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1.  The skin prick test – European standards 
Skin prick testing is an essential test procedure to confirm sensitization in IgE-mediated allergic disease in subjects with rhinoconjunctivitis, asthma, urticaria, anapylaxis, atopic eczema and food and drug allergy. This manuscript reviews the available evidence including Medline and Embase searches, abstracts of international allergy meetings and position papers from the world allergy literature. The recommended method of prick testing includes the appropriate use of specific allergen extracts, positive and negative controls, interpretation of the tests after 15 – 20 minutes of application, with a positive result defined as a wheal ≥3 mm diameter. A standard prick test panel for Europe for inhalants is proposed and includes hazel (Corylus avellana), alder (Alnus incana), birch (Betula alba), plane (Platanus vulgaris), cypress (Cupressus sempervirens), grass mix (Poa pratensis, Dactilis glomerata, Lolium perenne, Phleum pratense, Festuca pratensis, Helictotrichon pretense), Olive (Olea europaea), mugwort (Artemisia vulgaris), ragweed (Ambrosia artemisiifolia), Alternaria alternata (tenuis), Cladosporium herbarum, Aspergillus fumigatus, Parietaria, cat, dog, Dermatophagoides pteronyssinus, Dermatophagoides farinae, and cockroach (Blatella germanica). Standardization of the skin test procedures and standard panels for different geographic locations are encouraged worldwide to permit better comparisons for diagnostic, clinical and research purposes.
doi:10.1186/2045-7022-3-3
PMCID: PMC3565910  PMID: 23369181
Sensitization; Inhalant allergens; Skin prick test panel; Aallergies; Type I allergy; Diagnostic test; Asthma
2.  The biodiversity hypothesis and allergic disease: world allergy organization position statement 
Biodiversity loss and climate change secondary to human activities are now being associated with various adverse health effects. However, less attention is being paid to the effects of biodiversity loss on environmental and commensal (indigenous) microbiotas. Metagenomic and other studies of healthy and diseased individuals reveal that reduced biodiversity and alterations in the composition of the gut and skin microbiota are associated with various inflammatory conditions, including asthma, allergic and inflammatory bowel diseases (IBD), type1 diabetes, and obesity. Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of urban people in affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The risk is further enhanced by physical inactivity and a western diet poor in fresh fruit and vegetables, which may act in synergy with dysbiosis of the gut flora. Studies of immigrants moving from non-affluent to affluent regions indicate that tolerance mechanisms can rapidly become impaired in microbe-poor environments. The data on microbial deprivation and immune dysfunction as they relate to biodiversity loss are evaluated in this Statement of World Allergy Organization (WAO). We propose that biodiversity, the variability among living organisms from all sources are closely related, at both the macro- and micro-levels. Loss of the macrodiversity is associated with shrinking of the microdiversity, which is associated with alterations of the indigenous microbiota. Data on behavioural means to induce tolerance are outlined and a proposal made for a Global Allergy Plan to prevent and reduce the global allergy burden for affected individuals and the societies in which they live.
doi:10.1186/1939-4551-6-3
PMCID: PMC3646540  PMID: 23663440
Allergy plan; Biodiversity; Civilization disease; Epigenetics; Immune dysfunction; Microbiota; Microbiome; Urbanization
3.  Persistent asthma, co-morbid conditions and the risk of work disability: a prospective cohort study 
Allergy  2011;66(12):1598-1603.
Backround
This study examined whether asthma alone or together with chronic co-morbidity is associated with increased risk of long-term work disability.
Methods
We examined data from 2,332 asthmatic and 66,354 non-asthmatic public sector employees in Finland who responded to a survey between 1997 and 2004. Respondents were coded as persistent asthmatics based on the special reimbursement for continuous asthma medication by the Social Insurance Institution. Data on long-term work disability (sickness absences or disability pensions >90 days) were obtained from national registers. The risk of work disability was examined by Cox proportional hazard models adjusted for age, gender, socioeconomic status, type of employment contract and type of employer.
