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Center for Environmental and Respiratory Health Research, University of Oulu, P.O. Box 5000, FI-90014 Oulu, FinlandMedical Research Center, University of Oulu and Oulu University Hospital, Finland
Center for Environmental and Respiratory Health Research, University of Oulu, P.O. Box 5000, FI-90014 Oulu, FinlandMedical Research Center, University of Oulu and Oulu University Hospital, Finland
Center for Environmental and Respiratory Health Research, University of Oulu, P.O. Box 5000, FI-90014 Oulu, FinlandMedical Research Center, University of Oulu and Oulu University Hospital, Finland
Center for Environmental and Respiratory Health Research, University of Oulu, P.O. Box 5000, FI-90014 Oulu, FinlandMedical Research Center, University of Oulu and Oulu University Hospital, Finland
Cold weather commonly aggravates respiratory symptoms among adults with asthma.
•
Poor asthma control increases cold-weather related respiratory symptoms.
•
Both low and high BMI strengthen the effect of poor asthma control.
•
The effect of poor asthma control is also stronger among current smokers.
Abstract
Background
In the northern hemisphere people are exposed recurrently to cold air and asthmatics experience more respiratory symptoms. We hypothesized that subjects with poor asthma control are more prone to experience cold weather-related respiratory symptoms than those with good asthma control.
Methods
A population-based cross-sectional study of 1995 adult asthmatics (response rate 40.4%) living in the Northern Finland was conducted using a questionnaire where cold weather-related respiratory symptoms as well as questions related to asthma control were inquired. The Asthma Control Test (ACT) was defined based on five questions (disadvantage and occurrence of asthma symptoms, waking up because of asthma symptoms, use of rescue medication and self-assessment of asthma control during the past 4 weeks), and was divided into quartiles.
Results
Cold weather-related respiratory symptoms were more frequent among asthmatics with poorly controlled asthma (ACT Q1 vs. ACT Q4); adjusted prevalence ratio (PR) for shortness of breath (men 1.47, 95% confidence interval 1.22–1.77; women 1.18, 1.07–1.30), cough (men 1.10, 0.91–1.34; women 1.18, 1.08–1.30), wheezing (men 1.91, 1.31–2.78; women 1.48, 1.17–1.87), phlegm production (men 1.51, 1.06–2.14; women 1.62, 1.27–2.08) and chest pain (men 4.47, 1.89–10.56; women 2.60, 1.64–4.12). The relations between asthma control and symptom occurrence seemed stronger among smokers than never smokers and subjects with body mass index (BMI) below and above 25–30.
Conclusions
Our study provides new evidence that subjects whose asthma is poorly controlled are more prone to experience cold weather-related respiratory symptoms and even a slight worsening of asthma control increases symptom prevalences.
Asthma is a common chronic disease and globally the prevalence of doctor diagnosed asthma is 4.3%. It has been reported to affect especially Western countries, with a higher prevalence in Europe (5.1%) and in Finland (9.4%) than globally [
]. It has been indicated that those who have well controlled asthma have higher physical and mental health-related quality of life than those with poorly controlled asthma [
Most populations living in the northern hemisphere are recurrently exposed to cold air during their occupational or leisure time activities or while commuting [
]. Population-based epidemiologic studies have shown that the prevalence of respiratory symptoms experienced in cold temperature is substantially higher among people with a respiratory disease compared to healthy subjects [
There are no previous population-based epidemiologic studies investigating the role of asthma control as a determinant of cold weather-related asthma symptoms. Experience of such symptoms could lead to avoidance of outdoor activities in cold weather, which could lower the quality of life among subjects with asthma, especially in cold climates. A better understanding of the role of asthma control in experiencing cold weather-related respiratory symptoms would be useful for clinicians and health care personnel working with asthma management and for patients in their self-management of asthma. An improved ability to function in cold weather could reduce wintertime morbidity and mortality.
The objective of this study was to assess the relations between asthma control and the occurrence of cold weather-related respiratory symptoms. We hypothesized that subjects with poor asthma control are more prone to experience cold weather-related symptoms than subjects with good asthma control.
2. Methods
2.1 Study design and study population
The Northern Finnish Asthma Study (NoFAS) was initiated in 2012 as a population-based cross-sectional study of 17–73 year old adults with asthma living in the Northern Finland. The study was approved by the ethics committee of the Oulu University Hospital.
