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Introduction: Recurrent cough is little researched in adults. We investigated the prevalence, risk factors, and consequences of recurrent cough, and compared the results to those of isolated chronic cough., Methods: Cross-sectional email survey in an elderly community-based population. Recurrent cough was defined as ≥ 3 cough episodes within one year (each lasting ≥ 1 week) and no current chronic cough. Isolated chronic cough was defined as current cough lasting ≥ 8 weeks and no recurrent cough., Results: The prevalence of recurrent cough was 3.8% among all respondents (n = 5983). Recurrent cough was associated with asthma (aOR 3.32 (95% CI 2.13-5.18)), chronic rhinosinusitis (2.91 (1.89-4.46)), family history of chronic cough (2.59 (1.88-3.56)), analgesic intolerance (2.13 (1.27-3.57)), male gender (1.92 (1.39-2.66)), gastro-esophageal reflux disease (1.73 (1.21-2.47)), obstructive sleep apnoea (1.69 (1.23-2.32)), symptom sum (1.12 per symptom (1.03-1.22)), and younger age (0.96 per year (0.93-1.00)). Isolated chronic cough was associated with chronic rhinosinusitis (3.45 (2.39-4.97)), asthma (2.17 (1.38-3.41), gastro-esophageal reflux disease (1.80 (1.32-2.47)), family history of chronic cough (1.80 (1.35-2.41)), obstructive sleep apnoea (1.49 (1.12-2.00)), symptom sum (1.18 per symptom (1.10-1.27)), and body mass index (0.96 per unit (0.93-1.00)). Among subjects with recurrent and isolated chronic cough, the prevalence of depressive symptoms were 7.7% and 4.2%, p = 0.11, the Leicester Cough Questionnaire total scores 15.2 (14.6-15.8) and 16.3 (16.0-16.6), P = 0.001, and the mean number of yearly cough-related doctor`s visits 0.58 (0.45-0.71) and 0.36 (0.19-0.53), P = 0.007, respectively., Conclusion: The risk factors and consequences of recurrent and isolated chronic cough were comparable. Recurrent cough seems beneficial to address in cough evaluation., (© 2023. The Author(s).)

Introduction: Cough-related healthcare-seeking has not been studied specifically in the elderly, although chronic cough is most prevalent among them. We studied the frequencies and predictors of any (≥ 1) and repeated (≥ 3) doctor's visits due to any cough episode during the past year, and due to the current cough episode., Methods: This was a cross-sectional email survey among a Finnish community-based elderly population. Participants with current cough and age ≥ 64 years were included in the analyses (n = 1109)., Results: The proportions of participants with ≥ 1 and ≥ 3 cough-related doctor's visits during the past year were 25.9% and 7.1%, respectively. Repeated visitors accounted for 55.9% of the visits during the past year. These visits first increased with cough duration but decreased after 5 years. In the multivariate analysis, bronchiectasis [aOR 3.22 (CI95% 1.08-9.58)], asthma [2.62 (1.56-4.40)], chronic sputum production [1.61 (0.94-2.76)], low self-assessed health status [1.40 (1.04-1.88)] and Leicester Cough Questionnaire total score [1.34 per tertile (1.10-1.62)] predicted repeated cough-related doctor's visits during the past year. The proportions of ≥ 1 and ≥ 3 doctor's visits due to current cough were 31.8% and 15.5%, respectively. Among participants with current chronic cough, 60.1% had not visited a doctor., Conclusion: A minority of participants accounted for most of the cough-related doctor's visits during the past year, whereas most participants with chronic cough had never sought medical help for it. The heavy healthcare users were not those with the longest cough episodes. Repeated visitors due to cough were characterised by chronic phlegmy respiratory conditions, and quality-of-life impairment., (© 2023. The Author(s).)

