Global Asthma Network survey suggests more national asthma strategies could reduce burden of asthma.

BACKGROUND: Several countries or regions within countries have an effective national asthma strategy resulting in a reduction of the large burden of asthma to individuals and society. There has been no systematic appraisal of the extent of national asthma strategies in the world. METHODS: The Global Asthma Network (GAN) undertook an email survey of 276 Principal Investigators of GAN centres in 120 countries, in 2013-2014. One of the questions was: "Has a national asthma strategy been developed in your country for the next five years? For children? For adults?". RESULTS: Investigators in 112 (93.3%) countries answered this question. Of these, 26 (23.2%) reported having a national asthma strategy for children and 24 (21.4%) for adults; 22 (19.6%) countries had a strategy for both children and adults; 28 (25%) had a strategy for at least one age group. In countries with a high prevalence of current wheeze, strategies were significantly more common than in low prevalence countries (11/13 (85%) and 7/31 (22.6%) respectively, p<0.001). INTERPRETATION: In 25% countries a national asthma strategy was reported. A large reduction in the global burden of asthma could be potentially achieved if more countries had an effective asthma strategy.

Clinical relevance is associated with allergen-specific wheal size in skin prick testing.

BACKGROUND: Within a large prospective study, the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. OBJECTIVE: To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. METHODS: The GA(2) LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. RESULTS: Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. CONCLUSION: These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use.

Comparison of two twice-daily doses of budesonide/formoterol maintenance and reliever therapy.

The aim of this study was to compare two budesonide/formoterol maintenance doses within the budesonide/formoterol maintenance and reliever therapy concept and to identify possible patient characteristics at baseline which would predict a better response to a higher than standard maintenance dose. A total of 8,424 patients with symptomatic asthma when using an inhaled corticosteroid (ICS) with or without a long-acting ß(2)-agonist were randomised to budesonide/formoterol 160/4.5 µg, one (1 × 2) or two (2 × 2) inhalations b.i.d. Patients used the same inhaler as needed for symptom relief. The primary outcome variable was time to first severe asthma exacerbation. In the total study population, the time to first severe asthma exacerbation was prolonged by 18% with 2 × 2 versus 1 × 2 (hazard ratio 0.82; p = 0.03). Lung function (peak expiratory flow) was the only statistically significant predictor of a better response to 2 × 2. The mean daily ICS doses were 737 and 463 µg in the 2 × 2 and 1 × 2 groups, respectively. In a real-life setting, budesonide/formoterol maintenance and reliever therapy at the 2 × 2 maintenance dose did prolong time to first severe exacerbation but at a higher medication load. Patients with low lung function benefited most from the higher maintenance dose.

Effects of inhaled corticosteroids on metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 in the airways of asthmatic children.

BACKGROUND: The effects of corticosteroids on the level and expression of matrix metalloproteinase-8 (MMP-8; collagenase-2) and tissue inhibitors of metalloproteinases (TIMPs) in airway tissue are poorly characterized in vivo. METHODS: We compared MMP-8 and TIMP-1 levels in induced sputum and their expression in airway inflammatory cells of healthy children (n = 27) and of children with newly diagnosed asthma with mild (n = 20) or moderate symptoms (n = 19), before and after 6 months of treatment with inhaled budesonide. RESULTS: At baseline, MMP-8 was higher in asthmatic children with moderate symptoms, TIMP-1 was lower and the MMP-8/TIMP-1 ratio was higher in both groups of asthmatic children compared with controls. Inhaled budesonide increased TIMP-1 levels in both groups of asthmatic children and normalized the MMP-8/TIMP-1 ratio, and this paralleled the improvement in forced expiratory volume in 1 s in children with mild symptoms. At baseline, asthmatic children had significantly more MMP-8-positive macrophages than control children, whereas the number of TIMP-1-positive macrophages was almost the same. Budesonide decreased the percentage of MMP-8-positive macrophages and increased that of TIMP-1-positive macrophages; these changes were significant in asthmatic children with mild symptoms. CONCLUSIONS: Inhaled budesonide normalized the MMP-8/TIMP-1 ratio in asthmatic children by upregulation of TIMP-1 production and downregulation of MMP-8 production by airway macrophages. This change may be a biochemical marker of an effect on airway inflammation and possibly of an ongoing remodeling process that should be further investigated using biopsy specimens.

