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Background: The use of a transbronchial lung cryobiopsy (TBLC) is increasing as a diagnostic method of interstitial lung diseases (ILD). This study aimed to evaluate risk factors associated with clinically significant complications of TBLC in ILD patients., Methods: Patients referred to Kuopio or Tampere university hospitals, in Finland, for a suspected ILD were included. The TBLC was performed in an outpatient setting for 100 patients. Patients were mechanically ventilated in general anesthesia. Fluoroscopy guidance and prophylactic bronchial balloon were used. Complications, such as bleeding, pneumothorax, infections, and mortality were recorded. Moderate or serious bleeding, pneumothorax, or death ≤90 days were defined as clinically significant complications. A multivariable model was created to assess clinically significant complications., Results: The extent of traction bronchiectasis (Odds ratio [OR] 1.30, Confidence interval [CI] 1.03-1.65, p = 0.027) and young age (OR 7.96, CI 2.32-27.3, p = 0.001) were associated with the risk of clinically significant complications whereas the use of oral corticosteroids ≤30 days before the TBLC (OR 3.65, CI 0.911-14.6, p = 0.068) did not quite reach statistical significance. A history of serious cough was associated with the risk of pneumothorax (OR 4.18, CI 1.10-16.0, p = 0.036). Procedure associated mortality ≤90 days was 1%., Conclusion: The extent of traction bronchiectasis on HRCT and young age were associated with the risk of clinically significant complications whereas oral corticosteroid use did not quite reach statistical significance. A history of serious cough was associated with the risk of clinically significant pneumothorax., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Citric acid has been used as a cough provocation test for decades. However, the methods of administration have not been standardized. Inhaled mannitol is a novel cough provocation test, which has regulatory approval and can be performed utilizing a simple disposable inhaler in a standardized manner., Objective: To compare the mannitol and citric acid cough provocation tests with respect to their ability to identify subjects with chronic cough and their tolerability., Methods: Subjects with chronic cough (n = 36) and controls (n = 25) performed provocation tests with mannitol and citric acid. Both tests were video recorded. Cough sensitivity was expressed as coughs-to-dose ratios (CDR) and the cumulative doses to mannitol or concentration to citric acid evoking 5 coughs (C5). Forced expiratory volume in 1 s (FEV 1 ), visual analogue scales (VAS), test completion rates and the total cough frequencies were analysed., Results: Mannitol and citric acid CDR both effectively separated those with cough and the control subjects (AUC 0.847 and 0.803, respectively) as did C5 (AUC 0.823 and 0.763, respectively). There was a good correlation between the cough sensitivity provoked by the two stimuli, either expressed as CDR (r = 0.65, p < 0.001) or C5 (r = 0.53, p = 0.001). Both tests were similarly tolerated in terms of VAS, although more patients discontinued the mannitol test early, primarily due to cough., Conclusions: Mannitol and citric acid tests correlated well, equally identified subjects with chronic cough and their tolerability was similar. The feasibility issues, strict standardisation and regulatory approval may favour mannitol to be used in clinical cough research., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Management of chronic cough relies on the recognition of cough background disorders. It is not known whether certain cough triggers are associated with specific background disorders., Methods: This was an e-mail study to public service employees of two towns in Finland. The questionnaire included twelve triggers. Current asthma was defined as doctor's diagnosis of asthma and current wheezing. Chronic rhinosinusitis was defined as either nasal blockage or nasal discharge and either facial pain/pressure or reduction/loss of smell for more than three months. Gastroesophageal reflux disease was defined as heartburn and/or regurgitation on at least one day a week during the last three months. Idiopathic cough was defined as absence of any of them., Results: There were 421 subjects with current cough that had lasted at least eight weeks. Subfreezing air as a cough trigger was associated with an adjusted odds ratio (aOR) of 7.27 (4.09-12.9), (p < 0.001), for current asthma. The number of cough triggers