Objectives: Chronic cough is linked to various long-standing risk factors like asthma, chronic rhinitis and oesophageal reflux disease. On the contrary, acute and subacute cough are usually considered to be caused by acute respiratory infections. Little is known about the possible long-standing risk factors for acute and subacute cough. In this study, we have identified the long-standing risk factors for acute, subacute and chronic cough in order to identify the risk factors specifically associated with chronic cough., Design: A comprehensive 80-item questionnaire was sent via email to the participants., Setting: A community-based study to all public service employees of two towns in central Finland., Participants: There were 13 980 employees, of them 3697 responded (26.4%). Among the responders, there were 199 subjects with current daily acute cough (duration <3 weeks, prevalence 5.4%), 126 subjects with current daily subacute cough (duration 3-8 weeks, prevalence 3.4%) and 267 subjects with current daily chronic cough (duration >8 weeks, prevalence 7.2%)., Primary Outcome Measures: The risk factors that associated with each cough subtype. The subjects without any cough formed the reference group., Results: Several risk factors were associated with both short and long cough subtypes namely family history of chronic cough, moisture damage exposure and number of reported somatic symptoms. Furthermore, allergy was associated with acute and subacute cough. Current asthma and chronic rhinitis were associated with subacute and chronic cough. Oesophageal reflux disease and advanced age were associated with chronic cough., Conclusions: The specific risk factors for chronic cough were oesophageal reflux disease and advanced age. Acute and subacute cough should not be regarded merely as symptoms of acute respiratory infections but possible manifestations of long-standing risk factors. A new risk factor for all cough types was family history of chronic cough., Competing Interests: Competing interests: AML reports grants from Kuopion Hengityssäätiö Foundation, grants from Hengityssairauksien Tutkimussäätiö, during the conduct of the study; personal fees from Orion, Boehringer-Ingelheim, Roche to visit international scientific meetings , outside the submitted work. HOK reports grants from Kuopion Hengityssäätiö Foundation, grants from Hengityssairauksien Tutkimussäätiö, during the conduct of the study; personal fees from Mundipharma, Orion Pharma, Oy, Eli Lilly Finland, Boehringer Ingelheim Finland as payments for giving scientific lectures in gatherings organised by medical companies, personal fees from Takeda Leiras, Boehringer Ingelheim and Mundipharma to visit international scientific meetings, other from owning shares of Orion Pharma worth €25 000, outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The long-term prognosis of chronic cough and its determinants need to be clarified., Methods: This is a prospective, observational cohort study. Eighty-nine unselected subjects with chronic (> 8 weeks' duration) cough were carefully investigated: Clinical examination, symptom questionnaire, Leicester Cough Questionnaire (LCQ), skin prick tests, ambulatory peak expiratory flow monitoring, spirometry before and after 0.4 mgs of salbutamol, exhaled nitric oxide concentration measurement, hypertonic saline cough provocation test, and histamine bronchial provocation test. After five years, a letter was sent to the subjects containing questions about continuation of cough, smoking, indoor exposures, presence of co-morbidities, and current medication. It also contained LCQ and Cough Clinic diagnostic questionnaire. Sixty-eight subjects (76%) responded., Results: At five years, continuing regular cough was present in 31 (46%) of the subjects and continuing impairment in cough-related quality of life (less than 1.3 points' improvement in LCQ) in 32 (47%). Continuing regular cough was associated with presence of chronic rhinitis or esophageal reflux disease, baseline mild airway responsiveness to histamine, and baseline strong cough responsiveness to hypertonic saline. Continuing impairment in cough-related quality of life was associated with high body mass index, absence of atopy, absence of pets, and high number of background disorders (esophageal reflux disease, asthma, or chronic rhinitis)., Conclusions: Almost half of subjects with chronic cough suffered of the disorder at five years from initial assessment. Several possible determinants of poor prognosis could be identified.

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.)