Treatment with inhaled steroids in patients with symptoms suggestive of asthma but with normal lung function.

A total of 144 patients with lower airway symptoms suggestive of asthma, but who did not fulfil the functional criteria of asthma, were included in a randomised, double-blind, placebo-controlled 8-week "proof-of-concept" study with mometasone furoate (MF), 400 microg once daily. The primary efficacy variable was the mean change from baseline in six morning and evening weekly symptom scores: cough, sputum production, wheeze, shortness of breath, chest tightness and exercise-induced cough/wheeze. Total symptom scores were calculated after treatment for 4 and 8 weeks. Compared with placebo, MF improved total morning symptom score at 8 weeks. Changes in total evening symptom scores did not differ between treatments. MF improved all individual symptom scores more than placebo, although the differences in changes between treatments were not always statistically significant. Morning and evening peak expiratory flow rates increased with MF compared with placebo. MF reduced eosinophils and the levels of eosinophilic cationic protein in induced sputum. The results show that symptoms suggestive of asthma exist in patients without significant beta(2)-agonist reversibility or diurnal variability in peak flow. Once-daily MF may benefit some of these patients and a short course with inhaled corticosteroids may be tried. Responders should be better identified in further studies.

Disease marker combination enhances patient characterization in the Finnish sarcoidosis patients.

Sarcoidosis is an inflammatory disease of unknown etiology and multiple clinical phenotypes. Clinical manifestations range from asymptomatic disease to severe loss-of-function leading to the hypothesis that sarcoidosis might not be just one disease, but consists of several distinct disease entities each with potentially distinct genetic associations. We have previously demonstrated that in our series HLADRB1* 03:01 and haplotype HLA-DRB1*04:01-DPB1*04:01 are associated with good prognosis sarcoidosis. In our recent work, we found a novel SNP (rs9905945) in the 5'upstream region of the ACE gene to be associated with favorable disease prognosis as well. The main objective of this study was to expand the previous results and analyse combined influence of the found ACE SNP rs9905945 with the protective HLA markers HLADRB1* 03:01 and HLA-DRB1*04:01-DPB1*04:01 in 188 Finnish sarcoidosis patients (resolved disease, n = 90; persistent disease, n = 98). When combining the frequencies of the rs9905945 and of the HLA markers, the strongest association was found for a combination of either/or both HLA markers and rs9905945 for good disease prognosis (37.1% in resolved vs. 11.3% in persistent, p < 0.001, OR = 4.61, (95%CI 2.15-9.86)). In conclusion, we discovered that a combination of the ACE SNP rs9905945 and HLA markers enhance the accuracy for predicting disease course in Finnish sarcoidosis patients further characterizing genetic differences between Finnish sarcoidosis patients with different prognosis.

Usefulness of fine-needle aspiration biopsy of spleen in diagnosis of sarcoidosis.

Fine-needle aspiration biopsy of the spleen was carried out in 557 patients. In 381 cases, the aspiration was performed because of suspected sarcoidosis. The sensitivity of the technique was 59 percent and the specificity 97 percent. The cytologic picture of the spleen was abnormal in 184 patients with sarcoidosis and in seven patients with extrinsic allergic alveolitis. No major complications occurred. The method provides a simple, safe, quick, and reliable way of producing evidence of a granulomatous process in patients with suspected sarcoidosis. The biopsy method can be used with advantage before application of more invasive techniques.

Concentration of tumor-associated trypsin inhibitor (TATI) in pleural effusions.

