Clinical Question:
Can clinical data collected at the time of diagnosis of pneumonia predict patients who will develop severe disease?

Bottom Line:
A simple score using clinical data available at the time of the emergency department visit provides a practical diagnostic decision aid, and predicts the development of severe community-acquired pneumonia.

Reference:
Espana PP, Capelastegui A, Gorordo I, et al. Development and validation of a clinical prediction rule for severe community-acquired pneumonia. Am J Respir Crit Care Med 2006;174:1249-1256.

Study Design:
Decision rule (validation)

Synopsis:
In this study, the authors evaluated 1776 consecutive patients diagnosed with community-acquired pneumonia in a single emergency department to develop a clinical prediction rule that will identify patients who will develop severe disease (septic shock, severe sepsis, or disease requiring mechanical ventilation). In the multivariate analyses, eight independent predictive factors were correlated with severe community-acquired pneumonia: arterial pH <> 30 breaths/min, altered mental status, blood urea nitrogen > 30 mg/dl, oxygen arterial pressure <> or = 80 yr, and multilobar/bilateral lung affectation. From the beta parameter obtained in the multivariate model, a score was assigned to each predictive variable. The model shows an area under the curve of 0.92. This rule proved better at identifying patients evolving toward severe community-acquired pneumonia than either the modified American Thoracic Society rule, the British Thoracic Society’s CURB-65, or the Pneumonia Severity Index.

Clinical Question:
Can tachypnea be used to predict pneumonia in febrile children younger than two years of age?

Bottom Line:
This is a well done study with appropriate blinding of both the application of the clinical test and diagnosis of the target disease.
Tachypnea is an important predictive sign of pneumonia in febrile children younger than 2 years. Conversely, the absence of tachypnea obviates the need for chest radiography in most settings. The technique of auscultating the chest for a full 60 seconds to determine respiratory rates can be replicated in clinical practice. It is uncertain whether respiratory rates obtained by other means would be as useful as those obtained in this study. In the evaluation of febrile children younger than 2 years, respiratory rates below the standard of tachypnea as defined in this study correlated well with the absence of pneumonia. Applying this information to clinical practice may lead to decreased utilization of chest radiography, unnecessary exposure to radiation, and reduced costs.

Reference:
Taylor JA, Del Beccaro M, Done S, Winters W. Establishing Clinically Relevant Standards for Tachypnea in Febrile Children Younger Than 2 Years. Arch Ped Adol Med 1995; 149: 283-7. (January, 1996)

Study Design:
Cross-sectional

Synopsis:
Tachypnea is an important predictor of pneumonia in pediatric patients but there is no widely accepted definition of what it is, especially in febrile children. Values for normal respiratory rates were measured on well, sleeping children. An accurate definition for tachypnea among febrile children may aid clinicians in determining those likely to have pneumonia.

The authors did a prospective case series on children younger than 2 years presenting to the emergency department of a children’s hospital with a temperature of 38 degrees C or higher. Using a standardized method, respiratory rates were obtained on eligible children for 1 year. Study patients were classified as having pneumonia or no pneumonia based on clinical evaluation and chest radiograph findings. Receiver operating characteristic curves were constructed to select the values for respiratory rate that maximized sensitivity and specificity of tachypnea as a sign of pneumonia. Data were analyzed for 572 children; pneumonia was present in 42 (7%). The diagnostic utility of tachypnea was maximal when cutoff values for respiratory rates of 59/min in infants younger than 6 months, 52/min in those aged 6 through 11 months, and 42/min in those aged 1 to 2 years were selected. Based on these definitions, tachypnea as a sign of pneumonia had a sensitivity of 73.8%, specificity of 76.8%, positive predictive value of 20.1%, and negative predictive value of 97.4%.

Clinical Question:
Can longer stays in a specialized unit of an emergency department prevent hospitalization and improve care of adult asthmatics?

Bottom Line:
Treatment of selected patients with asthma in an EDTU results in the safe discharge of most such patients. This study suggests that quality gains and cost-effective measures can be achieved by the use of such units.

Reference:
McDermott MF, Murphy DG, Zalenski RJ, et al. A comparison between emergency diagnostic and treatment unit and
inpatient care in the management of acute asthma. Arch Intern Med 1997;157:2055−62.

