Jess Lambrechtsen

Low physical fitness in childhood is associated with the development of asthma in young adulthood: the Odense schoolchild study

Intense physical activity in children may either improve fitness and protect against asthma, or may trigger symptoms. The aim of this study was to determine whether physical fitness in childhood has an impact on the development of asthma. In this prospective, community-based study, 757 (84%) asymptomatic children with an average age at inclusion of 9.7 yrs were followed for 10.5 yrs. In both surveys a maximal progressive exercise test on a bicycle ergometer was used to measure physical fitness (maximal workload) and to induce airway narrowing. A methacholine provocation test was performed in the subjects at follow-up. During the 10-yr study period, 51 (6.7%) of the previously asymptomatic children developed asthma. These subjects had a lower mean physical fitness in 1985 than their peers: (3.63 versus 3.89 W x kg(-1); p=0.02) in boys and (3.17 versus 3.33 W x kg(-1); p=0.02) in girls. A weak correlation was found between physical fitness in childhood and airway responsiveness to methacholine at follow-up when adjusted for body mass index, age and sex (r=0.11; p<0.01). In a multiple regression analysis, physical fitness was inversely related to the development of physician diagnosed asthma, odds ratio=0.93 (0.87-0.99). Thus, the risk for the development of asthma during adolescence is reduced 7% by increasing the maximal workload 1 W x kg(-1). In conclusion, this study showed that physical fitness in childhood is weakly correlated with the development of asthma during adolescence and that high physical fitness seems to be associated with a reduced risk for the development of asthma.

High-sensitive C-reactive protein is associated with reduced lung function in young adults

Systemic inflammation has been associated with reduced lung function. However, data on the interrelationships between lung function and inflammation are sparse, and it is not clear if low-grade inflammation leads to reduced lung function. Associations between high-sensitive C-reactive protein (CRP) and spirometric lung function were assessed in a population-based cohort of ∼1,000 Danes aged 20 yrs. In males, the average decline in forced expiratory volume in one second (FEV1) in the highest CRP quintile was 23 mL·yr−1 versus 1.6 mL·yr−1 in the lowest quintile. In females, the average decline was 6.2 mL·yr−1 in the highest CRP quintile versus an increase of 1.8 mL·yr−1 in the lowest CRP quintile. In a multiple regression analysis adjusted for sex, body mass index, cardiorespiratory fitness, smoking, asthma, airway hyperresponsiveness and serum eosinophil cationic protein, higher levels of CRP at age 20 yrs were associated with a greater reduction in both FEV1 and forced vital capacity between ages 20 and 29 yrs. The findings show that higher levels of C-reactive protein in young adults are associated with subsequent decline in lung function, suggesting that low-grade systemic inflammation in young adulthood may lead to impaired lung function independently of the effects of smoking, obesity, cardiorespiratory fitness, asthma and eosinophilic inflammation.

Point-of-care ultrasonography in patients admitted with respiratory symptoms: a single-blind, randomised controlled trial

BACKGROUND When used with standard diagnostic testing, point-of-care ultrasonography might improve the proportion of patients admitted with respiratory symptoms who are correctly diagnosed 4 h after admission to the emergency department. We therefore assessed point-of-care ultrasonography of the heart, lungs, and deep veins in addition to the usual initial diagnostic testing in this patient population. METHODS In a prospective, parallel-group trial in the emergency department at Odense University Hospital, Odense, Denmark, patients (≥18 years) with a respiratory rate of more than 20 per min, oxygen saturation of less than 95%, oxygen therapy, dyspnoea, cough, or chest pain were randomly assigned in a 1:1 ratio with a computer-generated list to a standard diagnostic strategy (control group) or to standard diagnostic tests supplemented with point-of-care ultrasonography of the heart, lungs, and deep veins (point-of-care ultrasonography group). The primary endpoint was the percentage of patients with a correct presumptive diagnosis 4 h after admission to the emergency department. Only the physicians doing the primary clinical assessment and the auditors were masked. Analyses were by intention to treat. The study is registered with ClinicalTrials.gov, number NCT01486394. FINDINGS Between Dec 7, 2011, and March 15, 2013, 320 patients were randomly assigned to the control group (n=160) and point-of-care ultrasonography group (n=160). 158 patients in the point-of-care ultrasonography group and 157 in the control group were analysed. 4 h after admission to the emergency department, 139 patients (88·0%; 95% CI 82·8-93·1) in the point-of-care ultrasonography group versus 100 (63·7%; 56·1-71·3) in the control group had correct presumptive diagnoses (p<0·0001). The absolute and relative effects were 24·3% (95% CI 15·0-33·1) and 1·38 (1·01-1·31), respectively. No adverse events were reported. INTERPRETATION Point-of-care ultrasonography is a feasible, radiation free, diagnostic test, which alongside standard diagnostic tests is superior to standard diagnostic tests alone for establishing a correct diagnosis within 4 h. It should therefore be considered for routine use as part of the standard diagnostic tests in the emergency department for patients admitted with respiratory symptoms. FUNDING University of Southern Denmark, Odense University Hospital, and Højbjerg Fund.