We measured the concentration of tumor-associated trypsin inhibitor (TATI) in plasma and pleural fluid of 84 patients with pleural effusions of various causes. We observed elevated (greater than 30 micrograms/L) TATI levels in pleural fluid in 45 percent of patients with pleural effusion associated with malignant disease and in 15 percent of patients with benign disease. Similar results were obtained for TATI in plasma. The concentration of TATI in pleural fluid closely parallelled that in plasma. In patients with renal insufficiency and in patients with biliary obstruction, the TATI levels were elevated both in plasma and pleural fluid. A positive correlation was seen between the concentration of TATI and the activity of alkaline phosphatase in plasma. The results show that simultaneous determination of TATI in plasma and pleural fluid improves the diagnosis of cancer only marginally. Our results also support the hypothesis that elevated TATI levels may reflect an acute phase reaction caused by inflammatory disease or tissue destruction associated with cancer not only in inflammatory conditions, but also in malignant disease where the tumor itself is not producing TATI.

Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Study Group.

STUDY OBJECTIVE: To evaluate the efficacy of oral prednisolone, followed by inhaled budesonide, in patients with newly diagnosed (<3 months) stage I and stage II pulmonary sarcoidosis. DESIGN: Double-blind, placebo-controlled, parallel-group, multicenter study. SETTING: Twenty pulmonary medicine departments in Finland. PATIENTS: One hundred eighty-nine adult patients were randomized to treatment. Patients with erythema nodosum or stage IV sarcoidosis (pulmonary fibrosis), and patients requiring immediate treatment with oral corticosteroids for extrapulmonary lesions or chronic illnesses were excluded. TREATMENT: The patients received either oral prednisolone for 3 months (20 mg/d for 8 weeks, 15 mg/d for 2 weeks, and 10 mg/d for 2 weeks) followed by inhaled budesonide (Pulmicort Turbuhaler; Astra Draco; Lund, Sweden) for 15 months at 800 microg bid, or placebo tablets followed by placebo inhaler therapy. MEASUREMENTS: Chest radiographs, lung volumes (FVC), diffusing capacity of the lung for carbon monoxide (D(LCO)), serum angiotensin-converting enzyme (SACE), and beta2-microglobulin at 3-month intervals. RESULTS: After 3 months of treatment, radiographic improvements were seen in the active-treatment group when compared to the placebo-treatment group. At 6 months, the difference was still statistically significant. Later, no differences were found. In patients with initial stage I lesions, neither the FVC nor the D(LCO) (the percent predicted mean values) changed during the study, as they were normal from the beginning. In patients with initial stage II disease, the difference in the FVC mean values between the groups also remained unchanged throughout the study. In stage II patients treated for 18 months, but not earlier, the difference in D(LCO) became statistically significant; the largest differences were seen in patients with initial FVC values <80% of predicted and D(LCO) values <75% of predicted. The decrease in SACE in the active-treated stage II patients was significantly larger than in the placebo-treated patients. No difference was observed in adverse events between the active-treated patients and the placebo-treated patients. CONCLUSION: Treatment is not required for patients with stage I disease. An initial treatment with prednisolone followed by long-term inhalation of budesonide is more effective than placebo in patients with stage II disease. Sequential oral and inhaled corticosteroid therapy may be an alternative treatment regimen for stage II sarcoidosis patients, rather than long-term oral corticosteroid therapy alone.

Effect of early vs late intervention with inhaled corticosteroids in asthma.

One hundred five consecutive patients with mild or moderate asthma not earlier treated with inhaled corticosteroids and with a need of an inhaled bronchodilator of three or more doses a week, and/or asthma symptoms during day or night, and/or peak expiratory flow (PEF) or FEV1 less than 75% of predicted normal values were given an inhaled corticosteroid for 2 years (budesonide delivered via an inspiratory flow-driven multidose dry powder inhaler [Turbuhaler]). According to duration of symptoms, they were divided into six groups; from a duration less than 6 months up to a duration more than 10 years. PEF and FEV1 were measured before and after treatment for 3 months, 1 year, and 2 years. In the groups of patients with a duration of symptoms less than 2 years, mean FEV1 and PEF were significantly higher at all time points as compared with the baseline and as compared with the groups of patients with a longer duration of asthma symptoms. The maximum effects were usually seen after 1 year's treatment with maintained control during the second year. A significant negative correlation was found between duration of symptoms and maximum increases in PEF (r = -0.34; p = 0.0006) and FEV1 (r = -0.32; p = 0.0012), a correlation remaining also after correcting for baseline airway function. No correlation was found between the age of the patients or earlier regular use of beta 2-agonists and improvements in airway function. The results give some evidence that early treatment of asthma with an inhaled steroid may prevent patients from developing chronic airway obstruction. They also support current asthma treatment guidelines advocating early introduction of inhaled anti-inflammatory drugs.