Study Design:
Randomized controlled trial

Synopsis:
Emergency diagnostic and treatment units (EDTUs) may provide an alternative to hospitalization for patients with reversible diseases, such as asthma, who fail to adequately respond to emergency department therapy. The authors evaluate the medical and cost-effectiveness, patient satisfaction, and quality of life of patients receiving EDTU care for acute asthma compared with inpatient care. METHODS: A prospective, randomized clinical trial performed at 2 urban public hospitals enrolled patients with acute asthma (age range, 18-55 years) not meeting discharge criteria after 3 hours of emergency department therapy. Patients were treated with inhaled adrenergic agonists and steroids in an EDTU for up to 9 hours after randomization or with routine therapy in a hospital ward. Patients were followed up for 8 weeks. Discharge rate from the EDTU, length of stay, relapse rates, days missed from work or school, days incapacitated during waking hours, symptom-free days and nights, nocturnal awakenings, direct medical costs, patients satisfaction, and patient quality of life. The study consisted of 222 patients with asthma. Sixty-five patients (59%) treated in an EDTU were discharged home; the remainder were admitted to the hospital. There were no differences during the follow-up period in relapse rates (P = .74) or in any other morbidities between the EDTU and inpatient groups. There were significant differences in the length of stay, patient satisfaction, and quality of life favoring EDTU care. The mean (+/-SD) cost per patient in the EDTU group was $1202.79 +/- $1343.96, compared with $2247.32 +/- $1110.18 for the control group (P < .001).

Clinical Question:
In patients with chronic obstructive pulmonary disease, do anticholinergics provide better benefit than beta-2 agonists?

Bottom Line:
Inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, while beta2-agonists were associated with an increased risk for respiratory deaths. This suggests that anticholinergics should be the bronchodilator of choice in patients with COPD, and beta2-agonists may be associated with worsening of disease control.

Reference:
Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD. J Gen Intern Med 2006;21:1011-1019.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Anticholinergics and beta2-agonists have generally been considered equivalent choices for bronchodilation in chronic obstructive pulmonary disease (COPD). The authors assess the safety and efficacy of anticholinergics and beta2-agonists in COPD by comprehensively searching electronic databases from 1966 to December 2005, clinical trial websites, and references from selected reviews. They included randomized controlled trials of at least 3 months duration that evaluated anticholinergic or beta2-agonist use compared with placebo or each other in patients with COPD. They also evaluated the relative risk (RR) of exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, and deaths attributed to a lower respiratory event. Pooled results from 22 trials with 15,276 participants found that anticholinergic use significantly reduced severe exacerbations (RR 0.67, confidence interval [CI] 0.53 to 0.86) and respiratory deaths (RR 0.27, CI 0.09 to 0.81) compared with placebo. Beta2-agonist use did not affect severe exacerbations (RR 1.08, CI 0.61 to 1.95) but resulted in a significantly increased rate of respiratory deaths (RR 2.47, CI 1.12 to 5.45) compared with placebo. There was a 2-fold increased risk for severe exacerbations associated with beta2-agonists compared with anticholinergics (RR 1.95, CI 1.39 to 2.93). The addition of beta2-agonist to anticholinergic use did not improve any clinical outcomes.

Clinical Question:
In patients with short-term colored rhinitis, is antibiotic treatment more effective than placebo treatment?

Bottom Line:
Antibiotics are probably effective for acute purulent rhinitis. They can cause harm, usually in the form of gastrointestinal effects. Most patients will get better without antibiotics, supporting the current “no antibiotic as first line” advice.

Reference:
Arroll B, Kenealy T. Are antibiotics effective for acute purulent rhinitis? Systematic review and meta-analysis of placebo controlled randomised trials. BMJ 2006;333:279. Epub 2006 Jul 21.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
The authors systematically review the evidence for the effectiveness of antibiotics in acute purulent rhinitis (many guidelines advise against their use on the basis of one study that showed no effect). Medline, Embase, Cochrane Register of Controlled Trials, and reference lists of retrieved articles. Meta-analysis of data from double blind randomised placebo controlled trials comparing antibiotics with placebo for acute purulent rhinitis (duration less than 10 days). RESULTS: Seven studies were retrieved; four contributed data on benefits of antibiotics, and four contributed data on harms of antibiotics. The pooled relative risk of benefit for persistent purulent rhinitis at five to eight days with antibiotics was 1.18 (95% confidence interval 1.05 to 1.33). The numbers needed to treat ranged from 7 to 15 when the pooled relative risk was applied to the range of control event rates. The relative risk for adverse effects with antibiotics was 1.46 (1.10 to 1.94). The numbers needed to harm for adverse effects ranged from 12 to 78. No serious harms were reported in the placebo arms.

Clinical Question:
Does regular aspirin intake reduce adult-onset Asthma?

