Jörg D. Leuppi

Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia

BackgroundCommunity-acquired pneumonia (CAP) is the most frequent infection-related cause of death. The reference standard to diagnose CAP is a new infiltrate on chest radiograph in the presence of recently acquired respiratory signs and symptoms. This study aims to evaluate the diagnostic and prognostic accuracy of clinical signs and symptoms and laboratory biomarkers for CAP.Methods545 patients with suspected lower respiratory tract infection, admitted to the emergency department of a university hospital were included in a pre-planned post-hoc analysis of two controlled intervention trials. Baseline assessment included history, clinical examination, radiography and measurements of procalcitonin (PCT), highly sensitive C-reactive protein (hsCRP) and leukocyte count.ResultsOf the 545 patients, 373 had CAP, 132 other respiratory tract infections, and 40 other final diagnoses. The AUC of a clinical model including standard clinical signs and symptoms (i.e. fever, cough, sputum production, abnormal chest auscultation and dyspnea) to diagnose CAP was 0.79 [95% CI, 0.75–0.83]. This AUC was significantly improved by including PCT and hsCRP (0.92 [0.89–0.94]; p < 0.001). PCT had a higher diagnostic accuracy (AUC, 0.88 [0.84–0.93]) in differentiating CAP from other diagnoses, as compared to hsCRP (AUC, 0.76 [0.69–0.83]; p < 0.001) and total leukocyte count (AUC, 0.69 [0.62–0.77]; p < 0.001). To predict bacteremia, PCT had a higher AUC (0.85 [0.80–0.91]) as compared to hsCRP (p = 0.01), leukocyte count (p = 0.002) and elevated body temperature (p < 0.001). PCT, in contrast to hsCRP and leukocyte count, increased with increasing severity of CAP, as assessed by the pneumonia severity index (p < 0.001).ConclusionPCT, and to a lesser degree hsCRP, improve the accuracy of currently recommended approaches for the diagnosis of CAP, thereby complementing clinical signs and symptoms. PCT is useful in the severity assessment of CAP.

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial

IMPORTANCE International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE Time to next exacerbation within 180 days. RESULTS Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN19646069.

High prevalence of bronchial hyperresponsiveness and asthma in ice hockey players

The prevalence of asthma was studied in a ice hockey team compared with both a floor ball team and the Swiss population. Lung function, bronchial hyperresponsiveness to methacholine, asthma symptoms and exercise-induced asthma were measured in a cross-sectional prospective study. A positive response to the methacholine bronchial provocation test was found in 34.6% of the ice hockey players and 20.8% of the floor ball players (Swiss population 16.4%). The provocative dose causing a 20% fall in the forced expiratory volume in one second (PD20) was significantly lower in ice hockey players than in floor ball players, but there was no significant difference in the dose-response slopes between the two groups. Asthma was diagnosed in 19.2% of the ice hockey players and in 4.2% of the floor ball players (Swiss population 6.8%), whereas exercise-induced asthma was found in 11.5% of the ice hockey players and in 4.2% of the floor ball players. In conclusion, asthma and bronchial hyperresponsiveness seemed to be more common in ice hockey players than in floor ball players and in the Swiss population. Strenuous exercise at lower temperatures may be a risk factor for the higher prevalence of asthma and bronchial hyperresponsiveness, as well as the increased severity of bronchial hyperresponsiveness, particularly in ice hockey players.

Cough suppression during flexible bronchoscopy using combined sedation with midazolam and hydrocodone: a randomised, double blind, placebo controlled trial

Background: Current British Thoracic Society guidelines do not recommend routinely the combined use of a benzodiazepine and opiate during flexible bronchoscopy (FB). A randomised, placebo controlled, double blind study was undertaken to determine whether hydrocodone in combination with midazolan improves cough suppression during FB without increasing the risk of desaturation. Methods: 120 patients were randomised to receive midazolam and 5 mg IV hydrocodone or midazolam and placebo with topical anaesthesia. Pulse oximetry was recorded continuously during FB. Bronchoscopists and nurses charted their perception of cough and the patients rated their discomfort during the procedure on a 10 cm visual analogue scale (VAS). Results: There was no significant difference between the two groups with regard to the indication for FB, duration of procedure (21 (11) min v 22 (10) min, p = 0.570), doses of supplemental lignocaine (171 (60) mg v 173 (66) mg, p = 0.766) and midazolam (4.5 (2.3) mg v 4.9 (2.7) mg, p = 0.309), lowest oxygen saturation (94.8 (2.7) v 94.9 (2.7), p = 0.433), and desaturations ⩽90%. Perception of cough by both the bronchoscopist and the nurse was significantly lower in the hydrocodone group (3 (0–10) and 3 (0–10)) than in the placebo group (6 (0–10) and 6 (0–10)), respectively (p = 0.001). According to the VAS scale, patients’ tolerance was also significantly better with hydrocodone than with placebo (2 (0–8) v 3 (0–9), p = 0.043). Conclusion: The combination of midazolam and hydrocodone markedly reduces cough during FB without causing significant desaturation, especially when invasive diagnostic procedures are performed.

