Asthma Programme in Finland: Did the use of secondary care resources become more rational?

OBJECTIVES: The aims were to evaluate the profile of newly diagnosed adult asthma cases and the approach adopted to the secondary care management at the launch of the Finnish asthma programme in 1994 and seven years later, in 2001. METHODS: A retrospective medical record audit was made of non-acutely referred patients with asthma in 1994 (n=165) and in 2001 (n=133). Clinical profile data, numbers of out-patient visits and periods of in-patient care before and after asthma diagnosis were gathered from referral letters and secondary care records. RESULTS: The newly diagnosed asthma patients in 2001 were older, more obese and had more co-morbidities. The main asthma symptoms, such as dyspnoea, wheezing and cough, occurred equally in both years but were more often periodic than daily in 2001. Wheezing during auscultation was significantly less common in 2001. The diagnostic process was associated to a history of asthma in first-degree relatives (OR 5.34, 95% CI 1.12-24.49) in 1994 and a visit to a nurse prior to that to a physician (OR 3.13, 95% CI 1.17-8.37) in 2001. Secondary care visits per new case of asthma (7.3 in 1994 vs. 5.4 in 2001) and days in hospital (3.6 in 1994 vs. 0.95 in 2001) decreased significantly. CONCLUSIONS: The profile of asthma diagnosed in secondary care indicates milder disease with more co-morbidities in 2001 than in 1994.Trends towards assigning a more active role on the part of primary care physicians and more rational use of secondary care resources in the management of asthma were found.

A 10 year asthma programme in Finland: major change for the better.

BACKGROUND: A National Asthma Programme was undertaken in Finland from 1994 to 2004 to improve asthma care and prevent an increase in costs. The main goal was to lessen the burden of asthma to individuals and society. METHODS: The action programme focused on implementation of new knowledge, especially for primary care. The main premise underpinning the campaign was that asthma is an inflammatory disease and requires anti-inflammatory treatment from the outset. The key for implementation was an effective network of asthma-responsible professionals and development of a post hoc evaluation strategy. In 1997 Finnish pharmacies were included in the Pharmacy Programme and in 2002 a Childhood Asthma mini-Programme was launched. RESULTS: The incidence of asthma is still increasing, but the burden of asthma has decreased considerably. The number of hospital days has fallen by 54% from 110 000 in 1993 to 51 000 in 2003, 69% in relation to the number of asthmatics (n = 135 363 and 207 757, respectively), with the trend still downwards. In 1993, 7212 patients of working age (9% of 80 133 asthmatics) received a disability pension from the Social Insurance Institution compared with 1741 in 2003 (1.5% of 116 067 asthmatics). The absolute decrease was 76%, and 83% in relation to the number of asthmatics. The increase in the cost of asthma (compensation for disability, drugs, hospital care, and outpatient doctor visits) ended: in 1993 the costs were 218 million euro which had fallen to 213.5 million euro in 2003. Costs per patient per year have decreased 36% (from 1611 euro to 1031 euro). CONCLUSION: It is possible to reduce the morbidity of asthma and its impact on individuals as well as on society. Improvements would have taken place without the programme, but not of this magnitude.

Risk factors for rehospitalisation in COPD: role of health status, anxiety and depression.

The aim of the present study was to analyse the risk of rehospitalisation in patients with chronic obstructive pulmonary disease and associated risk factors. This prospective study included 416 patients from a university hospital in each of the five Nordic countries. Data included demographic information, spirometry, comorbidity and 12 month follow-up for 406 patients. The hospital anxiety and depression scale and St. George's Respiratory Questionnaire (SGRQ) were applied to all patients. The number of patients that had a re-admission within 12 months was 246 (60.6%). Patients that had a re-admission had lower lung function and health status. A low forced expiratory volume in one second (FEV1) and health status were independent predictors for re-admission. Hazard ratio (HR; 95% CI) was 0.82 (0.74-0.90) per 10% increase of the predicted FEV1 and 1.06 (1.02-1.10) per 4 units increase in total SGRQ score. The risk of rehospitalisation was also increased in subjects with anxiety (HR 1.76 (1.16-2.68)) and in subjects with low health status (total SGRQ score >60 units). When comparing the different subscales in the SGRQ, the closest relation between the risk of rehospitalisation was seen with the activity scale (HR 1.07 (1.03-1.11) per 4 unit increase). In patients with low health status, anxiety is an important risk factor for rehospitalisation. This may be important for patient treatment and warrants further studies.