Bottom Line:
Aspirin reduced the risk of newly diagnosed adult-onset asthma in a large randomized clinical trial of apparently healthy, aspirin-tolerant men. This result requires replication in randomized trials designed a priori to test this hypothesis; it does not imply that aspirin improves symptoms in patients with asthma.

Reference:
Aspirin and Decreased Adult-Onset Asthma: Randomized Comparisons from the Physicians’ Health Study.Barr RG, Kurth T, Stampfer MJ, Buring JE, Hennekens CH, Gaziano JM.Am J Respir Crit Care Med. 2006 Oct 26;

Study Design:
Randomized Double-Blind, placebo-controlled trial

Synopsis:
In an observational cohort study, women who self-selected for frequent aspirin use developed less newly diagnosed asthma than women who did not take aspirin. The authors explore whether low-dose aspirin decreased the risk of newly diagnosed asthma in a randomized double-blind, placebo-controlled trial. The Physicians’ Health Study randomized 22,071 apparently healthy male physicians, age 40-84 years at baseline and tolerant of aspirin over an 18-week run-in period, to 325mg aspirin or placebo on alternate days. The aspirin component was terminated after 4.9 years due principally to the emergence of a statistically extreme 44% reduction in risk of first myocardial infarction among those randomly assigned to aspirin. Physicians could self-report an asthma diagnosis on questionnaires at baseline, six months and annually thereafter. Asthma was not an a priori endpoint of the trial. Among 22,040 physicians without reported asthma at randomization, there were 113 new asthma diagnoses in the aspirin and 145 in the placebo group. The hazard ratio was 0.78 (95% confidence interval, 0.61 to 1.00; P=0.045). This apparent 22% lower risk of newly diagnosed asthma among those assigned to aspirin was not modified by baseline characteristics including smoking, body mass index, or age.

Clinical Question:
Is sequential chemotherapy with cisplatin/gemcitabine (CG) followed by mitoxantrone/methotrexate/mitomycin (MMM) effective in patients with malignant pleural mesothelioma?

Bottom Line:
This phase II study with the sequential approach of two active regimens showed a good disease control in MPM, with symptom improvement and only mild toxicity.

Reference:
Sequential chemotherapy with cisplatin/gemcitabine (CG) followed by mitoxantrone/methotrexate/mitomycin (MMM) in patients with malignant pleural mesothelioma. A multicenter Italian Phase II Study (SITMP1).Pinto C, Marino A, De Pangher Manzini V, Benedetti G, Galetta D, Mazzanti P, Del Conte G, dell’Amore D, Piana E, Giaquinta S, Lopez M, Martoni A. Lung Cancer. 2006 May;52(2):199-206

Study Design:
Randomized Controlled Trial (Multicenter Study)

Synopsis:
The author performed a multicenter phase II trial to evaluate the impact on the activity, efficacy, symptom control and safety of using two active regimens in a sequential schedule (cisplatin/gemcitabine followed by mitoxantrone/methotrexate/mitomycin) as first-line chemotherapy for unresectable malignant pleural mesothelioma (MPM). A total of 54 patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,200 mg/m(2) on days 1 and 8, every 3 weeks for four courses (CG regimen) followed by mitoxantrone 10 mg/m(2) on day 1, methotrexate 35 mg/m(2) on day 1 and mitomycin 7 mg/m(2) on day 1, every 3 weeks with mitomycin in alternate cycles for four courses (MMM regimen). They observed 3 complete responses (CRs) (5.6%) and 13 partial responses (PRs) (24.0%), with an overall response rate (ORR) of 29.6% (95% confidence interval, 17-42%), 33 stable disease (SD) (61.1%) and 5 progressive disease (PD) (9.2%). Median time to progression (TTP) was 9.5 months (range, 2-23). Median overall survival (OS) was 13 months (range, 3-33); 1-year survival rate was 63%. The treatment produced a good symptom control, with an improvement during chemotherapy in dyspnea and pain in 52.9 and 48.3% of patients, respectively. The major toxicity observed was hematological. Grades 3-4 NCI-CTC v 2.0 toxicity with the CG regimen included: neutropenia (11.1%), anemia (1.9%), thrombocytopenia (7.4%), vomiting (11.1%) and with the MMM regimen: neutropenia (35.2%), anemia (5.5%), thrombocytopenia (7.4%) and stomatitis (1.9%).

Clinical Question:
Do allergic rhinitis and sinusitis are associated severe asthmatic symptoms?

Bottom Line:
Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.

