find clinical research compelling for a variety of reasons that go beyond study design. While clinical practice guidelines and protocols based upon clinical research may improve care and decrease variability in practice, clinicians must be able to understand and articulate the rationale as to why a particular protocol or guideline is used or why an alternative approach is taken. Making this clinical reasoning explicit is necessary to understand practice variability.
Conclusions: Understanding the strengths and weaknesses of different kinds of medical knowledge for clinical decision making and factors beyond study design that make clinical research compelling to clinicians can provide a framework for understanding the role of clinical research in practice.
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