Results
Asthma increased the risk of all-cause long-term work disability, hazard ratio (HR) 1.8 (95 % CI 1.62–2.09) compared to controls (no asthma). Asthma and one other chronic co-morbidity increased the risk for long-term all-cause work disability with HR 2.2 (95% CI 1.78–2.83). Asthma together with two or more other chronic conditions increased the risk with HR 4.5 (95% CI 2.98–6.78). Asthma and depression increased the risk with HR 3.6 and the risk was especially high for permanent work-disability (HR 6.8). Among those with asthma there were more women, obesity (BMI ≥30), ex-smokers and lower-grade non-manual workers.
Conclusions
Asthma is associated with increased risk of long-term all-cause work disability. The risk increases further with chronic co-morbidities, and is especially high in patients with asthma and depression.
doi:10.1111/j.1398-9995.2011.02729.x
PMCID: PMC3203316  PMID: 21958351
Asthma; co-morbidity; sickness absence; work disability
4.  Clinical Use of Probiotics in Pediatric Allergy (cuppa): A World Allergy Organization Position Paper 
Background
Probiotic administration has been proposed for the prevention and treatment of specific allergic manifestations such as eczema, rhinitis, gastrointestinal allergy, food allergy, and asthma. However, published statements and scientific opinions disagree about the clinical usefulness.
Objective
A World Allergy Organization Special Committee on Food Allergy and Nutrition review of the evidence regarding the use of probiotics for the prevention and treatment of allergy.
Methods
A qualitative and narrative review of the literature on probiotic treatment of allergic disease was carried out to address the diversity and variable quality of relevant studies. This variability precluded systematization, and an expert panel group discussion method was used to evaluate the literature. In the absence of systematic reviews of treatment, meta-analyses of prevention studies were used to provide data in support of probiotic applications.
Results
Despite the plethora of literature, probiotic research is still in its infancy. There is a need for basic microbiology research on the resident human microbiota. Mechanistic studies from biology, immunology, and genetics are needed before we can claim to harness the potential of immune modulatory effects of microbiota. Meanwhile, clinicians must take a step back and try to link disease state with alterations of the microbiota through well-controlled long-term studies to identify clinical indications.
Conclusions
Probiotics do not have an established role in the prevention or treatment of allergy. No single probiotic supplement or class of supplements has been demonstrated to efficiently influence the course of any allergic manifestation or long-term disease or to be sufficient to do so. Further epidemiologic, immunologic, microbiologic, genetic, and clinical studies are necessary to determine whether probiotic supplements will be useful in preventing allergy. Until then, supplementation with probiotics remains empirical in allergy medicine. In the future, basic research should focus on homoeostatic studies, and clinical research should focus on preventive medicine applications, not only in allergy. Collaborations between allergo-immunologists and microbiologists in basic research and a multidisciplinary approach in clinical research are likely to be the most fruitful.
doi:10.1097/WOX.0b013e3182784ee0
PMCID: PMC3651185  PMID: 23282383
probiotics; prevention of allergy; pediatric allergy
5.  Endoscopic sinus surgery might reduce exacerbations and symptoms more than balloon sinuplasty 
Background:
Endoscopic sinus surgery (ESS) is considered after medical therapy failure of chronic rhinosinusitis (CRS). The balloon sinuplasty dilates the natural ostium without moving mucosa or bone. It still lacks evidence from randomized controlled trials. The aim of this retrospective controlled study was to compare the symptom outcomes after maxillary sinus surgery with either the ESS or the balloon sinuplasty technique. No previous or additional sinonasal operations were accepted.
Methods:
Two hundred eight patients with CRS without nasal polyps underwent either balloon sinuplasty or ESS. The patients who met with the inclusion criteria (n = 45 in ESS group and n = 40 in balloon group) replied to a questionnaire of history factors, exacerbations, and a visual analog scale (VAS) scoring of the change in symptoms, on average 28 ± 6 (mean ± SD) months postoperatively.
Results:
The groups were identical in the response rate (64%), patient characteristics, and the improvement in all of the asked symptoms. Patients with CRS-related comorbidity and/or present occupational exposure had a statistically significantly better symptom reduction after ESS than after balloon sinusotomy. Moreover, the balloon sinusotomy group reported a statistically significant higher number of maxillary sinus punctures and antibiotic courses during the last 12 months.