Objectives: Farming as an occupation is considered a risk factor for asthma and reduced lung function. By contrast, living on a farm during infancy has been reported to be associated with lower risk of asthma in adulthood. However, little is known about the association between farming environment during infancy and lung function in adulthood. We aimed to study the prospective longitudinal association between farming environment during infancy and lung function in adulthood., Design: A prospective birth cohort study., Setting: Northern Finland., Participants: 5666 participants born in 1966 were followed up at the age of 31 years., Primary Outcome Measures: Spirometry at the age of 31 years., Results: To be born into a farmer's family was associated with higher forced expiratory volume in 1 s (FEV1) (36 mL; 95% CI 6 to 67 mL) and forced vital capacity (FVC) (40 mL; 95% CI 5 to 75 mL) at the age of 31 years. Contact with farm animals during infancy was associated with higher FEV1. No associations were seen with FEV1/FVC (FEV1/FVC ratio). Having dogs in childhood revealed similar associations. There was a suggestive dose-dependent association with the number of animal species during childhood and higher FEV1 and FVC at adulthood, especially among women., Conclusions: Farming environment in early life may have a positive impact on lung function in adulthood., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Hyperglycaemia is very common during exacerbations of asthma and chronic obstructive pulmonary disease (COPD). However, its clinical significance is not clear. The objective of the present study was to assess whether exacerbation-associated hyperglycaemia affects long-term mortality in these patients., Design: A prospective, observational cohort study., Setting: A single hospital in eastern Finland., Participants: 153 consecutive patients who were hospitalised due to mild to moderate obstructive lung disease exacerbation (110 with asthma and 43 with COPD) and who survived at least 30 days., Interventions: Plasma glucose levels were recorded seven times during the first day on the ward. Several possible confounders were also recorded. The median follow-up time was 6 years and 2 months., Results: During the follow-up, 57 (37%) of the patients died. Previously diagnosed diabetes was strongly associated with elevated mortality (adjusted HR (aHR) 3.03 (1.28 to 7.18). The highest fasting glucose value (aHR 1.10 (1.01 to 1.20) per 1 mmol/L) and the highest postprandial glucose value ((aHR 1.07 (1.00 to 1.16)) were also associated with late mortality. However, the associations between highest glucose values and mortality vanished when the diagnosis of diabetes was included in the same model. Within the patients without diabetes, neither fasting (aHR 0.92 (0.42 to 2.02)) nor postprandial ((aHR 1.04 (0.50 to 2.12)) hyperglycaemia was associated with late mortality. There were no statistically significant differences in the underlying causes of death between the patients with and without diabetes., Conclusion: A history of diabetes but not hyperglycaemia during exacerbation of obstructive lung disease has impact on long-term mortality., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aim: To evaluate the association between hospitalisation for respiratory syncytial virus lower respiratory tract infection (RSV LRTI) in infancy and asthma, respiratory health-related quality of life and lung function at 28-31 years of age., Methods: In 2010, we carried out a 30-year follow-up on 43 adults admitted to Kuopio University Hospital, Finland, for RSV LRTI, 27 for bronchiolitis and 16 for pneumonia, between 1981 and 1982. Together with 86 population-based controls, they completed the Saint George's Respiratory Questionnaire and underwent prebronchodilator (pre-BD) and post-BD spirometry tests to measure percentage of predicted forced vital capacity (FVC%), percentage of predicted forced expiratory volume in 1 sec (FEV1%) and percentage of predicted FEV1/FVC (FEV1/FVC%)., Results: Both the pre-BD and post-BD FEV1% and FEV1/FVC% were significantly lower in former RSV LRTI patients than in the controls. The bronchiolitis patients had more asthma in adulthood than the controls and pneumonia in infancy was associated with lower St George's Respiratory Questionnaire (SGRQ) scores., Conclusion: Respiratory tract infection LRTI hospitalisation in infancy was associated with an increased risk of permanent obstructive lung function reduction in adulthood. The asthma risk was higher after hospitalisation for bronchiolitis, than in the controls, and respiratory health-related quality of life was lower after hospitalisation for pneumonia., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Recent studies have revealed that adulthood asthma has its origin in early childhood., Aim: The aim of the present study was to evaluate the prevalence of asthma and respiratory health-related quality of life in adults 30 years after hospitalization for bronchiolitis or pneumonia in infancy., Methods: Patients who were hospitalized for bronchiolitis or pneumonia at age under 24 months in 1981-1982 have been followed in repeated visits. In 2010, 48 of the 83 former patients with bronchiolitis (57.8%), 22 of the 44 former patients with pneumonia (50.0%), and 138 matched controls participated in the clinical study at the age of 28-31 years. The participants completed a structured questionnaire on respiratory symptoms, the Saint George's Respiratory Questionnaire (SGRQ), and underwent 2-week peak expiratory flow (PEF) monitoring. Asthma was defined as doctor-diagnosed and self-reported asthma based on doctor-prescribed medication for asthma, the presence of asthma-presumptive symptoms, and the results of home PEF monitoring., Results: Both doctor-diagnosed asthma (31.3% vs. 10.9% adjusted P = 0.002) and self-reported asthma (35.4% vs. 14.5% 0.003), as well as repeated on-demand use of bronchodilators (35.4% vs. 14.5% 0.002), and regular use of inhaled corticosteroids (20.8% vs. 8.7% 0.023) were more common in former bronchiolitis patients than in controls. Former bronchiolitis and pneumonia patients had higher total SGRQ scores than controls. The median scores were 5.4 (IQ(25-75) 0.0-14.7, P < 0.001) in bronchiolitis group, 4.9 (1.3-14.8, 0.012) in pneumonia group compared to controls 1.5 (0.0-6.0)., Conclusion: Hospitalization for bronchiolitis in infancy is associated with an increased risk of asthma, and an increased use of asthma medication in adulthood at the age of 28-31 years. Impaired respiratory health-related quality of life in adulthood as measured by the SGRQ is present after bronchiolitis and pneumonia in infancy., (© 2013 Wiley Periodicals, Inc.)