was largest in asthma, followed by chronic rhinosinusitis, gastroesophageal reflux, and idiopathic cough (7.05 (6.14-7.96), 4.94 (4.35-5.54), 4.60 (3.77-5.43), and 3.44 (3.02-3.86), respectively, p < 0.001). Presence of five or more triggers was associated with an aOR of 7.49 (3.96-14.2), (p < 0.001) for current asthma. Absence of any cough triggers increased the probability of idiopathic cough (aOR 2.71 (1.54-4.77), p = 0.001)., Conclusions: Subfreezing air as a cough trigger and multiple triggers are strongly associated with the presence of current asthma in chronic cough. Absence of any cough triggers increases the probability of idiopathic cough., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Stepping down from combination asthma therapy (inhaled corticosteroids (ICS) + long-acting β2 agonists (LABA)) is often avoided due to fear of exacerbations, which may lead to overmedication in well-controlled asthma. A better knowledge about the predictors of outcome might encourage clinicians to start stepping down more often than previously., Methods: In 55 subjects with well controlled asthma and combination therapy, LABAs were discontinued first, followed by ICS dose halving, and then cessation, in six weeks' intervals. The ability of Juniper's asthma control questionnaire (ACQ), ambulatory peak flow monitoring, spirometry, and hypertonic saline challenge to predict the outcomes of medication reductions were assessed., Results: The proportions of subjects experiencing an exacerbation at each step were: 4 out of 55 subjects (7%) after LABA cessation, 4 out of 25 subjects (16%) after ICS dose halving, and 21 out of 46 subjects (46%) after ICS cessation. All exacerbations could be managed on an outpatient basis. There were 126 step-downs altogether. ACQ score < 0.29 (likelihood ratio 2.30 (1.05-5.05)), ACQ without spirometry < 0.15 (2.17 (0.96-4.90)) and FEV1 > 96% of predicted (2.18 (1.03-4.61)) predicted a successful outcome after step-down. Cough responsiveness to saline, bronchoconstrictive responsiveness to saline, and peak flow variation were not associated with the outcome., Conclusion: Combination therapy can often be reduced in controlled asthma but total cessation of ICSs must be carefully considered. Simple investigations, namely asthma control assessment by validated questionnaire and spirometry, help to predict the outcome of stepping down., Trial Registry: The study was registered in ClinicalTrials.gov database (https://clinicaltrials.gov, KUH5801124)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: The present study examines how the trends in the prevalence of chronic bronchitis during the last three decades associate with changes in smoking habits during the same period., Methods: Altogether 47 896 subjects aged 25-74 years were examined in six independent cross-sectional population surveys repeated every five years between 1982 and 2007 in Finland. The presence of chronic bronchitis, smoking habits and other risk factors were measured by standard questionnaires., Results: During the study, the prevalence of chronic bronchitis was significantly higher in men than in women. In men aged 25-64 years, the prevalence of chronic bronchitis decreased from 19% in 1982 to 13% in 2007 (p for trend <0.001). The corresponding decrease in women aged 25-64 years was from 13% to 11% (p for trend 0.009). In men aged 65-74 years, the prevalence of chronic bronchitis decreased from 24% to 19% (p for trend 0.032). Simultaneously, male smoking decreased and smoking in middle-aged women increased. However, adjusting for the changes in smoking habits did not change the declining trends in the prevalence of chronic bronchitis. The significant declining trend in chronic bronchitis was seen separately in male current smokers and in male and female never smokers aged 45-74 years and the declining trend was the greatest in male current smokers. In general, female smokers with chronic bronchitis had smoked less than their male counterparts., Conclusion: There was a declining trend in the prevalence of chronic bronchitis which was probably explained by both a decrease in smoking and by other factors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: Lower respiratory infections in infancy may be associated with lung function deficits in adulthood. Our aim was to evaluate lung function, with a special focus on irreversible airway obstruction, thirty years after bronchiolitis or pneumonia in infancy., Methods: In 1981-1982, 83 children under two years of age were hospitalized for bronchiolitis and 