Discrepancy between coronary artery calcium score and HeartScore in middle-aged Danes: the DanRisk study

Background: Coronary artery calcification (CAC) is an independent and incremental risk marker. This marker has previously not been compared to the HeartScore risk model. Design: A random sample of 1825 citizens (men and women, 50 or 60 years of age) was invited for screening. Methods: Using the HeartScore model, the 10-year risk of fatal cardiovascular events based on gender, age, smoking, systolic blood pressure, and total cholesterol was estimated. A low risk was defined as <5%. The CAC score was calculated from a non-contrast enhanced cardiac-CT scan and given in Agatston U. Results: A total of 1257 (69%) of the invited subjects were interested in the screening. Due to previous cardiovascular disease or diabetes mellitus, 101 were excluded. Of the remaining 1156, 47% were men and 53% women; one half were 50 years old and the other half 60 years old. A low HeartScore was found in 901 of which 334 (37%) had CAC. A high HeartScore was recorded in 251 of which 80 (32%) did not have any CAC. High HeartScores and CAC were significantly more common in males than females. Conclusions: CAC is common in healthy middle-aged Danes with a low HeartScore, and, on the contrary, high-risk subjects very frequently do not have CAC. The therapeutic and prognostic implications of these observations remain to be clarified.

Focused Sonography of the Heart, Lungs, and Deep Veins Identifies Missed Life-Threatening Conditions in Admitted Patients With Acute Respiratory Symptoms

BACKGROUND Patients with acute respiratory symptoms still remain a diagnostic challenge. The aim of the study was to evaluate whether focused sonography could potentially diagnose life-threatening conditions missed at the primary assessment in a patient population consisting of admitted patients with acute respiratory symptoms. METHODS A prospective blinded observational study was conducted in a medical ED. Inclusion criteria were the presence of one or more of the following: respiratory rate > 20/min, oxygen saturation < 95%, oxygen therapy initiated, dyspnea, cough, or chest pain. After the initial assessment, focused sonography of the heart, lungs, and deep veins was performed by a physician blinded to patient history and the results of the primary assessment. RESULTS One hundred thirty-nine patients were included. The focused sonographic examinations could be performed in 134 patients (96%). Focused sonography identified 19 patients (14%) with an acute life-threatening condition missed at the primary assessment. Diagnostic performance of focused sonography for the diagnosis of an acute life-threatening condition, when using audit as gold standard, was as follows: sensitivity, 100% (95% CI, 85.2%-100%); specificity, 93.3% (95% CI, 86.7%-97.3%); positive predictive value, 76.7% (95% CI, 57.7%-90.1%); and negative predictive value, 100% (95% CI, 96.3%-100%). CONCLUSIONS Focused sonography of the heart, lungs, and deep veins is fast, highly feasible, and able to diagnose life-threatening conditions missed at the primary assessment in admitted patients with acute respiratory symptoms. In an ED setting sonography can be used both for ruling in and ruling out acute life-threatening conditions in these patients.