Conclusion:
ESS might be superior to balloon sinuplasty, especially in patients with risk factors. There is a need to perform more controlled studies on the treatment choices of CRS.
doi:10.2500/ajra.2012.26.3828
PMCID: PMC3903106  PMID: 23232189
Balloon sinuplasty; chronic sinusitis; endoscopy; occupation; sinus surgery
6.  The Finnish Allergy Programme 2008-2018 - scientific rationale and practical implementation 
Asia Pacific Allergy  2012;2(4):275-279.
There are no nationwide, comprehensive public health programmes on allergic disorders with set goals and systematic follow-up. The Finnish initiative is based on the idea that the so called allergy epidemic in modern, urban societies is caused by inadequately developed or broken tolerance. The immune system is not trained to make the difference between danger and non-danger (allergy) or the difference between self and non-self (autoimmune diseases). The immune dysfunction leads to inappropriate inflammatory responses and clinical symptoms. The 10-year implementation programme is aimed to reduce burden of allergies both at the individual and societal levels. This is done by increasing both immunological and psychological tolerance and changing attitudes to support health instead of medicalising common and mild allergy symptoms. Severe forms of allergy are in special focus, e.g. asthma attacks are prevented proactively by improving disease control with the help of guided self-management. Networking of allergy experts with primary care doctors and nurses as well with pharmacists is the key for effective implementation. Non-governmental organizations have started a campaign to increase allergy awareness and knowledge among patients and general public. It is time to act, when allergic individuals are becoming a majority of Western populations and their numbers are in rapid increase worldwide. The first results of the Finnish Programme indicate that allergy burden can be reduced with relatively simple means.
doi:10.5415/apallergy.2012.2.4.275
PMCID: PMC3486973  PMID: 23130334
Allergy programme; Asthma attack; Immune tolerance; Public health programme; Self-management
7.  Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA 
PLoS ONE  2012;7(9):e44008.
Rationale
Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies.
Objectives
To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.
Methods
The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever.
Main Results
We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status.
Conclusions
Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
doi:10.1371/journal.pone.0044008
PMCID: PMC3461045  PMID: 23028483
9.  Inspiratory flows through dry powder inhaler in chronic obstructive pulmonary disease: age and gender rather than severity matters 
Background:
Dry powder inhalers (DPIs) are inspiratory flow driven and hence flow dependent. Most patients with chronic obstructive pulmonary disease (COPD) are elderly and have poor lung function. The factors affecting their inspiratory flows through inhalers are unclear.
Objective:
To study peak inspiratory flows (PIFs) and their determinants through a DPI in COPD patients of varying age and severity.
Methods:
Flow-volume spirometry was performed in 93 COPD patients. Maximum PIF rates were recorded through an empty Easyhaler® (PIFEH; Orion Corporation, Espoo, Finland), a DPI that provides consistent dose delivery at inhalation rates through the inhaler of 28 L/min or higher.
Results:
The mean PIFEH was 54 L/min (range 26–95 L/min) with a coefficient of variation of 7%. All but two patients were able to generate a flow of ≥28 L/min. In a general linear model, the independent determinants for PIFEH were age (P = 0.02) and gender (P = 0.01), and forced expiratory volume in 1 s (FEV1) expressed as percent predicted was not a significant factor. The regression model accounted only for 18% of the variation in PIFEH.
Conclusion:
In patients with COPD, age and gender are more important determinants of inspiratory flow through DPIs than the degree of expiratory airway obstruction. Most COPD patients with varying age and severity are able to generate inspiratory flows through the test inhaler that is sufficient for optimal drug delivery to the lower airways.
PMCID: PMC2921694  PMID: 20714380
COPD; forced expiratory volume; peak inspiratory flow
10.  Transient Dimers of Allergens 
PLoS ONE  2010;5(2):e9037.
Background
Allergen-mediated cross-linking of IgE antibodies bound to the FcεRI receptors on the mast cell surface is the key feature of the type I allergy. If an allergen is a homodimer, its allergenicity is enhanced because it would only need one type of antibody, instead of two, for cross-linking.