Economic evaluation of the use of PCR assay in diagnosing pulmonary TB in a low-incidence area.

To determine whether polymerase chain reaction (PCR) testing in the initial diagnosis of pulmonary tuberculosis (TB) is cost-effective in a low-prevalence population, an economic evaluation was carried out between the smear and culture (NOPCR) and smear, culture and PCR (+PCR) strategies. A decision tree model based on retrospective laboratory data was developed to assess the strategies of testing patients with suspicion of TB. Direct healthcare costs prior to confirmation of TB or nontuberculous mycobacteria by PCR or culture were included. Effectiveness was measured by the probability of correct treatment and isolation decisions. In the baseline situation NOPCR costs Euro 29.50 less than the +PCR strategy per patient tested. According to sensitivity analyses, reducing PCR test price, shortening test performance time or increasing the proportion of smear-positive patients in the tested population would contribute to cost savings with the +PCR strategy. Routine polymerase chain reaction testing of all specimens from suspected tuberculosis patients in a low-prevalence population was not cost-saving. When the polymerase chain reaction assay was applied only to smear-positive sputum specimens, the smear and culture strategy was clearly dominated by it, i.e. the polymerase chain reaction smear-positive sputum strategy was less costly and more effective in producing correct treatment decisions and isolations.

The IL1A genotype is associated with nasal polyposis in asthmatic adults.

BACKGROUND: Nasal polyposis (NP) is a chronic inflammatory disease often found coexisting with asthma. As this disorder tends to cluster in families, a genetic predisposition has been suggested. Interleukin-1 (IL-1) has been proposed to play a role in the pathogenesis of NP. METHODS: We analysed the single G-to-T base exchange polymorphism in exon 5 at +4845 of the gene encoding IL-1alpha (IL1A) and the C-to-T base exchange polymorphism at -511 of the gene encoding IL-1beta (IL1B) in a population-based sample of adult asthma patients (n = 245). The data were assessed for correlation with data on history of NP and other phenotype-related characteristics. RESULTS: The prevalence of NP in our study group was 14.3%. The distribution of the IL1A genotype differed significantly between asthmatics with and without NP (P = 0.005). The risk of NP was markedly increased in allele G homozygous subjects (OR = 2.73; 95%CI = 1.40-5.32). In the case of IL1B we found no significant associations. Asthmatics with NP had more symptoms than others, but lung function and blood eosinophil counts were similar. CONCLUSIONS: Our study demonstrates an association of IL1A with NP inasthmatic patients and addresses the role of IL-1alpha as an inflammatory modulator in the pathogenesis of this disease.

No impairment of peripheral deposition in novel asthmatics treated with an MDI corticosteroid with spacer.

Pulmonary distribution and lung functions were evaluated during a 4-month inhaled corticosteroid treatment period in 10 steroid-naïve novel asthmatics with normal or slightly reduced lung functions. Patients were given a total daily dose of 1000 microg of beclomethasone dipropionate aerosol twice a day via a pressured metered dose inhaler with a large-volume chamber device (Volumatic, GlaxoSmith Kline, U.K.). Gamma lung scintigraphy and lung function tests were performed before and after 2 months and 4 months. Inhaled 99mTc-labelled beclomethasone dipropionate liposomes were used to assess lung deposition patterns during inhaled steroid therapy. Serum eosinophil cationic protein (ECP) concentration was used as a surrogate marker of asthmatic inflammation. Following beclomethasone treatment, all lung functions were enhanced, but only FVC values showed significant improvement. The FEV1/FVC ratio remained slightly reduced in spite of inhaled corticosteroid therapy. However, the association between changes in improved FVC values and reduced ECP levels proved to be statistically significant. In lung scintigraphy, no evidence of changes in pulmonary deposition patterns were seen during the follow-up period. We conclude that inhaled corticosteroid therapy can lead to improvements in lung functions and surrogate markers of airway inflammation in novel asthma without affecting the peripheral deposition pattern of aerosols.