Introduction: Hyperglycaemia is a well-known phenomenon among patients with an exacerbation of asthma or chronic obstructive pulmonary disease (COPD). It may be associated with increased risks of death and complications., Objectives: To define the prevalence and determinants of hyperglycaemia in patients with an exacerbation of asthma or COPD., Methods: This was a prospective, cross-sectional study including 153 hospitalised patients with an exacerbation of asthma or COPD. All received inhaled beta-2-adrenergic bronchodilators and oral glucocorticoids in internationally recommend doses. Plasma glucose was measured seven times during the first day. Hyperglycaemia was defined as fasting glucose >6.9 mmol/L or postprandial glucose >11.1 mmol/L. In addition, the family history for diabetes and the Karnofsky performance score were assessed. Height, weight, waist circumference, oxygen saturation, blood pressure, temperature and heart rate were measured. Glycosylated haemoglobin A1c (gHbA1c), C-reactive protein, leucocytes, urea and arterial blood gas values were analysed., Results: Eighty-two per cent of the patients demonstrated hyperglycaemia, with similar prevalence between asthma and COPD. Of the 130 patients without a previous diagnosis of diabetes, 79% showed hyperglycaemia. In binary logistic regression analysis, high gHbA1c, high C-reactive protein and Karnofsky score less than 80% associated with the presence of fasting hyperglycaemia. High gHbA1c and current smoking associated with postprandial hyperglycaemia., Conclusions: Hyperglycaemia is very common among hospitalised patients with an exacerbation of asthma or COPD. It is probably triggered by the medication and the patient's metabolic predisposition mainly determines its presence. Current smoking is the main treatable contributor to hyperglycaemia., (© 2013 John Wiley & Sons Ltd.)

Introduction: Asthma control and quality of life are poorly associated with traditional asthma biomarkers., Objectives: In the present study, we evaluated two new cough provocation tests in this respect., Methods: Asthma Control Questionnaire and Leicester Cough Questionnaire were completed by 36 stable asthmatics. Cough provocation tests with hypertonic saline and isocapnic hyperpnoea of dry air were performed, as well as spirometry, ambulatory peak expiratory flow (PEF) monitoring and exhaled nitric oxide (eNO) measurement., Results: Leicester Cough Questionnaire score correlated closely with cough responsiveness to hypertonic saline and isocapnic hyperpnoea (R = -0.66, P < 0.001 and R = -0.49, P = 0.002, respectively). Asthma Control Questionnaire score also correlated with the cough responsiveness to these tests (R = 0.52, P = 0.001 and R = 0.43, P = 0.008, respectively). Forced expiratory volume in 1 s (%predicted), diurnal PEF variation and eNO did not correlate with cough-related quality of life but showed some association with asthma control. There was a significant correlation between Leicester Cough Questionnaire and Asthma Control Questionnaire (R = -0.54, P = 0.001)., Conclusions: Asthma control and cough-related quality of life are more closely associated with cough responsiveness to the investigated cough provocation tests than to eNO and traditional indices of bronchial obstruction. Cough is a major contributor to poor asthma control., (© 2012 John Wiley & Sons Ltd.)