44 for pneumonia at Kuopio University Hospital, Finland. In 2010, 47 bronchiolitis patients, 22 pneumonia patients and 138 controls attended the study, including spirometry before (pre-BD) and after bronchodilatation (post-BD). The measured indices were forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), that were presented as % of predicted value (FVC% and FEV1%). FEV1/FVC was presented as both absolute FVC/FEV1-ratio and % of predicted (FEV1/FVC%). Irreversible airway obstruction was defined as post-BD FEV1/FVC% below 88% of predicted (FEV1/FVC% <88%) according to Finnish reference values or FEV1/FVC-ratio below fifth percentile (FEV1/FVC <5th percentile), according to Global Lung Function Initiative reference values., Results: All lung function indices were lower in former bronchiolitis patients and pre- and post-BD FEV1% in pneumonia patients, compared to controls. 21% of bronchiolitis (OR, 95%CI; 5.59, 1.72-18.21) and 9% of pneumonia patients (2.24, 0.34-13.56) had FEV1/FVC% <88% compared to controls (4%). Likewise 7 (15%) of bronchiolitis (7.07, 1.33-37.22) and 1 (5%) of pneumonia patients (1.73, 0.12-24.77) had FEV1/FVC <5th percentile compared to controls 2 (1%)., Conclusion: Evidence of reduced lung function was present 30 years after hospitalization for bronchiolitis or pneumonia in infancy. Irreversible airway obstruction after severe bronchiolitis in infancy suggests permanent, structural alterations in airways., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Airway responses to bronchial provocation tests are traditionally assessed with spirometry which necessitates considerable patient co-operation. It has been shown that coughing during bronchial provocation tests is related to the degree of bronchoconstriction which, in turn, is independent of patient co-operation. The aim of the present study was to evaluate the utility of coughing induced by the hypertonic histamine challenge in the differential diagnosis of asthma in a clinically relevant patient population. The study population consisted of 25 healthy volunteers, 30 asthmatics, and 82 non-asthmatic subjects with respiratory symptoms due to other diseases. Hypertonic histamine solution was administered with ultrasonic nebuliser with the challenges being videotaped. The cough response was expressed as the cumulative number of coughs divided by the final histamine concentration administered (CCR). The geometric mean (95% CI) of CCR for asthmatics was 302 (166-562) coughs per mg/ml, for the symptomatic controls 29.5 (20.0-43.7) coughs per mg/ml (p<0.001) and for the healthy controls 6.61 (3.02-14.5) (p<0.001) coughs per mg/ml. According to the ROC curve, the optimal cut-off point for logCCR was 2.22, with the specificity and sensitivity to detect asthma among symptomatic subjects being 86% and 70%. Cough response to hyperosmolar challenge may be useful in the differential diagnosis of airway diseases.

Purpose: To describe the 30-year cumulative incidence of chronic bronchitis and COPD in relation to smoking habits. The effect of chronic bronchitis on pulmonary function and mortality was also examined., Methods: Middle-aged men belonging to two rural Finnish cohorts of the Seven Countries Study (n = 1,711 in 1959) were followed up for up to 40 years until 2000. Standard questionnaires were used to measure chronic bronchitis, and repeated spirometry was used to evaluate pulmonary function during the 30 years. Forty-year mortality data were examined., Results: The cumulative incidence of chronic bronchitis and COPD was 42% and 32%, respectively, in continuous smokers, compared to 26% and 14% in ex-smokers and 22% and 12% in never-smokers. During the follow-up, subjects with chronic bronchitis had on average 252 mL (95% confidence interval, 211 to 293 mL) lower forced expiratory volume than those without it. The decrease in forced expiratory volume attributable to chronic bronchitis was most pronounced in those with persistent symptoms and in smokers. In subjects with chronic bronchitis, all-cause mortality was increased by a hazard ratio of 1.30 (95% confidence interval, 1.02 to 1.65). Smokers with chronic bronchitis who decreased their daily cigarette consumption increased their median life span by 2.4 years., Conclusions: The lifetime risk of chronic bronchitis among smokers is approximately two in five, and almost one half of smokers who have chronic bronchitis also acquire COPD. Chronic bronchitis is related to earlier death, also in never-smokers, probably partly through a rapid decline in pulmonary function.