Mycobacterium tuberculosis complex is not detected by DNA amplification assay in sputum specimens of patients with lung scars due to past pulmonary tuberculosis.

OBJECTIVE: To evaluate detection of false-positive sputum amplification assay results in former tuberculosis patients with residual pulmonary scars. DESIGN: A total of 268 sputum specimens from 25 war veterans with tuberculosis during 1940-1959, without adequate chemotherapy, and 19 subjects effectively treated for cavitary tuberculosis during 1980-1993 were tested by smear, culture and DNA amplification, as were 34 controls with no history of tuberculosis or pulmonary scars. RESULTS: No active tuberculosis cases were identified. All specimens were negative on DNA amplification and smear. Eight specimens from six subjects were positive on culture, revealing atypical mycobacteria. CONCLUSION: No genetic Mycobacterium tuberculosis material in sputum specimens of subjects with residual lesions of pulmonary tuberculosis and no false-positive amplification results were detected.

Interleukin-10 gene promoter region polymorphism is associated with eosinophil count and circulating immunoglobulin E in adult asthma.

BACKGROUND: IL-10 has several functional effects relevant to asthma. It can modulate IgE production and induce apoptosis in eosinophils. Polymorphisms of IL-10 gene have been shown to affect IL-10 production. OBJECTIVE: To establish whether IL-10 polymorphisms are associated with asthma and phenotype-related characteristics. METHODS: The frequency of three single base exchange polymorphisms (at positions - 1082, - 819 and - 592) and corresponding haplotypes of the IL-10 gene were analysed in 245 adult asthmatic subjects and 405 controls using PCR and restriction fragment length polymorphism (RFLP). The data were assessed for correlations with the eosinophil count, serum IgE and lung function. RESULTS: The IL-10 haplotype frequencies were similar in asthmatics and controls. Eosinophil count median was 2.0- to 3.2-fold higher among asthmatics with rare ATA/ATA genotype than in asthmatics with other genotypes. No such difference was seen in the control group. When analysed by IL-10 haplotype carrier state and gender, male asthmatics with ATA haplotype had 2.8-fold higher serum IgE than those without ATA. A converse association was found in male controls with ATA haplotype, who had 1.9-fold lower serum IgE than their ATA-negative counterparts. The high IL-10-producing GCC haplotype was associated with impaired lung function in smoking male controls while in asthmatics no clear effect on lung function was found with any of the haplotypes studied. CONCLUSION: These results suggest that the eosinophil counts and serum IgE are differently regulated by IL-10 genotype in asthmatic and in normal subjects. However, IL-10 polymorphism is not related to susceptibility in asthma.

Possibilities of formoterol to enhance the peripheral lung deposition of the inhaled liposome corticosteroids.

The pulmonary distribution and clearance of 99m-Tc-labelled beclomethasone dipropionate (Bec)--dilauroylphosphatidylcholine (DLPC) were compared in nine asthmatic patients on inhaled steroids after a 1-week medical treatment period of long-acting beta2-agonist formoterol. The patients were given formoterol 12 microg (OxisTurbuhaler) twice daily in addition to their own regular inhaled corticosteroid therapy. Gamma lung scintigraphy and lung function tests were performed before and after formoterol treatment. The bronchodilating effect ofthe combined therapy was significant: 1-week usage of inhaled formoterol enhanced peripheral lung deposition of beclomethasone liposome and thus diminished central/peripheral deposition ratio (C/P ratio). All measured lung function values except FEV1/FVC% improved after the medication period, although statistically significant levels were not reached. A systemic positive connection was seen between enhanced lung functions and greater lung deposition measured as AUC(0-24h)/24 Beclomethasone liposome formulation maintained its long-lasting effect in connection with formoterol treatment. At the 4-h measurement, 76% of the liposome-entrapped radioactivity still remained in the lungs before and 75% after the medication period.

Increase of asthma in adults in northern Finland?--a report from the FinEsS study.