The source population constituted of subjects who had received reimbursement for asthma medication according to The Social Insurance Institution of Finland and who lived in The Oulu University Hospital District (= The Northern Ostrobothnia Hospital District) in 2012. The Oulu University Hospital District is geographically the largest hospital district in Finland, covering 51.5% of the overall area. The adult population of this hospital district was in 2012 nearly 740,000. A random sample of 5000 subjects with the diagnosis of asthma received two self-administrated questionnaires, the basic NoFAS questionnaire and the St George's Respiratory Questionnaire. A total of 2033 subjects responded and returned the questionnaires. We excluded respondents whose age and sex were unknown in the study, so a total of 1995 subjects form the study population (40.0% response rate).
2.2 Determinant of interest
The main determinant of interest was the level of asthma control. Asthma control was evaluated by a self-administered questionnaire using The Asthma Control Test (ACT) [
]. ACT was based on 5 questions: 1. During the past 4 weeks, how much of the time did your asthma keep you from achieving much at work, school or at home? (All of the time, most of the time, some of the time, a little of the time, none of the time), 2. During the past 4 weeks, how often did you experience shortness of breath? (More than once a day, once a day, 3 to 6 times a week, once or twice a week, not at all), 3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning? (4 or more nights a week, 2 or 3 nights a week, once a week, once or twice, not at all), 4. During the past 4 weeks, how often have you needed your rescue inhaler or nebulizer asthma medication (such as albuterol)? (3 or more times per day, 1 or 2 times per day, 2 or 3 times per week, once a week or less frequently, not at all), 5. How would you rate your asthma control during the past 4 weeks? (Not at all controlled, poorly controlled, somewhat controlled, well controlled, completely controlled). For every question the first choice provides 1 point and the last choice 5 points, so the ACT can have scores from 5 to 25 where 5 indicates uncontrolled asthma and 25 totally controlled asthma. ACT score was then divided into quartiles, Q1 = 18 or lower, Q2 = 19–21, Q3 = 22–23 and Q4 = 24–25.
2.3 Outcomes
The main outcomes of interest were five cold weather-related respiratory symptoms. The following questions were used to define these outcomes: “Do you experience more asthma symptoms in cold weather than normally/usually: almost always, frequently, occasionally, rarely, or never?”. In the case the subject replied yes, we further asked: “Which asthma symptoms (you can mark more than one symptom): shortness of breath, prolonged cough, wheezing, phlegm production, chest pain?”
2.4 Covariates
Covariates were chosen to represent known or suspected determinants of cold weather-related respiratory symptoms. The following covariates were fitted in the multivariate models: sex, age, body mass index (BMI), smoking, cohabitation, education, exposure to second hand smoke (SHS), chronic obstructive pulmonary disease (COPD), allergic rhinitis, and cardiovascular diseases (hypertension, heart failure or coronary artery disease). Age was fitted into 5 categories (under 30, 30–39, 40–49, 50–59, and older than 59). In the multivariate analyses the category older than 59 was used as the reference category. BMI was also fitted as 5 categories (under 20, 20–25, 25–30, 30–35 and over 35), while normal weight (BMI = 20–25) formed the reference category. Smoking was categorized into 3 groups: never smokers (forming the reference category), ex-smokers and current smokers. Marital status was also divided into 3 categories: cohabitation (forming the reference category), single or separated, and divorced or a widow. For education, higher vocational or academic degree formed the reference category, while other two categories were comprehensive or upper secondary school degree, and vocational or upper secondary and vocational school degrees.
2.5 Statistical methods
We estimated the relations between the level of asthma control and the occurrence of cold weather -related symptoms applying prevalence ratios (PR) and their 95% confidence intervals (95% CI). In the crude analysis we compared the prevalences of the outcomes in four categories, Q1, Q2, Q3 and Q4. These were formed based on the quartiles of the ACT distribution, using the fourth category representing the best asthma control as the reference category. We estimated the prevalence ratio of each cold weather-related symptom contrasting the categories Q1-Q3 of the ACT (which represented compromised asthma control) against the reference category (= Q4). The multivariate analyses applied Poisson regression using logarithmic link function. The PRs were adjusted for the covariates described above. We also explored whether BMI and smoking influence the relations between asthma control and occurrence of cold-weather related respiratory symptoms by stratified analyses. Analyses were carried out using the GENMOD-procedure in the SAS software (SAS 9.3, SAS Institute, Inc., Cary, North Carolina).