Assessment of the bronchodilation response to short-acting beta2-adrenoreceptor agonists on pharmacologically induced bronchoconstriction has often been used to investigate airway smooth muscle beta2-adrenoreceptor function. However, little is known about factors affecting this response. In the present study, the bronchodilation response to 0.2 mg of salbutamol on histamine-induced bronchoconstriction was assessed in 101 steroid-naïve asthmatic subjects. The associations of the response with a wide range of challenge procedure-related variables, clinical asthma severity indicators, and blood markers of airway inflammation were investigated. The response was re-assessed after 6 and 12 weeks' therapy with inhaled budesonide. Baseline FEV1, final histamine concentration, and the maximal fall in FEV1 explained 35-59% of the total variation in the response to salbutamol, depending on the index chosen to express the response. Serum concentration of myeloperoxidase, an index of neutrophilic inflammation, was associated with a poor response. The preceding week daily PEF variation, rescue bronchodilator use, severity of asthmatic symptoms, blood eosinophil count, and serum eosinophilic cationic protein and eosinophilic protein X concentrations were not associated with the response. The salbutamol response seemed to diminish during budesonide treatment but when adjusted by the challenge procedure-related variables the treatment effect vanished. In conclusion, the bronchodilation response to salbutamol on histamine-induced bronchoconstriction is largely determined by challenge procedure-related variables. It seems to be unrelated to the clinical severity of asthma and is not affected by treatment with inhaled corticosteroids. Neutrophilic airway inflammation may be associated with a poor response.

Study Objective: To analyze the cough response to three airway challenges in order to clarify whether the recording of the provoked coughs would be beneficial in the management of asthma., Design: A prospective study., Setting: University hospital., Participants: Fifteen healthy subjects, 16 steroid-naïve subjects with asthma, and 16 subjects with steroid-treated asthma., Interventions: Inhalation challenges with isotonic histamine, hypertonic saline solution, and hypertonic histamine, using an ultrasonic nebulizer and 2-min tidal breathing method., Measurements: Airflow parameters were measured with a spirometer, and the coughs were recorded manually., Results: Coughing during the isotonic histamine challenge was associated with the degree of the bronchoconstriction induced. When this was taken into account, the healthy subjects coughed as frequently as the asthmatic subjects. During the two hypertonic challenges, the asthmatic subjects coughed more frequently than did the healthy subjects when the induced bronchoconstriction had not yet developed. At that stage of the hypertonic saline solution challenge, the mean coughing frequency was 0.7 coughs per minute (95% confidence interval [CI], 0.03 to 1.3 coughs per minute) for the healthy subjects, 2.7 coughs per minute (95% CI, 0.8 to 4.5 coughs per minute) for the steroid-naïve asthmatic subjects, and 1.3 coughs per minute (95% CI, 0.6 to 1.9 coughs per minute) for the steroid-treated asthmatic subjects (p = 0.018). For the hypertonic histamine challenge, the respective values were 0.8 coughs per minute (95% CI, 0.4 to 1.2 coughs per minute), 3.6 coughs per minute (95% CI, 2.4 to 4.9 coughs per minute), and 2.1 coughs per minute (95% CI, 1.0 to 3.1 coughs per minute; p = 0.001). This cough did not correlate with airway hyperresponsiveness., Conclusions: Coughing during isotonic histamine challenge seems to be a manifestation of bronchoconstriction, and recording of the coughs may not provide additional information to airflow measurements. Frequent coughing during hypertonic saline solution and hypertonic histamine challenges in the absence of bronchoconstriction is a pathologic phenomenon. Sensitivity to the cough-provoking effect of hypertonic challenges seems to be enhanced in patients with asthma but unrelated to airway hyperresponsiveness. Therefore, the recording of the provoked coughs during these challenges may add to the information obtained from airflow measurements.

