https://orcid.org/0000-0003-4512-8000
Figures
Abstract
This study determined the association between respiratory symptoms and death from respiratory causes over a period of 45 years. In four cohorts of random samples of Norwegian populations with 103,881 participants, 43,731 persons had died per 31 December 2016. In total, 5,949 (14%) had died from respiratory diseases; 2,442 (41%) from lung cancer, 1,717 (29%) chronic obstructive pulmonary disease (COPD), 1,348 (23%) pneumonia, 119 (2%) asthma, 147 (2%) interstitial lung disease and 176 (3%) other pulmonary diseases. Compared with persons without respiratory symptoms the multivariable adjusted hazard ratio (HR) for lung cancer deaths increased with score of breathlessness on effort and cough and phlegm, being 2.6 (95% CI 2.1–3.2) for breathlessness score 3 and 2.1 (95% CI 1.7–2.5) for cough and phlegm score 5. The HR of COPD death was 6.4 (95% CI 5.4–7.7) for breathlessness score 3 and 3.0 (2.4–3.6) for cough and phlegm score 5. Attacks of breathlessness and wheeze score 2 had a HR of 1.6 (1.4–1.9) for COPD death. The risk of pneumonia deaths increased also with higher breathlessness on effort score, but not with higher cough and phlegm score, except for score 2 with HR 1.5 (1.2–1.8). In this study with >2.4 million person-years at risk, a positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer. Respiratory symptoms are thus important risk factors, which should be followed thoroughly by health care practitioners for the benefit of public health.
Citation: Stavem K, Johannessen A, Nielsen R, Gulsvik A (2021) Respiratory symptoms and respiratory deaths: A multi-cohort study with 45 years observation time. PLoS ONE 16(11): e0260416. https://doi.org/10.1371/journal.pone.0260416
Editor: Koustubh Panda, University of Calcutta, INDIA
Received: March 11, 2021; Accepted: November 9, 2021; Published: November 22, 2021
Copyright: © 2021 Stavem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Our ethical approval granted by the Regional Committees for Medical and Health Research Ethics in Norway does not allow public sharing of the data. A data set can be made available for scientific analysis on request, provided that the respective research institution proofs handling of the data strictly in accordance with ethical regulations (written ethics protocol, full compliance with the Declaration of Helsinki). To ensure full anonymity only the main variables of the final analyses are provided. We confirm that the data file provided constitutes the minimal data set necessary to replicate the findings of your study in their entirety. Data requests can be made to corresponding author Knut Stavem (knut.stavem@medisin.uio.no<mailto:knut.stavem@medisin.uio.no>) Contact information to the Regional Ethics Committee: REC West - Secretariat University of Bergen, Faculty of Medicine, P.O. Box 7804, 5020 Bergen email: post@helseforskning.etikkom.no.
Funding: The authors received no specific funding for this work.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RN reports grants and personal fees from AstraZeneca, grants from GlaxoSmithKline, grants from Boehringer Ingelheim, outside the submitted work. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Introduction
Respiratory diseases, such as pneumonia, lung cancer and chronic obstructive pulmonary disease (COPD), remain a leading cause of disability and death worldwide [1–3]. Respiratory symptoms are important indicators of these diseases, and recording of respiratory symptoms is a cheap and easy screening method.
In the 1970s, at least one respiratory symptom was reported by 40% of the adult inhabitants of the Oslo city: cough in the morning, attacks of breathlessness, breathless when climbing stairs or wheezing [4]. The symptom burden remains high also in recent times, with approximately 20% reporting wheeze and >25% cough [5].
Respiratory symptoms are associated with all-cause and cardiovascular mortality [6–9]. Less is known about the association between respiratory symptoms and respiratory causes of death. The limited number of respiratory deaths in previous studies [10–12], and the non-random nature of some of the cohorts [10], limit generalisability of findings. In a recent general population study with <15 years of follow-up time, individuals with chronic respiratory symptoms and normal spirometry had increased mortality due to respiratory diseases [8, 13].
Large cohorts are needed to observe a sufficient number of deaths due to asthma and interstitial pneumonia, which are rare causes of death in the general population. We therefore extended a previous analysis [12] to investigate the long-term relationship between respiratory symptoms and mortality for several respiratory diseases by combining four general population cohorts [6].
This study reports on the association of self-reported subsets of respiratory symptoms such as breathlessness on effort, cough and phlegm, and attacks of breathlessness/wheeze with the mortality from lung cancer, pneumonia/influenza, COPD, asthma and interstitial pneumonias over 45 years.