Fine-needle aspiration biopsy of the spleen in diagnosis of sarcoidosis.

Splenic fine-needle aspiration is a simple, safe bedside procedure by which cells typical of the sarcoid granuloma can be rapidly detected. Not only does it appear to be a valuable diagnostic procedure, but it offers a reliable method for demonstrating multisystem involvement in sarcoidosis.

Use of budesonide in the treatment of pulmonary sarcoidosis.

Twenty patients with active sarcoidosis (increased serum ACE activity) and progressive pulmonary disease (stages 2-3) were treated with inhaled budesonide instead of with oral glucocorticosteroids in an open clinical study. Results after an 18-month treatment are reported. A general improvement in chest roentgenograms and FVC was noted. Serum ACE activity was normalized. The results indicate that pulmonary manifestations of sarcoidosis can be treated with the inhaled steroid, budesonide. In this way the risk of systemic side effects is considerably reduced. The final place of inhaled budesonide in the treatment of sarcoidosis must be determined via placebo-controlled and comparative, double-blinded clinical studies in larger series of patients.

The Finnish leukaemia group: levamisole in maintenance therapy of acute myeloid leukemia in adults.

The Finnish Leukaemia Group has carried out a randomized, multicenter trial to study the effect of levamisole on the remission maintained with 6-mercaptopurine and methotrexate in acute myeloid leukaemia in adults. Levamisole was given on 3 consecutive days every 2 weeks. Twenty-five patients received only chemotherapy, while 26 patients received levamisole as well. The patients receiving levamisole showed significantly better remission duration than those given only chemotherapy (P = 0.033, Mantel's summary chi 2-text). There are four long term survivors in the levamisole group versus none in the chemotherapy group. The remissions have lasted 48-75 months.

The mode of presentation of sarcoidosis in Finland and Hokkaido, Japan. A comparative analysis of 571 Finnish and 686 Japanese patients.

We compared the clinical picture of sarcoidosis in patients diagnosed at Mjölbolsta hospital in Finland in 1955-1987 with those diagnosed in Sapporo in 1964-1988. The female:male ratios showed a slight female predominance. The mean age (SD) at diagnosis was 41.5 (13.0) years at Mjölbolsta and 30.0 (15.4) years in Sapporo. In both series, half of the patients had been detected at mass x-ray surveys. The presenting symptoms varied considerably among the symptomatic patients. At Mjölbolsta hospital, 189 patients (33%) had cough, 21% fever, 21% general malaise, 18% dyspnoea, 18% erythema nodosum, 16% joint pain and only 27 patients (5%) had eye symptoms. In Sapporo, 245 patients (41%) had eye symptoms, 18 (4%) had enlarged peripheral lymph nodes, 14 (3%) had cough, 10 (2%) had fever. Erythema nodosum did not occur as a presenting symptom in Sapporo. The chest radiographs showed bilateral hilar lymphadenopathy (BHL, stage I) in 48% of the Mjölbolsta patients and in 57% of the Sapporo patients. Stage II lesions were seen in 39% and 20%, and stage III lesions in 12% and 5% respectively. Only 1% had a normal chest radiograph at Mjölbolsta hospital as compared with 18% in Sapporo. The Sapporo patients were more obstructive but the proportion of smokers was also higher. No difference in diffusion capacity was seen.