Methodology/Principal Findings
An analysis of 55 crystal structures of allergens showed that 80% of them exist in symmetric dimers or oligomers in crystals. The majority are transient dimers that are formed at high protein concentrations that are reached in cells by colocalization. Native mass spectrometric analysis showed that native allergens do indeed form transient dimers in solution, while hypoallergenic variants of them exist almost solely in the monomeric form. We created a monomeric Bos d 5 allergen and show that it has a reduced capability to induce histamine release.
Conclusions/Significance
The results suggest that dimerization would be a very common and essential feature for allergens. Thus, the preparation of purely monomeric variants of allergens could open up novel possibilities for specific immunotherapy.
doi:10.1371/journal.pone.0009037
PMCID: PMC2816702  PMID: 20140203
11.  A 10 year asthma programme in Finland: major change for the better 
Thorax  2006;61(8):663-670.
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 which had fallen to €213.5 million in 2003. Costs per patient per year have decreased 36% (from €1611 to €1031).
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.
doi:10.1136/thx.2005.055699
PMCID: PMC2104683  PMID: 16877690
asthma; guidelines; medication programme; costs
12.  Persistence of oxidant and protease burden in the airways after smoking cessation 
Background
Oxidative stress is associated with the pathogenesis of cigarette smoke related lung diseases, but longitudinal effects of smoking cessation on oxidant markers in the airways are unknown.
Methods
This study included 61 smokers; 21 with chronic bronchitis or COPD, 15 asthmatics and 25 asymptomatic smokers followed up for 3 months after smoking cessation. Fractional exhaled nitric oxide (FeNO), sputum neutrophil counts, sputum 8-isoprostane, nitrotyrosine and matrix metalloproteinase-8 (MMP-8) were investigated at baseline and 1 and 3 months after smoking cessation.
Results
After 3 months 15 subjects had succeeded in quitting of smoking and in these subjects symptoms improved significantly. Unexpectedly, however, sputum neutrophils increased (p = 0.046) after smoking cessation in patients with chronic bronchitis/COPD. At baseline, the other markers did not differ between the three groups so these results were combined for further analysis. Sputum 8-isoprostane declined significantly during the follow-up at 3 months (p = 0.035), but levels still remained significantly higher than in non-smokers. The levels of FeNO, nitrotyrosine and MMP-8 did not change significantly during the 3 months after smoking cessation.
Conclusion
Whilst symptoms improve after smoking cessation, the oxidant and protease burden in the airways continues for months.
doi:10.1186/1471-2466-9-25
PMCID: PMC2697135  PMID: 19473482
13.  Eight Years of Severe Allergic Reactions in Finland: A Register-Based Report 
Background
No data have been available on severe allergic reactions in Finland.
Materials and Methods
We summarize the data accumulated from 2000 to 2007 in the national register established at the Skin and Allergy Hospital of the Helsinki University Central Hospital, where physicians voluntarily report on patients with severe allergic reactions.
Results
During the period, the 530 reported cases of severe allergic reactions represented an annual frequency of 0.001%. Of the patients, 66% were adults and 56% were female, with a median age of 27 years. Food was the causative agent in 53% of the cases, drugs in 26%, allergen preparations in 12%, and insects in 8%. Dermatologic symptoms were reported in 85%, respiratory in 76%, cardiovascular in 50%, gastrointestinal in 33%, and eye/nose symptoms in 18%. The reaction was a life-threatening anaphylactic shock in 26% of the cases, with no deaths reported. Patients were treated with intramuscular adrenaline in 75% of the cases. Not only nuts and seeds, but also fruit and vegetables were the most important allergens for the adults. Nuts were also important allergens for children, along with milk, egg, and wheat. In addition, many "exotic" allergens were identified: patent blue, carmine dye, yeast, buckwheat, and macrogol.
Conclusions
Severe allergic reactions are underreported, but a register reflects the real-life situation and helps to identify new causative agents. It also contributes to improvements in first aid treatment practice.
doi:10.1097/WOX.0b013e3181898224
PMCID: PMC3650993  PMID: 23282762
allergen preparation; anaphylaxis; drug; food; insect; register
14.  Should milk-specific IgE antibodies be measured in adults in primary care? 
Objective
To study the association of milk-IgE antibodies in serum to milk-related gastrointestinal symptoms in adults in primary care.