BACKGROUND: According to previous studies, the prevalence of asthma has been lower in Finland than in other Nordic countries. In the present study, we assessed the prevalence of asthma and respiratory symptoms in northern Finland and calculated risk factors for these conditions. METHODS: In November 1995, 7937 randomly selected subjects, 20-69 years of age, in northern Finland were invited to participate in a postal questionnaire survey. Complete answers were received from 6633 subjects (83.6%). RESULTS: Asthma diagnosed by a physician was reported by 6.0%, while 6.3% were using asthma medicines. Asthma was most common in young adults and the elderly. The prevalence of wheezing during the previous 12 months was reported by 19.7%, while wheezing with shortness of breath apart form colds during the previous 12 months was reported by 7.1%. Only small differences between the sexes were found in prevalence of asthma and respiratory symptoms. All symptoms were strongly smoking-dependent. Sixty-three percent of men and 42% of women were current or ex-smokers. Family history of obstructive airway disease was the strongest risk factor for asthma (OR 2.9), while increasing age, smoking, and family history of obstructive airway disease were the most important risk factors for frequent wheeze. CONCLUSIONS: The results indicate that the prevalence of asthma and symptoms associated with asthma in adults in northern Finland is now similar to that observed in Sweden and the other Nordic countries.

The efficacy of a new salbutamol metered-dose powder inhaler in comparison with two other inhaler devices.

An open cross-over and randomized study was carried out in order to compare the efficacy and safety of inhaled salbutamol delivered from a new 50 microg dose(-1) metered-dose dry powder inhaler Taifun, and a commercially available 50 microg dose(-1) dry powder inhaler Turbuhaler, and a conventional 100 microg dose(-1) pressurized metered-dose inhaler with a spacer (pMDI+S). Twenty-one patients, aged 21-70 years, with stable asthma and with demonstrated reversibility upon inhalation of salbutamol were included in the study. On three separate study days, the patients received a total dose of 400 microg of salbutamol from the dry powder inhalers and a dose of 800 microg from the pMDI+S in a cumulative fashion: 1,1, 2 and 4 doses at 30 min intervals. The percent change in forced expiratory volume in 1 sec (FEV1), was used as the primary efficacy variable. Salbutamol inhaled via the Taifun produced greater bronchodilation than the other devices. The difference in percent change in FEV1 between the Taifun and the other devices was statistically significant at the two first dose levels, but diminished towards the higher doses when the plateau of the dose-response curve was reached. The estimated relative dose potency of the Taifun was approximately 1.9- and 2.8-fold compared to the Turbuhaler and the pMDI+S, respectively. The Taifun caused a slight, but clinically insignificant, decrease in serum potassium concentration. There were no significant changes in the other safety parameters (blood pressure, heart rate and electrocardiogram recordings) with any of the used devices. In conclusion, this study indicates that salbutamol inhaled via the Taifun is more potentthan salbutamol inhaled from the other devices tested. In practise, a smaller total dose of salbutamol from theTaifun is needed to produce a similar bronchodilatory response. All treatments were equally well tolerated.

Evaluation of commercial DNA and rRNA amplification assays for assessment of treatment outcome in pulmonary tuberculosis patients.

To evaluate the clinical utility of the DNA and RNA amplification assays in monitoring the efficacy of tuberculosis treatment, 416 sputum specimens collected from 15 smear-positive tuberculosis patients during and after treatment were tested for the presence of Mycobacterium tuberculosis by microscopy, culture, polymerase chain reaction (Cobas Amplicor Mycobacterium Tuberculosis Test; Roche, Switzerland) and AMTDT 2 (Amplified Mycobacterium Tuberculosis Direct Test; Gen Probe, USA). All patients were cured, and no relapses were found. Results of both amplification assays re mained positive longer than results of either smear or culture. Four of 15 patients were positive by polymerase chain reaction and/or AMTDT 2 at the completion of treatment. Subsequent sputum specimens from these patients converted to negative within 2.5-12 months. The present data do not support the routine use of qualitative amplification assays for monitoring the treatment response of smear-positive tuberculosis patients.

Bee venom induces high histamine or high leukotriene C4 release in skin of sensitized beekeepers.