The mechanisms of cough in asthma are unclear. Asthma is associated with an oxidative stress. Many reactive oxygen species sensitize or activate sensory C-fibers which are capable to induce cough. It was hypothesized that oxidative stress in the airways might contribute to the cough severity in asthma. Exhaled breath condensate samples were collected in ten healthy and 26 asthmatic subjects. The concentration of 8-isoprostane was measured. In addition, the subjects filled in Leicester Cough Questionnaire and underwent cough provocation tests with dry air hyperpnoea and hypertonic saline, among other measurements. Among the asthmatic subjects, high 8-isoprostane was associated with severe cough response to hyperpnoea (p=0.001), low Leicester Cough Questionnaire values (indicating severe subjective cough, p=0.02), and usage of combination asthma drugs (p=0.03-0.04). However, the 8-isoprostane concentrations did not differ significantly between the healthy and the asthmatic subjects. Airway oxidative stress may be associated with experienced cough severity and measured cough sensitivity in asthma., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Asthmatic patients are hypersensitive to the cough-provoking effect of hypertonic aerosols. 15- hydroxyeicosatetraenoic acid (15(S)-HETE) and leukotriene (LT) B4 are asthma-related mediators which can be released upon hypertonic stimuli, and both are potent agonists of the transient receptor potential vanilloid subfamily member 1 (TRPV1), a major cough receptor. Therefore, they are potential mediators for hypertonicity-provoked cough. Twenty-six asthmatic and ten healthy subjects underwent a hypertonic saline cough provocation test. Exhaled breath condensate was collected before and after the test, and the concentrations of 15(S)-HETE and LTB4 were analysed. Neither the baseline concentrations of these mediators nor the saline test-induced changes in them were associated with cough responsiveness to hypertonicity. High baseline 15(S)-HETE was associated with aspirin hypersensitivity and high LTB4 with male sex and large variability in ambulatory peak flow measurements. The TRPV1 agonists 15(S)-HETE and LTB4 seem not to be involved in the cough response to hypertonicity in asthmatic patients.

Background and Aims: Bronchial provocation tests may be utilised to monitor the efficacy of the corticosteroid treatment. Unfortunately, these measurements necessitate good patient cooperation during the spirometry. Coughing during such tests is related to the degree of the bronchoconstriction and occurs involuntarily, i.e. independent of patient cooperation. This study aimed to evaluate the utility of a hypertonic histamine challenge-induced cough in assessing the efficacy of inhaled corticosteroid treatment., Methods: A total of 16 steroid-naïve asthmatics and 10 non-asthmatic, symptomatic controls received 800-microg beclomethasone (Beclomet Easyhaler(R), Orion Ltd., Orion Pharma, Helsinki, Finland) via powder inhaler per day for 8 weeks. Videoed inhalation challenge with hypertonic histamine solution was performed before and after the treatment. Symptom questionnaire was completed before both challenges. The airway responsiveness to hypertonic histamine was expressed as the cumulative number of coughs divided by the final histamine concentration administered [coughs/concentration ratio (CCR)] and as the provocative concentration of histamine to induce a 20% fall in FEV(1)(PC(20))., Results: CCR [geometric mean; 95% confidence interval (CI)] of the asthmatic subjects decreased from 494 (209-1168) to 73.6 (29.8-182) coughs per mg/mL (P = 0.002). Their PC(20) levels were 1.31 (1.07-1.60) and 1.91 (1.33-2.74) mg/mL over the treatment period (P = 0.01). The symptom frequency also decreased significantly in the asthmatics (P = 0.039). There were no significant changes in PC(20) level, in CCR level or in symptom frequency in non-asthmatic subjects during the treatment., Conclusions: Hypertonic histamine challenge-induced cough and PC(20) are sensitive measures in assessing the treatment effect in asthma. The cough response may be especially useful in subjects who cannot perform spirometry reliably.