Design
Open clinical study.
Setting
Five outpatient clinics in primary care in Southern Finland.
Subjects
A total of 756 subjects who reported milk-related gastrointestinal symptoms in primary care and as controls 101 subjects with no such symptoms.
Methods
IgE values for specific food antigens were measured (Pharmacia CAP System) in a total of 857 subjects. All food screen-positive samples (>0.35 IU/l) were analysed further for IgE for untreated skimmed milk (milk-IgE) and for boiled milk. Those found positive for milk-IgE were invited for an open milk challenge test.
Results
Some 5.4% (46/857) of all subjects had a positive IgE antibody screen for food antigens. Of those with a positive food screen, 28% (13/46) had milk-IgE antibodies comprising 1.5% of the total group screened. The prevalence of milk-IgE was not statistically different between those with milk-related symptoms and those with no such symptoms. IgE antibodies for boiled milk were rare. All specific IgE antibody levels were low. Bloating was the only observed symptom in milk challenge tests.
Conclusion
IgE antibodies to cow's milk were relatively rare in the adult population and were not indicative of milk protein allergy. The observed IgE levels were low and did not correlate with subjective milk-related symptoms. The measurement of milk-specific IgE in adults should be discouraged in outpatient clinics.
doi:10.1080/02813430802117442
PMCID: PMC3406635  PMID: 18609255
Abdominal symptoms; cow's milk; food hypersensitivity; primary care
15.  Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study) 
Archives of Disease in Childhood  2007;93(8):654-659.
Objective:
To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma.
Patients, design and interventions:
176 children aged 5–10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 μg twice daily for 1 month, 200 μg twice daily for months 2–6, 100 μg twice daily for months 7–18); (2) budesonide, identical treatment to group 1 during months 1–6, then budesonide for exacerbations as needed for months 7–18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1–18. Exacerbations were treated with budesonide 400 μg twice daily for 2 weeks.
Main outcome measures:
Lung function, the number of exacerbations and growth.
Results:
Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7–18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth.
Conclusions:
Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment.
doi:10.1136/adc.2007.116632
PMCID: PMC2532957  PMID: 17634183
16.  Allergic rhinitis and asthma: inflammation in a one-airway condition 
BMC Pulmonary Medicine  2006;6(Suppl 1):S5.
Background
Allergic rhinitis and asthma are conditions of airway inflammation that often coexist.
Discussion
In susceptible individuals, exposure of the nose and lungs to allergen elicits early phase and late phase responses. Contact with antigen by mast cells results in their degranulation, the release of selected mediators, and the subsequent recruitment of other inflammatory cell phenotypes. Additional proinflammatory mediators are released, including histamine, prostaglandins, cysteinyl leukotrienes, proteases, and a variety of cytokines, chemokines, and growth factors. Nasal biopsies in allergic rhinitis demonstrate accumulations of mast cells, eosinophils, and basophils in the epithelium and accumulations of eosinophils in the deeper subepithelium (that is, lamina propria). Examination of bronchial tissue, even in mild asthma, shows lymphocytic inflammation enriched by eosinophils. In severe asthma, the predominant pattern of inflammation changes, with increases in the numbers of neutrophils and, in many, an extension of the changes to involve smaller airways (that is, bronchioli). Structural alterations (that is, remodeling) of bronchi in mild asthma include epithelial fragility and thickening of its reticular basement membrane. With increasing severity of asthma there may be increases in airway smooth muscle mass, vascularity, interstitial collagen, and mucus-secreting glands. Remodeling in the nose is less extensive than that of the lower airways, but the epithelial reticular basement membrane may be slightly but significantly thickened.
Conclusion
Inflammation is a key feature of both allergic rhinitis and asthma. There are therefore potential benefits for application of anti-inflammatory strategies that target both these anatomic sites.
doi:10.1186/1471-2466-6-S1-S5
PMCID: PMC1698498  PMID: 17140423
17.  Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma 
Thorax  2003;58(6):494-499.