Histamine is the principal mediator released in the skin during immediate bee venom allergy but the significance of cysteinyl leukotrienes in these reactions is not known. We measured skin histamine and cysteinyl leukotriene release induced by bee venom in six sensitized beekeepers with the skin microdialysis technique. The skin was dialyzed for 2 h after skin prick test with bee venom, and the release of histamine and leukotriene C4 (LTC4) into the microdialysis fractions was measured. Leukotriene E4 (LTE) and methylhistamine excretion into the urine was assayed and whole blood histamine release test was performed. The release of histamine in the skin was variable: either high delayed, high immediate and delayed, weak release or no marked release. The histamine releasability in the skin correlated with that in whole blood. The three subjects with low histamine release exhibited high LTC4 release in the skin as well as high LTE4 excretion into the urine. Thus, the histamine and LTC4 releases were inversely associated with each other. These differences may explain the variation in the clinical reaction by bee stings in sensitized beekeepers.

Comparison of the efficacy and safety of mometasone furoate dry powder inhaler to budesonide Turbuhaler.

Mometasone furoate (MF) administered by dry powder inhaler (DPI) was composed with budesonide (BUD) Turbuhaler in the treatment of moderate persistent asthma. The patients were randomized to one of four treatment groups: MF DPI (100, 200, 400 microg b.i.d) or BUD Turbuhaler. 400 microg b.i.d in a 12-week, active-controlled, evaluator-blind, multicentre international trial. The primary efficacy variable was the mean change from baseline to endpoint (last treatment visit) in forced expiratory volume in one second (FEV1). Changes in FEV1 showed a statistically significant superiority (p<0.05) of MF DPI 200 and 400 microg b.i.d compared with the BUD Turbuhaler 400 microg b.i.d treatment. Significant superiority (p<0.05) was also seen in scores for several secondary efficacy variables when MF DPI was compared with BUD Turbuhaler treatment. MF DPI 200 microg b.i.d was comparable to MF DPI 400 microg b.i.d in therapeutic benefit. The incidence of oral candidiasis was no more than 3% in any group. All treatments were well tolerated. A total daily dose of 400 microg of mometasone furoate administered by dry powder inhaler provides a well-tolerated treatment for patients with moderate persistent asthma and results in a significantly greater improvement, when compared to a daily dose of 800 microg BUD Turbuhaler in the parameters measured in this study.

Serum ECP and MPO, but not urinary LTE4, are associated with bronchial hyper-responsiveness.

A random population-based sample of 131 subjects was used to assess the value of serum eosinophil cationic protein (ECP), serum myeloperioxidase (MPO), and urinary leukotriene E4 (LTE4) in predicting bronchial hyper-responsiveness measured by methacholine challenge. Special interest was focused on the history of aspirin intolerance and on smoking as contributing factors. The mean serum ECP and MPO were higher in hyper-reactive [provocational dose causing a 20% fall in forced expiratory volume in 1 sec. (PD20) < or = 6900 micrograms] than in non-hyper-reactive subjects (22.3 vs. 13.2 micrograms l-1, P < 0.001 and 377 vs. 278 micrograms l-1, P = 0.001, respectively). This was also seen in current smokers vs. never smokers (17.2 vs. 12.9 micrograms l-1, P = 0.03 and 372 vs. 286 micrograms l-1, P = 0.04, respectively). There were no differences in baseline urinary excretion of LTE4 between hyper-reactive and non-hyper-reactive subjects. During the 2 h after methacholine challenge, urinary LTE4 excretion increased from 53.8 and 69.0 ng mmol-1 creatinine in non-hyper-reactive subjects, but there was no change in hyper-reactive subjects (non-hyper-reactive vs. hyper-reactive, P = 0.06). The increase was greatest in subjects with aspirin intolerance causing urticaria or angioedema but not aggravation of asthma (from 58.5 to 87.2 ng mmol-1 creatinine), probably due to extrapulmonary leukotriene production. Our results indicate that serum ECP and MPO, but not urinary LTE4 (even in subjects with a history of aspirin intolerance), predict bronchial hyper-responsiveness to methacholine. The subject's smoking history must be taken into account when these parameters are considered.