Plasma Pro-Adrenomedullin But Not Plasma Pro-Endothelin Predicts Survival in Exacerbations of COPD

BACKGROUND Plasma endothelin and adrenomedullin are increased in patients with pulmonary arterial hypertension, hypoxia, and pulmonary infections, conditions that predict survival in patients with COPD. We investigated whether plasma pro-endothelin-1 (proET-1) and/or pro-adrenomedullin (proADM) on admission to the hospital for acute exacerbation predict survival in patients with COPD. METHODS We examined 167 patients who had been admitted to the hospital for acute exacerbation, and we followed them up for 2 years. We measured plasma C-terminal (CT) proET-1 and mid-regional (MR) proADM on hospital admission, after 14 to 18 days, and after 6 months. In addition to plasma CT proET-1 and MR proADM, we assessed with Cox regression univariate and multivariate analyses the predictive value of clinical, functional, and laboratory parameters on 2-year survival. We analyzed the time to death by Kaplan-Meier curves. RESULTS Compared to recovery and stable state, CT-proET-1 and MR-proADM were significantly increased on hospital admission (p < 0.001 and p = 0.002, respectively). MR-proADM, but not CT-proET-1, was associated with increased in-hospital mortality (p = 0.049) and independently predicted 2-year survival (p = 0.017). ProADM plasma levels > 0.84 nmol/L on hospital admission increased the mortality risk within 2 years from 13 to 32% (p = 0.004). By contrast, age (p = 0.779), Charlson comorbidity score (p = 0.971), body mass index (p = 0.802), FEV(1) percent predicted (p = 0.741), PAo(2) (p = 0.744), PAco(2) (p = 0.284), leukocyte counts (p = 0.333), C-reactive protein (p = 0.772), procalcitonin (p = 0.069), pulmonary arterial hypertension (p = 0.971), and CT-proET-1 (p = 0.223) were not independently associated with 2-year survival. CONCLUSIONS This study shows that plasma proADM but not plasma proET-1 on admission to the hospital for acute exacerbation independently predicts survival, thus suggesting that this biomarker could be used to predict prognosis in patients with COPD.

Exhaled nitric oxide levels in atopic children: relation to specific allergic sensitisation, AHR, and respiratory symptoms

Background: Exhaled nitric oxide (eNO), which has been proposed as a measure of airway inflammation, is increased in atopic subjects. This raises the question of whether eNO provides any additional information about airway inflammation in asthmatic subjects, other than as a marker for atopy. A study was undertaken to determine whether eNO levels in a population of atopic children are associated with sensitisation or natural exposure to specific allergens, and to examine the relationship between eNO, airway responsiveness, and current respiratory symptoms. Methods: Exhaled NO and airway responsiveness to histamine were measured in winter and in summer in 235 children aged 8–14 years who had been classified as atopic by skin prick testing. Current respiratory symptoms, defined as wheeze or cough during the month preceding the test, were measured by a parent completed questionnaire. Airway hyperresponsiveness (AHR) was defined as a dose response ratio (DRR) of >8.1 (% fall in forced expiratory volume in 1 second (FEV1)/μmol + 3). Results: Sensitisation to house dust mite was associated with raised eNO levels in winter while sensitisation to Cladosporium was associated with raised eNO levels in both winter and summer. Grass pollen sensitisation was not associated with raised eNO levels in either season. Exhaled NO correlated significantly with DRR histamine (r=0.43, p<0.001) independently of whether the children had current symptoms or not. In children with current wheeze, those with AHR had eNO levels 1.53 (95% CI 1.41 to 1.66) times higher than those without AHR (p=0.006). Neither DRR (p=1.0) nor eNO levels (p=0.92) differed significantly between children with or without persistent dry cough in the absence of wheeze. Conclusions: In atopic children, raised eNO levels are associated with sensitisation to perennial allergens, but not to seasonal allergens such as grass pollen. In this population, an increase in eNO is associated with AHR and current wheezing, suggesting that eNO is more than just a marker for atopy.

Natural exposure to Alternaria spores induces allergic rhinitis symptoms in sensitized children.