Background: Respiratory function and airway inflammation can be evaluated in preschool children with special techniques, but their relative power in identifying young children with asthma has not been studied. This study was undertaken to compare the value of exhaled nitric oxide (FENO), baseline lung function, and bronchodilator responsiveness in identifying children with newly detected probable asthma.
Methods: Ninety six preschool children (age 3.8–7.5 years) with asthmatic symptoms or history and 62 age matched healthy non-atopic controls were studied. FENO was measured with the standard online single exhalation technique, and baseline lung function and bronchodilator responsiveness were measured using impulse oscillometry (IOS).
Results: Children with probable asthma (n=21), characterised by recent recurrent wheeze, had a significantly higher mean (SE) concentration of FENO than controls (22.1 (3.4) ppb v 5.3 (0.4) ppb; mean difference 16.8 ppb, 95% CI 12.0 to 21.5) and also had higher baseline respiratory resistance, lower reactance, and larger bronchodilator responses expressed as the change in resistance after inhalation of salbutamol. Children with chronic cough only (n=46) also had significantly raised mean FENO (9.2 (1.5) ppb; mean difference 3.9 ppb, 95% CI 0.8 to 7.0) but their lung function was not significantly reduced. Children on inhaled steroids due to previously diagnosed asthma (n=29) differed from the controls only in their baseline lung function. The analysis of receiver operating characteristics (ROC) showed that FENO provided the best power for discriminating between children with probable asthma and healthy controls, with a sensitivity of 86% and specificity of 92% at the cut off level of 1.5 SD above predicted.
Conclusions: FENO is superior to baseline respiratory function and bronchodilator responsiveness in identifying preschool children with probable asthma. The results emphasise the presence of airway inflammation in the early stages of asthma, even in young children.
doi:10.1136/thorax.58.6.494
PMCID: PMC1746693  PMID: 12775859
18.  Sustained reduction in bronchial hyperresponsiveness with inhaled fluticasone propionate within three days in mild asthma: time course after onset and cessation of treatment 
Thorax  2003;58(6):500-504.
Background: Bronchial hyperresponsiveness (BHR) is characteristic of asthmatic airways, is induced by airway inflammation, and is reduced by inhaled corticosteroids (ICS). The time course for the onset and cessation of the effect of ICS on BHR is unclear. The effect of inhaled fluticasone propionate (FP) on BHR in patients with mild persistent asthma was assessed using time intervals of hours, days and weeks.
Methods: Twenty six asthmatic patients aged 21–59 years were selected for this randomised, double blind, parallel group study. The effect of 250 µg inhaled FP (MDI) administered twice daily was compared with that of placebo on BHR assessed using a dosimetric histamine challenge method. The dose of histamine inducing a decrease in forced expiratory volume in 1 second (FEV1) by 15% (PD15FEV1) was measured before and 6, 12, 24 and 72 hours, and 2, 4 and 6 weeks after starting treatment, and 48 hours, 1 week and 2 weeks after cessation of treatment. Doubling doses of changes in PD15FEV1 were calculated and area under the curve (AUC) statistics were used to summarise the information from individual response curves.
Results: The increase in PD15FEV1 from baseline was greater in the FP group than in the placebo group; the difference achieved significance within 72 hours and remained significant until the end of treatment. In the FP group PD15FEV1 was 1.85–2.07 doubling doses above baseline between 72 hours and 6 weeks after starting treatment. BHR increased significantly within 2 weeks after cessation of FP treatment.
Conclusions: A sustained reduction in BHR to histamine in patients with mild asthma was achieved within 3 days of starting treatment with FP at a daily dose of 500 µg. The effect tapered within 2 weeks of cessation of treatment.
doi:10.1136/thorax.58.6.500
PMCID: PMC1746689  PMID: 12775860
20.  Cell specific markers for eosinophils and neutrophils in sputum and bronchoalveolar lavage fluid of patients with respiratory conditions and healthy subjects 
Thorax  2002;57(5):449-451.
Methods: Induced sputum and bronchoalveolar lavage fluid samples from 14 patients with respiratory conditions and four healthy individuals were studied. Antigens were detected at their intracellular sites in cells with well preserved structures using optimal techniques for fixation, permeabilisation, and immunolabelling.