Prevalence of asthma, aspirin intolerance, nasal polyposis and chronic obstructive pulmonary disease in a population-based study.

BACKGROUND: Remarkable overlap exists in symptoms between asthma and chronic obstructive pulmonary disease (COPD), and the symptoms of the patients with mild asthma are often falsely thought to be caused by smoking. The objective of the study was to determine the prevalence of doctor-diagnosed asthma, asthmatic symptoms and doctor-diagnosed COPD in an adult population. The prevalence and relation to asthma of aspirin intolerance, nasal polyposis, allergic rhinitis and smoking habits were also examined. METHODS: Postal questionnaire survey of a population-based random sample (4300) of adult women and men aged 18-65 years served by the Päijät-Häme Central Hospital in southern Finland (a region with 208 000 inhabitants) was performed. RESULTS: The non-response-adjusted prevalence (Drane's linear method) of doctor-diagnosed asthma was 4.4% (95% CI: 3.3-5.5%) and of COPD 3.7% (95% CI: 2.7-4.8%). The prevalence of allergic rhinitis was 37.3% (95% CI: 33.3-41.2%), and of overall aspirin intolerance 5.7% (95% CI: 4.4-7.1%). The observed prevalence of aspirin intolerance causing shortness of breath or attacks of asthma was 1.2% and it was higher in patients with doctor-diagnosed asthma than without (8.8% versus 0.8%, relative risk [RR] = 11.4, P < 0.0001), and higher in those with allergic-like rhinitis than without (2.6% versus 0.3%, RR = 7.7, P < 0.0001). The prevalence of nasal polyposis was 4.3% (95% CI : 2.8-5.8%). CONCLUSIONS: The current prevalence of doctor-diagnosed asthma among adults is 4.4%, and allergic rhinitis, nasal polyposis and aspirin intolerance are associated with an increased risk of asthma. There is also association between aspirin-induced asthma and allergic-like rhinitis.

Autoantibodies against oxidised low-density lipoprotein in patients with obstructive sleep apnoea.

Autoantibodies against oxidised low-density lipoprotein (OxLDL-Abs) have been proposed to be an indicator of endothelial dysfunction and a novel tool for finding individuals with a high cardiovascular risk. In a cross-sectional study, OxLDL-Abs were measured in 297 patients with obstructive sleep apnoea (OSA) and 54 controls using an enzyme-linked immunosorbent assay. The autoantibodies were increased in patients with OSA when compared to controls (age, body mass index (BMI) and gender adjusted, p = 0.001). However, within the OSA patients, OxLDL-Abs were not related to smoking, hypertension or BMI, and there was a weak negative correlation (r = -0.16, P = 0.007) between age and levels of OxLDL-Abs. In conclusion, at present the measurement OxLDL-Abs still remains a method for basic research and is not applicable for screening of at-risk patients with OSA.

Pulmonary distribution and clearance of two beclomethasone liposome formulations in healthy volunteers.

The pulmonary distribution and clearance of 99mTc-labelled beclomethasone dipropionate (Bec) dilauroylphosphatidylcholine (DLPC) and dipalmitoylphosphatidylcholine (DPPC) liposomes were compared in 11 healthy volunteers using gamma scintigraphy. As delivered by using the Aerotech jet nebulizer both liposome aerosols had a suitable droplet size (mass median aerodynamic diameter 1.3 microm) allowing deep pulmonary deposition. However, in the total drug output during the inhalation there was a relatively large difference between DLPC and DPPC of 11.4 and 3.1 microg, respectively. In a gamma camera study no significant differences existed in the central/peripheral lung deposition between the DLPC and DPPC formulations. Progressive clearance of both Tc-labelled Bec liposomes was seen: 24 h after inhalation, 79% of the originally deposited radioactivity of DLPC liposomes and 83% of that of DPPC liposomes remained in the lungs. Thus there was slightly slower clearance of inhaled liposomes using DPPC instead of DLPC. We conclude that both liposome formulations are suitable for nebulization, although aerosol clouds were more efficiently made from the DLPC liposome suspension. Our results support the view that liposome encapsulation of a drug can offer sustained release and drug action in the lower airways.