There is significant overlap in the responsiveness to direct airway challenges, such as the histamine challenge, between asthmatic and non-asthmatic subjects, which decreases their accuracy in the diagnosis of asthma. To minimise this overlap, a new test, hypertonic histamine challenge, was developed. Fifteen healthy subjects, 16 subjects with steroid-naive asthma, and 16 asthmatic subjects undergoing inhaled corticosteroid treatment underwent inhalation challenges with hypertonic saline, isotonic histamine, and hypertonic histamine, using an ultrasonic nebuliser and 2-min tidal breathing method. The increase in histamine solution tonicity decreased the histamine PC20 values only in the steroid-naive asthmatic subjects (1.1 (0.5-2.7) vs. 0.5 (0.2-1.2) mg/ml, P = 0.047). Using 1mg/ml as the cut-off value, the sensitivity, specificity, and accuracy of the hypertonic histamine challenge to detect steroid-naive asthma was 81%, 100%, and 90%. The respective values for the isotonic histamine challenge were 56%, 100%, and 77%. Furthermore, there was a statistically significant difference in the hypertonic histamine PC20 between steroid-naive and steroid-treated asthmatic subjects, which could not be detected in the isotonic histamine PC20. The hypertonic histamine PC20 was highly repeatable, with a single determination 95% range of +/-1.35 doubling concentrations. The hypertonic histamine challenge was safe but provoked more cough and throat irritation than the other two challenges. In conclusion, compared with a conventional, isotonic histamine challenge, hypertonic histamine challenge may be more accurate in the diagnosis of asthma and also, more capable to detect the effects of inhaled corticosteroid treatment.

Study Objectives: To define whether coughing during mannitol challenge is a nonspecific side effect of this challenge or is associated with asthma., Design: A prospective study., Setting: University hospital., Participants: Thirty-seven steroid-naive, asthmatic subjects and 10 healthy subjects., Measurements: The participants completed a symptom questionnaire, recorded peak expiratory flows (PEFs), and underwent spirometry, skin tests, and bronchial provocations with mannitol, histamine, and cold air. Seventeen of the asthmatic subjects were treated with budesonide, 800 micro g per day, and the measurements were repeated after 3 and 6 months of treatment. Coughs were recorded during the mannitol challenges, and the cough sensitivity was expressed as the cumulative number of coughs divided by the cumulative dose of mannitol., Results: The asthmatic subjects coughed more during the mannitol challenge than the healthy subjects (8.3 coughs per 100 mg [95% confidence interval (CI), 6.2 to 11.0] vs 1.1 coughs per 100 mg [95% CI, 0.4 to 3.0]; p < 0.0001). Even those asthmatic subjects who did not develop bronchoconstriction after the maximal cumulative dose of mannitol (635 mg) coughed significantly more than the healthy subjects (53 coughs [95% CI, 34 to 72] vs 12 coughs [95% CI, 4 to 21]; p = 0.003). Budesonide treatment decreased the cough sensitivity (p = 0.023), which was significantly associated with improvements in overall symptom frequency, cough frequency, diurnal PEF variation, FEV(1), and bronchial hyperresponsiveness., Conclusions: Coughing during mannitol challenge is associated with asthma and occurs independently of bronchoconstriction. It can be used to study the mechanisms of asthmatic cough. Furthermore, the measurement of the mannitol-provoked coughing may be useful both in the diagnosis of asthma as well as in the assessment of the effects of an anti-inflammatory therapy on this common disorder.