The prognosis of pulmonary sarcoidosis in Finland and Hokkaido, Japan. A comparative five-year study of biopsy-proven cases.

BACKGROUND AND AIM OF THE STUDY: The frequency and clinical picture of sarcoidosis are different in Finland and Hokkaido, Japan. The aim of this study was to compare the normalisation rate of chest radiographic changes in patients with biopsy-proven sarcoidosis. METHOD: The chest radiographs of 437 Finnish and 457 Japanese patients were used and, for the purpose of this study, double-checked in order to make sure that the interpretations were identical. On a yearly basis the radiographs were classified as normalised, improved, unchanged or deteriorated. RESULTS: Normalisation of chest radiographs occurred in 73% of the Japanese and 40% of the Finnish patients. The difference between the two series was significant (p < 0.001). Gender, young age, presence or absence of symptoms or extrapulmonary lesions at diagnosis or treatment with corticosteroids did not influence the difference between the two series. Of the 191 Finnish and 309 Japanese patients with initial stage I disease a normal chest radiograph was obtained in 47% of the Finnish and 76% of the Japanese patients (p < 0.001), despite the fact that the Finnish series included patients with erythema nodosum, who had a 59% normalisation rate. Of the 186 Finnish and 125 Japanese patients with initial stage II disease, normalisation of the chest radiographs was seen in 36% of the Finnish and in 73% of the Japanese patients (p < 0.001). No difference in normalisation rate was seen between stage III patients. CONCLUSION: The prognosis of pulmonary sarcoidosis in Japanese patients in Hokkaido is significantly better than that in Finland defined as normalisation rate of the chest radiographs.

Formoterol used as needed--clinical effectiveness.

A number of studies have already demonstrated the clinical effectiveness of formoterol when used as maintenance therapy in patients requiring both a beta2-agonist with a long duration of action and a regular inhaled corticosteroid. However, formoterol has a unique mechanism of action that gives it both fast- and long-acting properties. Hence the question arises as to whether formoterol can also be used as first-line reliever medication in addition to maintenance therapy. Compared with terbutaline, formoterol used as needed in steroid-treated mild to moderate asthma has superior efficacy, not only significantly improving peak flow, but also the exacerbation rate. In moderate to severe asthma, formoterol used as needed has demonstrated efficacy comparable with salbutamol and terbutaline in improving symptoms and lung function. Single doses of formoterol have also been shown to result in protection against exercise-induced bronchoconstriction for periods up to 12 h. Furthermore, bronchoprotection was maintained following repeated dosing, although further research is needed to confirm the duration of protection achieved with frequent and regular use. Initial research also suggests that formoterol is as effective and well tolerated as terbutaline in the treatment of acute asthma attacks. The evidence presented supports the use of formoterol on an as-needed basis for effective asthma control.

Asthma control and steroid doses 5 years after early or delayed introduction of inhaled corticosteroids in asthma: a real-life study.

UNLABELLED: We evaluated asthma control and medication use 5 years after introduction of an inhaled corticosteroid (budesonide via Turbuhaler) in 462 patients with persistent asthma and symptoms of different duration. An early treatment group with symptoms for <2 years (group A) was compared with a delayed treatment group (group B) (median duration 5 years and 3 months). Most patients received budesonide 400 microg twice daily as initial dose. We report 5-year follow-up data on 404 patients (group A n = 253; group B n = 151) and on a few more patients after treatment for 6 months, 1 year and 3 years. At 5 years the mean maintenance doses of budesonide were 412 microg (A) and 825 microg (B), respectively (P<0.001). Nevertheless, treatment goals (normal lung function, normal exercise tolerance, minimal use of reliever medication, no asthma exacerbations) were all statistically significantly more frequently achieved in group A. At 5 years group B patients also used significantly more additional asthma medications, e.g. inhaled long-acting beta2-agonists by 64% compared with 6% in group A. In group A 43 patients (17%) had been able to stop budesonide treatment compared to five patients (3%) in group B. A subgroup of group B patients with higher mean baseline FEV1 values than group A showed nevertheless significantly poorer response. No treatment-related serious adverse events were reported. Budesonide was well tolerated in both groups. CONCLUSION: Duration of asthma symptoms when starting treatment with an inhaled corticosteroid is an important determinant for the response. Early treatment gives significantly better airway function and asthma control than delayed treatment and at lower maintenance doses.