3. Results
3.1 Characteristics of the study population
Table 1 presents the characteristics of the study population according to sex. One third (34.7%) of the study subjects were men. More than half of the subjects (58.2%) were 50 years or older. One third (32.5%) of the study subjects were normal weight according to their body mass index, whereas two thirds were overweight or obese (63.2%). More than half of the subjects (51.5%) had never smoked, while less than one fifth were current smokers (18.5%).
Table 1Characteristics of the study population, The Northern Finnish Asthma Study 2012.
Characteristic
Men n (%)
Women n (%)
Total n (%)
692 (34.69)
1303 (65.31)
1995 (100.0)
Age
<30
71 (10.26)
141 (10.82)
212 (10.63)
30–39
91 (13.15)
177 (13.58)
268 (13.43)
40–49
111 (16.04)
243 (18.65)
354 (17.74)
50–59
218 (31.50)
428 (32.85)
646 (32.38)
>60
201 (29.05)
314 (24.10)
515 (25.81)
Body mass index
<20
9 (1.32)
74 (5.81)
83 (4.24)
20–25
207 (30.26)
430 (33.75)
637 (32.53)
25–30
286 (41.81)
420 (32.97)
706 (36.06)
30–35
137 (20.03)
230 (18.05)
367 (18.74)
>35
45 (6.58)
120 (9.42)
165 (8.43)
Missing
8
29
37
Marital status
Single
121 (17.51)
155 (11.91)
276 (13.86)
Marriage/Cohabitation
498 (72.07)
963 (74.02)
1461 (73.34)
Divorced, separated or widow
72 (10.42)
183 (14.07)
255 (12.80)
Missing
1
2
3
Education
Low
205 (29.71)
298 (22.99)
503 (25.33)
Medium
348 (50.43)
673 (51.93)
1021 (51.41)
High
137 (19.86)
325 (25.08)
462 (23.26)
Missing
2
7
9
Smoking
Current smoker
134 (19.59)
231 (17.96)
365 (18.53)
Ex-smoker
268 (39.18)
323 (25.12)
591 (30.00)
Never smoked
282 (41.23)
732 (56.92)
1014 (51.47)
Missing
8
17
25
Second hand smoke
Yes
447 (65.54)
828 (64.44)
1275 (64.82)
No
235 (34.46)
457 (35.56)
692 (35.18)
Missing
10
18
28
Note: Education: Low = comprehensive or upper secondary school degree, Medium = vocational or upper secondary and vocational school, High = higher vocational or academic.
3.2 Cold weather-related symptoms in relation to asthma control
The frequency of experiencing cold-weather related symptoms, applying the time scale from never to almost always, was the higher the lower the asthma control was, when expressed as the quartile of ACT (Fig. 1). Table 2 presents the prevalences of the studied symptoms according to the quartiles of the ACT score, separately among men and women. In general, the symptom prevalences were the lowest in the highest ACT quartiles representing the best asthma control.
Fig. 1Cold weather-related symptoms according to the ACT quartile.
Table 2The prevalences and prevalence ratios of cold weather-related respiratory symptoms according to the level of asthma control, The Northern Finnish Asthma Study 2012.
There was an increasing trend of the prevalences and prevalence ratios according to the decreasing asthma control for all the symptoms both among men and women, although there were some differences in the magnitude. When comparing the adjusted PRs (aPRs), poor asthma control was the strongest determinant of chest pain, both in men (4.47) and women (2.60) and the weakest for cough, in men (1.10) and women (1.18), and shortness of breath in women (1.18). The effect estimates were of the same magnitude for wheezing (1.91), phlegm production (1.51) and shortness of breath (1.47) in men and for phlegm production (1.62) and wheezing (1.48) in women.
Table 3 shows the relations between asthma control and the respiratory symptom occurrences according to body mass index. There was a pattern of effect estimates indicating that the studied relations were weakest with a BMI range 25–30 and stronger both in the lower and higher BMI categories.
Table 3The prevalence ratios (PR) of cold weather-related respiratory symptoms and the level of asthma control according to body mass index, The Northern Finnish Asthma Study 2012.