Asymptomatic bronchial hyperresponsiveness to exercise in childhood and the development of asthma related symptoms in young adulthood: the Odense Schoolchild Study

BACKGROUND Exercise testing may be of value in identifying a group of children at high risk of subsequently developing respiratory symptoms. As few longitudinal studies have investigated this issue, the bronchial hyperresponsiveness to exercise in asymptomatic children was evaluated as a risk factor for developing asthma related symptoms in young adulthood. METHODS A community based sample of 1369 schoolchildren, first investigated in 1985 at a mean age of 9.7 years, was followed up after a mean of 10.5 years. Nine hundred and twenty children (67%) were asymptomatic in childhood and 777 (84.9%) of these were re-investigated at follow up. At the first examination a maximum progressive exercise test on a bicycle ergometer was used to induce airway narrowing. The forced expiratory volume in one second (FEV1) after exercise was considered abnormal if the percentage fall in FEV1 was more than 5% of the highest fall in the reference subjects characterised by having no previous history of asthma or asthma related symptoms. The threshold for a positive test was 8.6% of pre-exercise FEV1. RESULTS One hundred and three subjects (13%) had wheeze within the last year at follow up and, of these, nine (9%) had been hyperresponsive to exercise in 1985. One hundred and seventy subjects (22%) had non-infectious cough within the previous year, 11 of whom (6%) had been hyperresponsive to exercise in 1985. Multiple regression analysis showed that subjects with hyperresponsiveness to exercise had an increased risk of developing wheeze compared with subjects with a normal response to exercise when the fall in FEV1 after exercise was included as a variable (threshold odds ratio (OR) 2.3 (95% CI 1.1 to 5.5)). The trend was not significant when exercise induced bronchospasm was included as a continuous variable (OR 1.02 (95% CI 0.97 to 1.06)). CONCLUSIONS Asymptomatic children who are hyperresponsive to exercise are at increased risk of developing new symptoms related to wheezing but the predictive value of exercise testing for individuals is low.

Plasma proteome profiling of atherosclerotic disease manifestations reveals elevated levels of the cytoskeletal protein vinculin.

UNLABELLED Atherosclerosis is a chronic disease of the arterial wall that is recognized as the leading cause of mortality and morbidity worldwide. There is an eminent need for better biomarkers that can aid in patient care before the onset of the first cardiovascular event. We used quantitative proteomics to identify proteins with altered concentrations in plasma samples from four groups: 1) Individuals without cardiovascular symptoms and without the presence of coronary calcium, 2) individuals without cardiovascular symptoms, but with high amounts of coronary calcium, 3) individuals operated because of atherosclerotic diseases, and 4) individuals with an acute coronary syndrome. Immunoassays and SRM-MS were used for single patient verification of candidate proteins. Proteins involved in cardiovascular diseases i.e. serum amyloid protein A (SAA), C-reactive protein (CRP), and apolipoprotein(a) [apo(a)] displayed an increased expression profile from groups 1 to 4. The top-most elevated protein, vinculin (Vcl) displayed a similar profile. Immunoassays confirmed the expression profile of apo(a) and CRP. A 5-plex SRM-MS assay for Vcl, SAA, CRP, apo(a) and thrombospondin-4 (TSP-4) was developed for multiplex verification in all 120 individual samples. The 5-plex SRM assay confirmed a statistically significant up-regulation of Vcl in the acute coronary syndrome group. BIOLOGICAL SIGNIFICANCE The aim of this study was to identify new candidate plasma markers of atherosclerosis manifestations, which may develop into screening-, diagnostic- or monitoring biomarkers for risk stratification of cardiovascular disease (CVD). At present no studies have elucidated the proteomic changes that occur along with several stages and manifestations of atherosclerotic disease. By using 4-plex iTRAQ, we identified and quantified proteins with altered concentrations in pooled plasma samples from 120 individuals from four middle-aged groups. Proteins involved in cardiovascular diseases i.e. serum amyloid protein A (SAA), C-reactive protein (CRP), and apolipoprotein(a) [apo(a)] displayed an increased expression profile along with increased manifestations of CVD. A novel candidate marker was identified as vinculin (Vcl), a multi-protein linker that connects cell-matrix adhesions and cell-cell adhesions to the actin-based cytoskeleton. Immuno- and SRM-assays were used for single patient validation of candidate proteins. While further studies needs to address the role of Vcl in the development of atherosclerosis, the combined data provided in this report offers a catalog of the proteomic changes that occurs in plasma over several stages and manifestations of atherosclerotic disease.