Results: Anti-EPO antibodies reacted only with eosinophils, and anti-HNL antibodies only with neutrophils. Anti-ECP antibodies reacted with both eosinophils and neutrophils and anti-MPO antibodies with neutrophils and monocytes. Cells not stained by monoclonal anti-EPO and anti-HNL antibodies included lymphocytes, monocytes, macrophages, squamous epithelial cells, and ciliated epithelial cells.
Conclusions: EPO, a unique component of eosinophils, and HNL, a unique component of neutrophils, are useful markers for the identification of eosinophils and neutrophils, respectively, in sputum and bronchoalveolar lavage fluid.
doi:10.1136/thorax.57.5.449
PMCID: PMC1746329  PMID: 11978925
21.  Asthma programme in Finland: a community problem needs community solutions 
Thorax  2001;56(10):806-814.
doi:10.1136/thorax.56.10.806
PMCID: PMC1745939  PMID: 11562522
22.  Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial 
BMJ : British Medical Journal  2003;327(7420):891.
Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone.
Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol.
Participants Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for ≥ 1 year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a β agonist improvement of ≥ 12% in FEV1.
Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation.
Results 20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to 5.0%). With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasone significantly increased FEV1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P ≤ 0.001), whereas FEV1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated.
Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.
PMCID: PMC218809  PMID: 14563743
23.  Societal and health care benefits of early use of inhaled steroids 
Thorax  1998;53(12):1005-1006.
PMCID: PMC1745132  PMID: 10195067
24.  Toxic-Metabolite-Producing Bacteria and Fungus in an Indoor Environment 
Toxic-metabolite-emitting microbes were isolated from the indoor environment of a building where the occupant was suffering serious building-related ill-health symptoms. Toxic substances soluble in methanol and inhibitory to spermatozoa at <10 μg (dry weight) ml−1 were found from six bacterial isolates and one fungus. The substances from isolates of Bacillus simplex and from isolates belonging to the actinobacterial genera Streptomyces and Nocardiopsis were mitochondriotoxic. These substances dissipated the mitochondrial membrane potential (Δψ) of boar spermatozoa. The substances from the Streptomyces isolates also swelled the mitochondria. The substances from isolates of Trichoderma harzianum Rifai and Bacillus pumilus damaged the cell membrane barrier function of sperm cells.
doi:10.1128/AEM.67.7.3269-3274.2001
PMCID: PMC93010  PMID: 11425751
25.  Occurrence of exercise induced bronchospasm in elite runners: dependence on atopy and exposure to cold air and pollen 
OBJECTIVES: To study factors affecting the occurrence of exercise induced bronchospasm (EIB) in elite runners. METHODS: Fifty eight elite runners, 79% of them belonging to Finnish national teams, volunteered. The athletes answered a questionnaire on respiratory symptoms. Skin prick tests were used to investigate atopy, and spirometry to examine lung function at rest and after an exercise challenge test (ECT) at subzero temperature in the winter and after a similar ECT in the summer at the end of the birch pollen season. RESULTS: Definitive EIB (a post- exercise reduction of 10% or more in forced expiratory volume in one second (FEV1) was observed in five (9%) of the 58 runners. A subgroup consisting of 19 non-atopic symptom-free runners with no family history of asthma was used to establish a normal range for post-exercise reduction in FEV1. When this group's mean exercise induced change in FEV1 minus 2 SDs (a reduction of 6.5% or more in FEV1) was taken as the lower limit of the reference range, 15 (26%) of the runners had probable EIB in either the winter or the pollen season. The occurrence of probable EIB depended on atopy (odds ratio increased with number of positive skin prick test reactions, p < 0.05). Nine (22%) of the 41 runners, challenged in both the winter and the pollen season, had probable EIB only in the winter, and three (7%) had it only in the pollen season. Only one runner (2%) had EIB in both tests. CONCLUSIONS: Mild EIB is common in Finnish elite runners and is strongly associated with atopy. Seasonal variability affects the occurrence of EIB, and thus exercise testing should be performed in both cold winter air and the pollen season to detect EIB in elite runners. 



PMCID: PMC1756081  PMID: 9631218

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