Background and Aims: Chronic cough is associated with an enhanced excitability of airway cough receptors, possibly due to action of neurotrophins. The present study aimed to compare the neurotrophin levels between healthy subjects and patients with chronic cough and to analyze the factors associated with these levels., Methods: Serum and sputum levels of nerve growth factor (NGF), serum levels of brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were analyzed by enzyme immunoassay in 19 healthy subjects and 47 patients with chronic cough. In addition, cough sensitivity to hypertonic saline was assessed, cough diary was kept, Leicester Cough Questionnaire was filled in, peak flow was monitored and spirometry, skin prick tests, exhaled nitric oxide measurement and histamine challenge were performed., Results: The NGF levels did not differ between the healthy subjects and the patients with chronic cough and were not associated with any index describing cough severity. However, these levels in both serum (P = 0.01) and sputum (P = 0.025) samples were associated with asthma. There was a statistically significant association between serum and sputum NGF levels (R = 0.45, P = 0.026). The serum BDNF levels did not differ between the groups and were not associated with any of the background characteristics. The serum NT-3 levels were below the detection limit in most subjects and therefore these data were not analyzed., Conclusions: Neither chronic cough nor its severity is associated with abnormal neurotrophin levels. High NGF levels among some patients with chronic cough may indicate a presence of asthma.

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.

Introduction: Although classical asthma is associated with airway hyperresponsiveness (AHR), this condition is also present in many cardiopulmonary disorders undermining the rational basis of its measurement in the differential diagnosis of asthma. We have recently introduced a new method to investigate AHR, the hypertonic histamine challenge (HHC)., Objective: The aim of this study was to evaluate the differential diagnostic power of HHC in a clinically representative sample of 138 patients., Methods: Fifty-seven patients from the outpatient clinic of the authors' hospital with symptoms indicative of asthma were consecutively recruited. Asthma was confirmed in 31 subjects. The remaining 26 subjects formed the control group, in conjunction with seven patients with COPD, 15 patients with interstitial lung disease, 21 patients with rhinitis, 13 patients with heart failure and 25 healthy controls. Hypertonic histamine solution was administered with an ultrasonic nebuliser., Results: Only the PC(20) values of asthmatic subjects differed statistically significantly from those of the healthy group (P < 0.0001). The receiver operator characteristic curve indicated that a PC(20) value of 0.83 mg/mL would be the optimal cut-off point of HHC to separate the asthmatics from the symptomatic controls with a sensitivity of 81% and specificity of 70%. With the PC(20) values of 0.1 and 4.0 mg/mL, the sensitivities were 42% and 100%, and the specificities were 96% and 40%, respectively. In these limits, HHC either confirmed or excluded asthma in 64 out of 138 patients (46%)., Conclusion: The authors' attempt to improve the accuracy of the airway challenge test by combining direct and indirect challenges did not overcome the diagnostic limitations of previously utilised airway challenges.

Objectives: Bronchial provocation tests that assess airway hyperresponsiveness (AHR) are known to be useful in assisting the diagnosis of asthma and in monitoring inhaled corticosteroid therapy. We reviewed the use of bronchial provocation tests that use stimuli that act indirectly for monitoring the benefits of inhaled corticosteroids., Data Source: Published clinical trials investigating the effect of inhaled corticosteroids on bronchial hyperresponsiveness in persons with asthma were used for this review., Study Selection: Studies using indirect stimuli to provoke airway narrowing such as exercise, eucapnic voluntary hyperventilation, cold air hyperventilation, hypertonic saline, mannitol, or adenosine monophosphate (AMP) to assess the effect of inhaled corticosteroids were selected., Results: Stimuli acting indirectly result in the release of a variety of bronchoconstricting mediators such as leukotrienes, prostaglandins, and histamine, from cells such as mast cells and eosinophils. A positive response to indirect stimuli is suggestive of active inflammation and AHR that is consistent with a diagnosis of asthma. Persons with a positive response to indirect stimuli benefit from daily treatment with inhaled corticosteroids. Symptoms and lung function are not useful to predict the long-term success of inhaled corticosteroid dose as they usually resolve rapidly, and well before inflammation and AHR has resolved. Following treatment, AHR to indirect stimuli is attenuated. Further, during long-term treatment, asthmatics can become as non-responsive as non-asthmatic healthy persons, suggesting that asthma is not active., Conclusions: Non-responsiveness to indirect bronchial provocation tests following inhaled corticosteroids occurs weeks to months following the resolution of symptoms and lung function. Non-responsiveness to indirect stimuli may provide a goal for adequate therapy with inhaled corticosteroids.