Improving Medication Adherence in Patients with Hypertension: A Randomized Trial

BACKGROUND AND PURPOSE In patients with hypertension, medication adherence is often suboptimal, thereby increasing the risk of ischemic heart disease and stroke. In a randomized trial, we investigated the effectiveness of a multifaceted pharmacist intervention in a hospital setting to improve medication adherence in hypertensive patients. Motivational interviewing was a key element of the intervention. METHODS Patients (n = 532) were recruited from 3 hospital outpatient clinics and randomized to usual care or a 6-month pharmacist intervention comprising collaborative care, medication review, and tailored adherence counseling including motivational interviewing and telephone follow-ups. The primary outcome was composite medication possession ratio (MPR) to antihypertensive and lipid-lowering agents, at 1-year follow-up, assessed by analyzing pharmacy records. Secondary outcomes at 12 months included persistence to medications, blood pressure, hospital admission, and a combined clinical endpoint of cardiovascular death, stroke, or acute myocardial infarction. RESULTS At 12 months, 20.3% of the patients in the intervention group (n = 231) were nonadherent (MPR <0.80), compared with 30.2% in the control group (n = 285) (risk difference -9.8; 95% confidence interval [CI], -17.3, -2.4) and median MPR (interquartile range) was 0.93 (0.82-0.99) and 0.91 (0.76-0.98), respectively, P = .02. The combined clinical endpoint was reached by 1.3% in the intervention group and 3.1% in the control group (relative risk 0.41; 95% CI, 0.11-1.50). No significant differences were found for persistence, blood pressure, or hospital admission. CONCLUSIONS A multifaceted pharmacist intervention in a hospital setting led to a sustained improvement in medication adherence for patients with hypertension. The intervention had no significant impact on blood pressure and secondary clinical outcomes.

Soluble urokinase plasminogen activator receptor is in contrast to high-sensitive C-reactive-protein associated with coronary artery calcifications in healthy middle-aged subjects

OBJECTIVE The main objective of this study was to investigate the association between two markers of low-grade inflammation; soluble urokinase plasminogen activator receptor (suPAR) and high-sensitive C-reactive protein (hs-CRP); and coronary artery calcification (CAC) score detected by cardiac computed tomography (CT) scan. DESIGN A cross sectional study of 1126 randomly sampled middle-aged men and women. METHODS CAC score was measured by a non-contrast cardiac CT scan and total 10-year cardiovascular mortality risk was estimated using the Systematic Coronary Risk Evaluation (SCORE). Plasma samples were analysed for suPAR and hs-CRP. The association of suPAR and hs-CRP to CAC was evaluated by logistic regression analyses adjusting for categorised SCORE. The additive effect of suPAR to SCORE was evaluated by comparing area under curve (AUC) and net reclassification improvement (NRI). RESULTS The odds of being in a higher CAC category, i.e. having more severe CAC, increased 16% (odds ratio (OR) 1.16, p = 0.02) when plasma suPAR concentration increased 1 ng/ml, and this was more pronounced in women (OR 1.30, p = 0.01) than in men (OR 1.15, p = 0.05). In comparison, hs-CRP was not associated with CAC category (OR 1.00, p = 0.90). When adding suPAR to categorised SCORE, AUC increased from 0.66 to 0.70 (p = 0.04) in women and from 0.65 to 0.68 (p = 0.03) in men. NRI was significant in men (NRI 19.3%, 95% CI 6.1-32.6, p = 0.004) as well as in women (NRI 20.8%, 95%CI 1.0-40.7, p = 0.04), without significant gender difference. CONCLUSIONS suPAR, but not hs-CRP, appeared to be associated with CAC score independently of SCORE. The association was strongest in women.

The relation between coronary artery calcification in asymptomatic subjects and both traditional risk factors and living in the city centre: a DanRisk substudy

Abstract.  Lambrechtsen J, Gerke O, Egstrup K, Sand NP, Nørgaard BL, Petersen H, Mickley H, Diederichsen ACP (Svendborg Hospital, Svendborg; Odense University Hospital, Odense; SVS, Esbjerg; Institute of Regional Health Services Research, University of Southern Denmark; Vejle Hospital, Vejle; and Odense University Hospital, Odense, Denmark). The relation between coronary artery calcification in asymptomatic subjects and both traditional risk factors and living in the city centre: a DanRisk substudy. J Intern Med 2012; 271: 444–450.