Allergic rhinitis is associated with exposure to inhaled allergens. Allergic sensitization to the fungus Alternaria is common, especially in warm climates, but the relevance of sensitization to Alternaria in the generation of rhinitis has not been elucidated. The aim of this study was to determine whether natural exposure to Alternaria induces rhinoconjuctivitis symptoms in Alternaria‐sensitized children. Symptoms of rhinoconjuctivitis in 132 atopic (measured by skin prick tests) children (aged 7–12 years) in inland New South Wales Australia were measured using parent‐completed questionnaires in summer and winter 1998. Airborne concentrations of Alternaria spores and grass pollen were measured throughout the study period using a Burkard volumetric trap. The relation between airborne concentrations of Alternaria spores and symptoms of rhinoconjunctivitis was examined using Wilcoxons matched pairs signed ranked test and generalized estimating equations. The proportion of children atopic to Alternaria reporting symptoms of rhinitis was significantly higher in the summer, when airborne concentrations of Alternaria were high, than in the winter, when airborne concentrations were low (66.2% vs. 38.2% for nasal symptoms at night, p = 0.0001, 70.6% vs. 51.52% for nasal symptoms during the day, p = 0.02). The proportion of children using anti‐allergic treatment was also higher in summer than in winter (anti‐allergic medication for the nose 39.7% vs. 17.7%, p = 0.0003). A strong correlation between airborne concentrations of grass pollen and Alternaria was found (R = 0.94, p < 0.001). However, when all children atopic to ryegrass were excluded from the analyses, significant associations between symptoms and season remained. We conclude that exposure to Alternaria spores may be an important cause of allergic rhinoconjunctivitis.

General practitioner's adherence to the COPD GOLD guidelines: baseline data of the Swiss COPD Cohort Study

PRINCIPLES: Chronic obstructive pulmonary disease (COPD) is a major burden on patients and healthcare systems. Diagnosis and the management of COPD are often administered by general practitioners (GPs). This analysis investigated the adherence of GPs in Switzerland to the Global Initiative for Chronic Obstructive Lung Diseases (GOLD) guidelines. METHODS: As part of an ongoing investigation into the effect of GPs prescriptions on the clinical course of COPD, 139 GPs submitted a standardised questionnaire for each COPD patient recruited. Information requested included spirometric parameters, management and demographic data. Participating GPs were provided with and received instruction on a spirometer with automatic feedback on quality. Patients were grouped by the investigators into the GOLD COPD severity classifications, based on spirometric data provided. Data from the questionnaires were compared between the groups and management was compared with the recommendations of GOLD. RESULTS: Of the 615 patients recruited, 44% did not fulfil GOLD criteria for COPD. Pulmonary rehabilitation was prescribed to 5% of all patients and less than one-third of patients exercised regularly. Less than half the patients in all groups used short-acting bronchodilators. Prescribing long-acting bronchodilators or inhaled corticosteroids conformed to GOLD guidelines in two-thirds of patients with GOLD stage III or IV disease, and approximately half of the less severe patients. Systemic steroids were inappropriately prescribed during stable disease in 6% of patients. CONCLUSIONS: Adherence to GOLD (COPD) guidelines is low among GPs in Switzerland and COPD is often misdiagnosed or treated inappropriately. This is probably due to poor knowledge of disease definitions.

Association between nasal and bronchial symptoms in subjects with persistent allergic rhinitis

Background:  The association between nasal and bronchial symptoms, and the course of bronchial responsiveness and airway inflammation in house dust mite sensitive persistent rhinitis over a prolonged time period has not been thoroughly explored.

Quality of Spirometry in Primary Care for Case Finding of Airway Obstruction in Smokers

Background: Diagnosis of chronic obstructive pulmonary disease (COPD) and its severity determination is based on spirometry. The quality of spirometry is crucial. Objectives: Our aim was to assess the quality of spirometry performed using a spirometer with automated feedback and quality control in a general practice setting in Switzerland and to determine the prevalence of airflow limitation in smokers aged ≧40 years. Method: Current smokers ≧40 years of age were consecutively recruited for spirometry testing by general practitioners. General practitioners received spirometry training and were provided with an EasyOne™ spirometer. Spirometry tests were assigned a quality grade from A to D and F, based on the criteria of the National Lung Health Education Program. Only spirometry tests graded A–C (reproducible measurements) were included in the analysis of airflow limitation. Results: A total of 29,817 spirometries were analyzed. Quality grades A–D and F were assigned to 33.9, 7.1, 19.4, 27.8 and 11.8% of spirometries, respectively. 95% required ≤5 trials to achieve spirometries assigned grade A. The prevalence of mild, moderate, severe and very severe airway obstruction in individuals with spirometries graded A–C was 6, 15, 5 and 1%, respectively. Conclusion: Spirometries in general practice are of acceptable quality with reproducible spirometry in 60% of measurements. Airway obstruction was found in 27% of current smokers aged ≧40 years. Office spirometry provides a simple and quick means of detecting airflow limitation, allowing earlier diagnosis and intervention in many patients with early COPD.