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.

Objective: Inhaled mannitol induces both bronchoconstriction and cough. Nedocromil sodium greatly attenuates mannitol-induced bronchoconstriction. Knowledge about the effect of nedocromil on mannitol-provoked cough might, therefore, clarify the mechanisms of this response., Methodology: Inhalation challenges with mannitol powder were performed after inhalation of 8 mg of nedocromil or its placebo in 24 subjects with asthma. The study was double-blind, randomised, and placebo-controlled. The mannitol-provoked coughs were manually recorded and the mannitol-induced bronchoconstriction was measured with a spirometer., Results: The cumulative dose of mannitol that provoked at least two coughs tended to be higher on the nedocromil day than on the placebo day (34 (22--53) mg vs 26 (18--37) mg, P=0.051). The cumulative number of coughs per dose of mannitol was slightly, but significantly, lower on the nedocromil than on the placebo day (4.2 (2.8--6.3) coughs/100 mg vs 6.1 (4.0--9.4) coughs/100 mg, P=0.037). However, when analysed on a constant-dose basis, nedocromil provided no protection for coughing (-1% protection), whereas the protection for bronchoconstriction was clear (55% protection)., Conclusions: Nedocromil strongly attenuates mannitol-induced bronchoconstriction but has a negligible effect on mannitol-provoked cough. Therefore, these responses seem to have different pathways in asthma. Recording of both provoked coughs and induced bronchoconstriction during mannitol challenge may provide supplementary information about a patient's disease.

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.

Objective: The aim of the study was to investigate whether treatment using inhaled corticosteroids decreases airway responsiveness to inhaled mannitol in asthmatic subjects., Methodology: Before treatment or a change in treatment with inhaled corticosteroids, 18 asthmatic subjects had measurements of lung function and airway sensitivity to mannitol taken and they completed a self-administered questionnaire on asthma symptoms. The procedure was repeated 6-9 weeks after taking 800-2400 microg/day of budesonide., Results: There were significant reductions in airway sensitivity (provoking dose to induce a 15% fall in FEV1 (PD15)) and airway reactivity measured by the response dose ratio (RDR; final percentage fall FEV1/total dose of mannitol administered). The PD15 (Gmean (95%CI)) increased from 78 mg (51, 117) before treatment to 289 mg (202, 414) following treatment (P < 0.001). All subjects had a significant increase beyond the repeatability of 0.9 doubling doses with seven subjects becoming unresponsive. There was a 4.2 (3.4, 4.9)-fold improvement in the RDR with the value before the treatment period 0.18 (0.12, 0.28) decreasing to 0.04 (0.03, 0.08) following treatment (P < 0.001). These improvements were associated with significant improvements in lung function and symptom severity., Conclusion: Treatment with the inhaled corticosteroid budesonide caused a decrease in airway sensitivity and reactivity to inhaled mannitol and this was associated with expected improvements in lung function and symptoms.

Purpose: To clarify the associations of climatic indices with chronic respiratory symptoms, with a final aim to approximate the effects of climate change on them. Methods: An e-mail survey was directed to the members of the Finnish Pensioners` Federation. The mean 20-years’ precipitation and temperature in each subjects’ home municipality were obtained from the Finnish Meteorological Institute, separately for summer and winter. Adjusted multivariate models were utilized to investigate the associations of the climatic indices with chronic rhinosinusitis, chronic cough, wheezing with dyspnea, and sleep apnea. Results: There were 6189 responders from 283 municipalities. Chronic rhinosinusitis and chronic cough were most prevalent in the southeastern regions of the country, where the precipitation counts were highest. In the multivariate models, winter precipitation in the home municipality increased the risks of chronic rhinosinusitis and chronic cough [adjusted OR 1.80 (1.30–2.51) per 100 mm, p < 0.001, and 1.57 (1.19–2.07) per 100 mm, p = 0.001, respectively]. Wheezing with dyspnea and sleep apnea were not associated with the climatic indices. Conclusion: Chronic rhinosinusitis and chronic cough were associated with long-term winter precipitation. Given the anticipated increase in winter precipitation in Northern America and Northern Europe, the prevalences of chronic rhinosinusitis and chronic cough may increase there. [ABSTRACT FROM AUTHOR]