Reference:
Allergic rhinitis and sinusitis in asthma: differential effects on symptoms and pulmonary function.Dixon AE, Kaminsky DA, Holbrook JT, Wise RA, Shade DM, Irvin CG.Chest. 2006 Aug;130(2):429-35

Study Design:
Randomized controlled trial (multicenter study)

Synopsis:
Allergic rhinitis and sinusitis are frequently associated with asthma. The authors determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. They did a cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year).

Clinical Question:
Does cyclophosphomide improve symptoms in patients with scleroderma lung disease?

Bottom Line:
One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study.

Reference:
Tashkin DP, Elashoff R, Clements PJ, et al, for the Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-2666.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Interstitial lung disease is a common complication of scleroderma (systemic sclerosis), occurring in nearly half the patients. No clearly effective treatment exists, and although cyclophosphomide has been used, it had not been studied in a well-designed clinical trial. In this study, 156 patients with scleroderma, evidence of active alveolitis, a functional vital capacity (FVC) between 45% and 85% of predicted, and exertional dyspnea were recruited from 13 centers for the study. Those receiving corticosteroids and those who had taken cyclophosphomide previously were excluded. The included patients were randomly assigned to either cyclophosphomide (1 mg/kg initially, increasing by 25 mg per month to a final dose of 2 mg/kg) or matching placebo. The primary patient-oriented outcome was a dyspnea score ranging from -9 (worst) to +9 (best). Groups were balanced and analysis was by intention to treat. The mean age of participants was 48 years, 70% were women, and they’d had scleroderma for a mean of 3.2 years. Of 159 eligible patients who entered the study, 54 in the cyclophosphomide group and 55 in the placebo group completed the 1-year study. After 1 year, the dyspnea score had increased from 5.6 to 7.0 in the active treatment group and decreased from 5.6 to 4.1 in the placebo group; this difference was statistically significant and is also considered clinically significant. A disability score also improved slightly in the cyclophosphomide group and declined in the placebo group. The FVC decreased by 1% in the active treatment group compared with 2.6% in the placebo group (P = .03), while total lung capacity remained stable in the treatment group and decreased from 67.9% of predicted to 64.7% of predicted in the control group. Serious adverse events probably due to cyclophosphamide (leukopenia with pneumonia and leukopenia with gastroenteritis) occurred in 2 patients, and 2 patients in each group died (unrelated to treatment).

Clinical Question:
In patients hospitalized for treatment of community-acquired pneumonia, can treatment be stopped after 3 days if the patient has substantially improved?

Bottom Line:
Dogma successfully challenged: In patients who respond well to initial treatment, stopping antibiotic therapy after 3 days is just as effective as continuing treatment for the standard 8 days.

Reference:
el Moussaoui R, de Borgie CA, van den Broek P, et al. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ 2006;332:1355-1358.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
To compare the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days’ treatment. The authors did a randomised, double blind, placebo controlled non-inferiority trial on 9 secondary and tertiary care hospitals in the Netherlands. The subject are adults with mild to moderate-severe community acquired pneumonia (pneumonia severity index score < or = 110). Patients who had substantially improved after three days’ treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (n = 63) or placebo (n = 56) three times daily for five days. The primary outcome measure was the clinical success rate at day 10. Secondary outcome measures were the clinical success rate at day 28, symptom resolution, radiological success rates at days 10 and 28, and adverse events. Baseline characteristics were comparable, with the exception of symptom severity, which was worse in the three day treatment group. In the three day and eight day treatment groups the clinical success rate at day 10 was 93% for both (difference 0.1%, 95% confidence interval–9% to 10%) and at day 28 was 90% compared with 88% (difference 2.0%,–9% to 15%). Both groups had similar resolution of symptoms. Radiological success rates were 86% compared with 83% at day 10 (difference 3%,–10% to 16%) and 86% compared with 79% at day 28 (difference 6%,–7% to 20%). Six patients (11%) in the placebo group and 13 patients (21%) in the active treatment group reported adverse events (P = 0.1).

There are a couple of notable limitations to this study. First, the patients in the short-treatment group had a median age of 54 years compared with 60 years in the 8-day group, and these younger patients may be more likely to respond to the short course, thus skewing the results. Second, the study was conducted in the Netherlands, where resistance patterns may be different than in other countries. Finally, the study was conducted in 9 hospitals over 3 years, which works out to less than 5 patients per hospital per year recruited into the study. Given the imbalance in age and this sparse representation, these patients could be highly selected and not representative of the typical patient admitted to a community hospital.