<20
20–25
25–30
30–35
35≥
Adjusted PR
Adjusted PR
Adjusted PR
Adjusted PR
Adjusted PR
Shortness of breath
Q4 (best control)
1.00
1.00
1.00
1.00
1.00
Q3
1.69 (1.05–2.72)
1.07 (0.90–1.29)
1.04 (0.90–1.20)
1.09 (0.85–1.39)
1.28 (0.86–1.89)
Q2
1.66 (1.00–2.78)
1.25 (1.06–1.46)
1.19 (1.05–1.34)
1.32 (1.05–1.65)
1.04 (0.67–1.61)
Q1 (worst control)
1.74 (1.06–2.85)
1.38 (1.19–1.60)
1.18 (1.04–1.34)
1.42 (1.15–1.75)
1.25 (0.86–1.82)
Cough
Q4 (best control)
1.00
1.00
1.00
1.00
1.00
Q3
1.02 (0.56–1.84)
0.91 (0.76–1.09)
0.94 (0.80–1.11)
1.14 (0.89–1.46)
0.98 (0.66–1.46)
Q2
1.26 (0.71–2.22)
1.03 (0.88–1.20)
1.00 (0.86–1.15)
1.33 (1.05–1.67)
0.99 (0.71–1.40)
Q1 (worst control)
1.52 (0.92–2.51)
1.25 (1.10–1.43)
1.02 (0.89–1.18)
1.30 (1.03–1.63)
1.29 (0.97–1.72)
Wheezing
Q4 (best control)
1.00
1.00
1.00
1.00
1.00
Q3
0.85 (0.39–1.86)
1.05 (0.70–1.58)
1.35 (0.95–1.91)
1.28 (0.71–2.31)
0.55 (0.24–1.28)
Q2
0.93 (0.45–1.94)
1.20 (0.82–1.76)
1.38 (0.98–1.94)
1.86 (1.08–3.20)
0.81 (0.43–1.54)
Q1 (worst control)
0.72 (0.31–1.65)
1.75 (1.24–2.47)
1.69 (1.23–2.33)
2.44 (1.47–4.07)
1.29 (0.77–2.17)
Phlegm production
Q4 (best control)
1.00
1.00
1.00
1.00
1.00
Q3
1.26 (0.53–2.95)
1.28 (0.90–1.83)
1.45 (1.03–2.05)
1.19 (0.68–2.09)
1.45 (0.42–5.05)
Q2
1.60 (0.70–3.63)
1.41 (1.00–1.97)
1.28 (0.91–1.80)
1.51 (0.88–2.59)
1.94 (0.63–5.98)
Q1 (worst control)
1.19 (0.51–2.78)
1.50 (1.07–2.08)
1.60 (1.16–2.21)
1.77 (1.07–2.91)
2.54 (0.85–7.54)
Chest pain
Q4 (best control)
1.00
1.00
1.00
1.00
1.00
Q3
1.18 (0.33–4.22)
1.11 (0.45–2.75)
1.37 (0.70–2.68)
3.33 (0.75–14.86)
*2.38 (0.27–21.05)
Q2
1.67 (0.45–6.25)
1.87 (0.86–4.10)
1.26 (0.66–2.38)
2.62 (0.57–12.04)
*2.38 (0.29–19.72)
Q1 (worst control)
0.96 (0.21–4.34)
3.98 (1.98–7.99)
2.35 (1.33–4.16)
5.69 (1.39–23.34)
*4.84 (0.68–34.54)
Note: Prevalence rates are adjusted for sex and age; * = Prevalence rates are crude because of too small group sizes.
Bold values indicate statistical significance of the effect estimates at p < 0.05.
Table 4 presents the adjusted PR's separately for never smokers, ex-smokers and current smokers. For all the symptoms except shortness of breath the effect estimate was stronger among current smokers compared with never smokers.
Table 4The prevalence ratios of cold weather-related respiratory symptoms and the level of asthma control according to smoking, The Northern Finnish Asthma Study 2012.