Beta 2-agonists administered by a dry powder inhaler can be used in acute asthma.

Patients with acute asthma attending the emergency room were included in a double-blind, double-dummy and parallel group study to investigate whether a dry powder inhaler (Turbuhaler) can be used in acute asthma. If so, the aim was to establish the potency relationship between a beta 2-agonist (salbutamol) administered by the dry powder inhaler and the pressurized metered-dose inhaler (pMDI). Eighty-six patients with a mean age of 38 years and forced expiratory volume in 1 s (FEV1) of 37% of predicted normal value were randomized at Siriraj Hospital in Bangkok to either Turbuhaler (50 micrograms dose -1) or pMDI (100 micrograms dose -1) with spacer (Volumatic). Doses of 100 + 300 + 300 + 300 micrograms salbutamol were given at 0, 15, 30 and 45 min via Turbuhaler and repeated at 90, 105, 120 and 135 min (total dose 2000 micrograms). The same inhalation schedule with identical number of doses was used for the pMDI with spacer but in double doses (total 4000 micrograms), assuming a dose-potency ratio of salbutamol administered via Turbuhaler compared with the pMDI of 2:1. At 85 min after the first dose, 60 mg prednisolone was given orally. FEV1 was measured 10 min after each dosing. Peak inspiratory flow (PIF) through Turbuhaler was measured on each dosing occasion. Plasma (P)-salbutamol, serum (S)-potassium concentrations, pulse rate, blood pressure and adverse events were recorded. No statistically significant differences were observed in the increase in FEV1 between the groups: 55 min (165 min) after the first dose, the increase was 0.47 l and 47% (0.64 l and 63%) in the Turbuhaler group, and 0.46 l and 42% (0.68 l and 65%) in the pMDI group. Mean PIF though Turbuhaler was 49 l min -1 (range 26-68) at first inhalation and increased to 60 l min -1 (range 38-86). There was no correlation between the initial PIF through Turbuhaler and the initial FEV1 response. P-salbutamol and S-potassium values correlated well. A larger decrease in S-potassium was noticed after 75 min in the pMDI group (0.38 mmol l -1) compared with the Turbuhaler group (0.23 mmol l -1) (P = 0.02). In conclusion, the use of a dry powder inhaler, Turbuhaler, was investigated in the emergency room treatment of acute asthma, and was as effective as a pMDI with spacer. Half the dose of salbutamol administered via Turbuhaler was as effective as the full dose given via a pMDI with spacer.

Familial sarcoidosis in Finland and Hokkaido, Japan--a comparative study.

Two or more cases of sarcoidosis in one family is not unusual. To compare the frequencies of familial sarcoidosis in Finland and Hokkaido, Japan, and to analyse the type of associations reported, we collected data on all patients visiting hospitals for sarcoidosis in 1984 in Finland (1378 patients) and Hokkaido (208 patients), including information about familial sarcoidosis. We also analysed the familial cases seen among 571 sarcoidosis patients diagnosed at the Mjölbolsta hospital in Finland from 1955 to 1987 and among 686 Japanese patients seen in Sapporo from 1964 to 1988. In 1984, 50 sarcoidosis patients visiting Finnish hospitals and nine sarcoidosis patients in Hokkaido reported as familial cases. Of the sarcoidosis patients seen in Finland at the Mjolbolsta hospital in 1955-1987, 27 had a family member with the same disease, while this number was 20 in the Sapporo hospital in 1964-1988. Those surveys give a prevalence of familial sarcoidosis in Finland of 3.6-4.7% and in Hokkaido of 2.9-4.3%. Among familial cases, the dominating relationships were sister-brother and mother-child relationships.