Study Objectives: To compare a new bronchial provocation test, the mannitol challenge, with cold air and histamine challenges to demonstrate airway hyperresponsiveness (AHR) in patients with difficult-to-diagnose asthma., Design: A prospective study., Participants: Thirty-seven consecutive patients with recently diagnosed, steroid-naive, mild, or atypical asthma fulfilling the diagnostic criteria of Finnish Social Insurance Institution, and 10 healthy control subjects., Interventions: Each subject completed a symptom questionnaire and underwent spirometry, diffusion capacity measurement, skin-prick tests, and bronchial provocations with mannitol, histamine, and cold air. The severity of asthma was classified according to the Global Initiative for Asthma (GINA)., Results: Fifty-one percent of the asthmatic patients responded to mannitol (> or =15% fall in FEV(1)), 24% to cold air (> or =9% fall in FEV(1)), and 81% or 49% to histamine (provocative dose causing a 15% fall in FEV(1) [PD(15)] < 1.0 mg or < 0.4 mg, respectively). None of the healthy control subjects responded. The GINA classification was not associated with responsiveness to any of the challenges., Conclusions: Mannitol is more sensitive than cold air in demonstrating AHR in patients with mild or atypical asthma. Histamine was more sensitive than both mannitol and cold air if 1.0 mg was used as a cut-off value for histamine PD(15). However, if the cut-off value for histamine PD(15) is lowered to 0.4 mg, which represents a specific diagnosis of asthma according to previous studies, the sensitivity values of mannitol and histamine challenges are comparable.

Study Objectives: To compare the sensitivity and validity of mannitol, histamine, and cold air challenges to demonstrate the effect of inhaled corticosteroids (ICS) in asthma., Design: A prospective study., Participants: Seventeen patients with recently diagnosed, steroid-naive asthma who fulfilled the diagnostic criteria of Finnish Social Insurance Institution and were hyperresponsive to both mannitol and histamine., Interventions: The following procedures were carried out at baseline and after 3 months and 6 months of treatment with inhaled budesonide, 800 microg/d: symptom assessment with a questionnaire, ambulatory peak expiratory flow (PEF) measurements twice daily for 2 weeks, and bronchial challenges with mannitol, histamine, and cold air., Results: Budesonide decreased the sum symptom score, daily use of bronchodilating drugs, and diurnal PEF variation, but did not change FEV(1) percentage of predicted significantly. In addition, budesonide significantly decreased mannitol (p = 0.005) and histamine (p = 0.002) response dose ratios. The magnitude of the budesonide-induced change in responsiveness to these two challenges did not differ significantly. The effect of budesonide on cold air responsiveness did not reach statistical significance (p = 0.064). Change in mannitol responsiveness correlated significantly with the changes in sum symptom score and in FEV(1). Change in cold air responsiveness correlated with the changes in sum symptom score and in diurnal PEF variation. Change in histamine responsiveness correlated only with change in FEV(1)., Conclusions: Mannitol challenge is both a sensitive and valid test to demonstrate the effects of ICS in asthma. Histamine challenge is equally sensitive for this purpose, but its validity may be lower than that of mannitol challenge. Cold air challenge seems to be a valid test to demonstrate the effects of ICS, but its sensitivity may be lower than that of mannitol and histamine challenges.

Study Objectives: To identify which tests would be useful in selecting patients for a specific inhalation challenge with bovine dander allergens (bSIC)., Design: A prospective study., Setting: A university hospital., Patients: Thirty-seven dairy farmers with a clinical suspicion of occupational asthma due to bovine allergens., Interventions: Each patient (n = 27) underwent histamine challenge, mannitol challenge, exhaled nitric oxide (NO) measurement, bovine-specific serum IgE measurement, and skin-prick test (SPT) with bovine allergens prior to undergoing a bSIC., Results: Eleven patients responded to the inhalation challenge with bovine allergens. The sensitivity and specificity of the tests, based on this response, were 82% and 65%, respectively, for the histamine challenge; 20% and 94%, respectively, for the mannitol challenge; 27% and 77%, respectively, for the NO measurement; 82% and 100%, respectively, for the bovine-specific serum IgE measurement; and 100% and 50%, respectively, for the SPT. Multiple regression analysis revealed that only IgE-mediated sensitivity to bovine allergens, but neither bronchial hyperreactivity nor exhaled NO concentration, contributed significantly to the response., Conclusion: Only the SPT with bovine allergens and bovine-specific serum IgE measurements were useful in selecting patients for the bSIC. This challenge should not be performed in SPT-negative subjects. A diagnosis of occupational asthma due to bovine dander allergens could be made without an inhalation challenge test in asthmatic patients with high bovine-specific serum IgE levels. This practice would eliminate the need for the majority of bSICs.