Never smoker
Ex smoker
Current smoker
Adjusted
Adjusted
Adjusted
Shortness of breath
Q4 (best control)
1.00
1.00
1.00
Q3
1.09 (0.95–1.25)
1.04 (0.87–1.24)
1.21 (0.96–1.53)
Q2
1.25 (1.11–1.40)
1.23 (1.05–1.44)
1.16 (0.92–1.48)
Q1 (worst control)
1.32 (1.18–1.48)
1.27 (1.09–1.48)
1.26 (1.02–1.57)
Cough
Q4 (best control)
1.00
1.00
1.00
Q3
0.93 (0.81–1.06)
0.91 (0.76–1.10)
1.14 (0.85–1.54)
Q2
1.02 (0.90–1.15)
1.06 (0.90–1.24)
1.25 (0.95–1.63)
Q1 (worst control)
1.17 (1.05–1.30)
1.05 (0.89–1.24)
1.42 (1.11–1.82)
Wheezing
Q4 (best control)
1.00
1.00
1.00
Q3
0.98 (0.72–1.33)
1.19 (0.80–1.76)
1.84 (1.00–3.37)
Q2
1.18 (0.89–1.55)
1.54 (1.06–2.22)
1.51 (0.82–2.77)
Q1 (worst control)
1.55 (1.20–2.00)
1.68 (1.18–2.40)
2.64 (1.54–4.53)
Phlegm production
Q4 (best control)
1.00
1.00
1.00
Q3
1.22 (0.92–1.61)
1.47 (1.01–2.14)
1.58 (0.68–3.68)
Q2
1.29 (0.99–1.68)
1.47 (1.01–2.13)
2.07 (0.96–4.43)
Q1 (worst control)
1.58 (1.24–2.03)
1.71 (1.19–2.44)
2.36 (1.14–4.87)
Chest pain
Q4 (best control)
1.00
1.00
1.00
Q3
1.16 (0.62–2.19)
1.78 (0.84–3.78)
2.75 (0.56–13.49)
Q2
1.59 (0.92–2.76)
1.51 (0.69–3.29)
2.88 (0.63–13.15)
Q1 (worst control)
2.94 (1.80–4.79)
3.47 (1.76–6.82)
5.03 (1.17–21.69)
Note: Prevalence rates are adjusted for sex and age.
Bold values indicate statistical significance of the effect estimates at p < 0.05.
The results of our population-based study indicate that cold weather commonly aggravates respiratory symptoms among adults with asthma. In addition, there is a trend between worsening of the asthma control and increasing prevalence of cold weather-related respiratory symptoms.
Our results provide for the first time evidence that poor asthma control increases the risk of cold weather-related respiratory symptoms both in men and women. The observation was strengthened by a dose-response pattern showing an increasing risk related to the worsening of asthma control. The relative effect of poor asthma control was the strongest on cold weather induced chest pain (aPR 4.47 in men and 2.60 in women) and the weakest on cough in both men (aPR 1.10) and women (aPR 1.18) and shortness of breath (aPR 1.18) in women. The adjusted prevalence ratios for wheezing and phlegm production in men and women and shortness of breath in men varied from 1.48 to 1.91. The relations between asthma control and cold weather-related symptom occurrence seemed stronger among current smokers than never smokers and weaker among subjects with a BMI between 25 and 30 compared to subjects with a lower or higher BMI.
The effects of cold exposure on the respiratory tract can be mediated indirectly either through skin cooling [
]. These changes may be caused by cooling of the skin causing unfavorable reflexive changes in the airways, or by cooling and drying of the nasal and airway mucosa which could lead to hyperosmolality, which could cause neural activation and bronchoconstriction [
]. The higher prevalence of cold weather-related respiratory symptoms among subjects with asthma could be a consequence of their reduced capacity to warm and humidify the inhaled air [
]. These could explain the observed increase in the occurrence of cold weather-related symptoms among asthmatics of this study, as well as in some previous Finnish population-based studies [
]. They are thought to indicate airways obstruction and inflammatory process that may take place during worsening of asthma due to environmental exposures, physical exercise or insufficient medication. Thus, the presence of these symptoms is likely to relate to asthma control per se. On the other hand during poor asthma control subjects with asthma may become more sensitive to the adverse effects of airways stimuli, such as exposure to cold weather or tobacco smoke. Thus, a combination of poor asthma control and unusually strong adverse environmental exposure may lead to a vicious cycle with intensive symptoms experienced in cold weather. Weak asthma control and its association with cold weather-related respiratory symptoms could partially be explained by the effects of body composition on thermal responses. The lesser amount of symptoms among overweight (BMI 25–30) persons could be related to the insulative properties of subcutaneous adipose tissue and reduced heat loss from the skin to the cold environment [
]. Increased symptom-reporting among obese individuals, on the other hand, is probably mediated through other factors than thermoregulatory responses.