Introduction: Although β 2-adrenoceptor (β 2AR) agonists have been associated with a lower risk of Parkinson's disease (PD), the findings are inconclusive and may reflect confounding by indication. We studied the association between inhaled β 2AR agonists and risk of PD in persons with asthma or chronic obstructive pulmonary disease (COPD). Methods: The nested case-control study was conducted within a register-based Finnish Parkinson's disease study (FINPARK) and included 1406 clinically verified PD cases diagnosed during 1999– 2015, who also had asthma/COPD > 3 years before PD. PD cases were matched with up to seven controls by age, sex, duration of asthma/COPD, pulmonary diagnosis, and region (N = 8630). Cumulative and average annual exposure to short- and long-acting β 2AR agonists before a 3-year lag period was assessed with quartiles of defined daily doses (DDDs). Adjusted odds ratios (aORs) were calculated with 95% confidence intervals (CIs) using conditional logistic regression. Results: Cumulative exposure to either short- or long-acting β 2AR agonists was not associated with a risk of PD. With average annual exposure, a decreased risk was observed only for the highest quartile of long-acting β 2AR agonists (aOR 0.75; 95% CI 0.58– 0.97). In the stratified analysis the lowest risk estimates were observed among those with both asthma and COPD diagnoses. The suggestion of an inverse association was seen for the highest quartile of long-acting β 2AR agonists in asthma. Discussion: Higher levels of exposure to β 2AR agonists were not consistently associated with a reduced risk of PD. The inverse association in the highest category of average annual exposure to long-acting β 2AR agonists may be explained by unmeasured confounding, such as disease severity or smoking. [ABSTRACT FROM AUTHOR]

Objectives. To describe the mechanisms and management of cold air-provoked respiratory symptoms. Study design. A literature review. Methods. The review includes human epidemiological studies, human and animal experimental studies, as well as human studies about management of the cold air-provoked respiratory symptoms. Results. Cold air is unlikely to be a causal factor initiating respiratory diseases but a symptom trigger. In the present review, the airway responses beyond these symptoms were divided into three types. The short-term responses are those that develop within minutes in response to sudden cooling of the airways. Subjects with asthma or rhinitis are especially prone to these responses. The long-term responses are those that develop in response to repeated and longstanding cooling and drying of the airways, usually in endurance athletes. Finally, there are the physiological, reflex-mediated lower-airway responses to cooling of the skin or upper airways. Conclusions. The mechanisms beyond cold air-provoked respiratory symptoms vary considerably and mainly depend on the individual's susceptibility and the ventilation level during the cold exposure. An understanding of these mechanisms is essential for successful management of the symptoms. [ABSTRACT FROM AUTHOR]

Background Bacterial colonization during wheezing in early childhood has been associated with short-term relapses of wheezing, but no study has addressed the effects of Streptococcus pneumoniae colonization on long-term outcome of wheezing. The aim of the present study was therefore to evaluate whether pneumococcal (PNC) colonization during the first wheezing episode in early childhood is a determinant of asthma, atopy or lung function in the long term. Methods In 1981-82 83 infants were hospitalized for first wheezing episode at <24 months of age. PNC colonization was defined as positive nasopharyngeal aspirate for S. pneumoniae either in culture or antigen detection on hospital admission. Atopy and repeated wheezing or asthma were diagnosed on all follow-up visits from infancy until the age of 28-31 years. Spirometry was conducted at the ages of 8-10, 18-20 and 28-31 years. Results PNC colonization was found in 25/83 infants (30%) during hospitalization for wheezing in infancy. PNC colonization was not associated with later atopy, repeated wheezing, asthma or lung function at any time during the 30 year follow up. Conclusion PNC colonization during the first wheezing episode in early childhood is not a determinant of subsequent wheezing or later asthma, atopy or lung function in childhood, adolescence or adulthood. [ABSTRACT FROM AUTHOR]