Based on the results of this study we propose that improvement of asthma control with the help of appropriate asthma medication and application of self-management methods will eventually reduce cold weather-related respiratory symptoms among subjects with asthma. Further, we suggest quitting of smoking as a way to reduce airways reactivity to cold weather.
4.1 Validity of results
Our study population represents adults with doctor-diagnosed asthma living in a geographically defined area, which is served by The Oulu University Hospital. The main determinant of interest was asthma control, which was assessed by applying the Asthma Control Test (ACT). ACT was based on information collected by a standardized self-administrated questionnaire and it has been shown to indicate asthma control reliably by applying validated questions [
]. Asthmatics were randomly selected from the records of The Social Insurance Institution of Finland. This guarantees a valid diagnosis of asthma that follows the strict criteria that are requested before the person is eligible to receive the reimbursement for asthma medication in Finland [
]. The questionnaires were distributed by The Social Insurance Institution of Finland, as under the law the investigators were not allowed to approach the participants directly. This may explain why the response rate (40%) was satisfactory, but lower than the response rates in our other recent epidemiologic studies [
]. We cannot exclude the possibility that participation activity could have been associated to some extent with asthma control, but it is not plausible that any major systematic selection process would have been related to the main outcomes of interest in a way that could introduce a selection bias.
Some bias may have been introduced in the assessment of the outcome, which was based on self-reported, retrospective information on cold weather-related symptoms. The season when the questionnaire was answered by each study subject was unknown for a large group of subjects, so that parameter could not be included in the analyses. The season can influence on how well subjects remember having had their symptoms and that might cause some non-differential misclassification.
Potential determinants of asthma control other than cold temperature could serve as potential confounders. We were able to adjust for them in the Poisson regression analysis, which excludes them as potential explanations for our findings.
4.2 Synthesis with previous knowledge
Based on our systematic literature search there are no previous studies on the relations between asthma control and cold weather-related respiratory symptoms. Three previous studies have reported prevalences of cold weather-related respiratory and cardiovascular symptoms in adult populations [
In the present study, the estimated prevalences of cold weather-related respiratory symptoms among those with good asthma control were similar compared with the estimates from the few previous population-based studies. However the estimates among those with poor asthma control were substantially higher than the prevalences reported in earlier studies, which showed that for example cold weather-related shortness of breath ranged between 56% and 71% among 25–74 year old asthmatics of the general population [
]. On the other hand, in The Espoo Cohort Study the prevalences of cold weather-related symptoms were lower (6–51%) among young adults (20–27 years) with asthma [
] than in our study. This could reflect better control of the disease in younger population. This is supported by the fact that only 16–20% of persons below 30 years of age in our study had poor asthma control.
There was some indication that BMI modifies the relation between poor asthma control and cold weather-related symptom occurrence so that among slightly overweight subject this relation is weakest. There is substantial evidence that high BMI increases the occurrence of respiratory symptoms [
]. Our observation could be explained by these competing protective and adverse effects. Further our results indicate that the relations between poor asthma control and symptom occurrence is stronger among current smokers. Smoking is a well-establish cause of airways irritation [
]. Our findings suggest both smoking and cold weather contribute to airways reactivity and increased occurrence of respiratory symptoms.
5. Conclusions
Our study indicates that those asthmatics whose asthma is poorly controlled are more prone to experience cold weather-related respiratory symptoms. Even a slight worsening of the asthma control seems to increase experiencing respiratory cold weather-related symptoms. This finding is important for asthmatic patients, who should be advised about proper protection against cold weather and who should receive adequate medication to reduce cold weather-related symptoms and to prevent potential more severe adverse health effects. On the other hand, increasing experience of symptoms by asthmatics during the cold season may indicate worsening of asthma control and indicate that the person has an immediate need for more extensive medical care. The results of this study are applicable especially for populations residing in the northern hemisphere, who are exposed to cold weather during their daily activities sometimes during rather long time periods.
Conflicts of interest
None.
Acknowledgements
This study was supported by The Research Foundation of the Pulmonary Diseases, The Jalmari and Rauha Ahokas Foundation, The Väinö and Laina Kivi Foundation, The Finnish Anti-Tuberculosis Association Foundation, and the University of Oulu strategic funds.
The authors would like to thank The Social Insurance Institution of Finland for recruiting the study population.
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