Materials and methods
Study population
This multicohort study used harmonized individual-level data from four cross-sectional surveys in the City of Oslo 1972 and 1998–1999, Hordaland County in 1985, 1988–1989 (including Sauda municipality in Rogaland county) and 1998–1999 [14]. Oslo, the capital of Norway, had 477,476 inhabitants in 1972 and 499,693 persons in 1998. Hordaland county is a combined rural and urban (Bergen) population with 399,702 persons in 1985, 405,063 in 1988 and 428,823 in 1998. Sauda is a rural municipality with 5,416 inhabitants in 1988.
The target populations were born 1902–1973. The sample frames were updated lists from the Norwegian National Population Registry. Invitees were drawn at random for the 1972 (Oslo 72), 1985 (Hordaland 85) and 1998–1999 (Oslo/Hordaland 98–99) surveys. The 1988–1990 survey (Støvlunge 88–90) invited all men born 1914–1958, plus a 10% sample of the general population of City of Bergen examined in a previous cohort in 1965–1970 [14, 15], leading to about 6% women in this cohort. We excluded those included in one cohort from later cohorts. The eligible population sample comprised 158,702 unique persons. We have previously presented the recruitment and pooling of these cohorts [6].
The analyses included respondents who provided information on smoking, education, occupational exposure to dust/gas and respiratory symptoms, in total 103,881 persons; 65% of the sample of unique persons (Table 1).
The study was approved by the Committee on Medical Research Ethics (reference 2017/1679), The Norwegian Data Inspectorate (07/00414) and The Norwegian Directorate of Health (07/948).
Questionnaire
We used a questionnaire, which was a modification of one approved by the British Medical Research Council`s (MRC) Committee on Research into Chronic Bronchitis in 1966. The validity of the Norwegian respiratory questionnaire has been evaluated [16], and compared with the original MRC questionnaire [17].
The questionnaire included 11 questions about respiratory symptoms (S1 Table), covering current cough, phlegm, wheezing, periods of cough and/or phlegm and breathlessness, which were aggregated into three symptom groups: breathlessness scored 0 to 4; cough and/or phlegm symptoms scored 0 to 5, and attacks of breathlessness and wheezing scored 0 to 2 [6]. A higher score represents more severe symptoms.
The questionnaire also included questions on smoking history [18] and occupational exposure to air pollution. Smoking was categorized as current smokers (daily at the time of the study), ex-smokers, or never-smokers. Tobacco consumption was estimated from number of cigarettes per day (1 cigarette = 1 g), and grouped as <10 g, 10–19 g and ≥20 g. Occupational exposure to air pollution was defined by responding “yes” to “Have you been exposed to particles, gases or damp at your working place?”
No self-reported cardiopulmonary disease was defined as negative replies to 10 questions on treatments by physician or hospitals of asthma, bronchitis, emphysema, pleuritis, lung tuberculosis, other pulmonary disease, myocardial infarction, angina pectoris, hearth failure or other hearth diseases.
Follow-up and census data
Date of death, emigration and cause of death until 31 December 2016 were obtained from the National Cause of Death Registry. All inhabitants of Norway have a unique personal identification number that allows complete follow-up until death or emigration. In total, 156,896 persons were initially observed. A total of 103,881 respondents with known smoking status and complete responses were followed; median follow-up was 27.4 years, maximum 45.2 years. They represented 2,449,538 person-years at risk.
Highest attained education was extracted from the national census for each decade and grouped according to the maximum length of education using three levels: compulsory education (7–10 years), medium level (11–13 years) and university level (≥14 years).
The overall inclusion rate in the analyses was 65% of the target population and varied for the baseline examination from 81% of the target population of the cohort of 1972 to 62% in the cohort of 1998–1999. The distribution of participants of the various groups was almost identical in the target population and the population of respondents with regard to age, sex and education (S2 Table).
Classification of causes of death
Classification of respiratory causes as underlying causes of death was done using the European Shortlist for Causes of Death, 2012 [19, 20], with two modifications: 1) Because there were few cases with influenza, this was combined with pneumonia; 2) Interstitial pneumonias were extracted from “Other diseases of the respiratory system” and analyzed as a separate entity (Table 2).
Statistical analysis
Descriptive statistics are presented in frequency tables as number (%). For start dates for observations in the cohorts, we used 5 October 1972 in the Oslo county 1972 cohort, the 15th of the actual starting month in the Hordaland county and Sauda municipality cohort 1988–1990, and the actual start date in the other two cohorts. Other missing start dates for participants were imputed using the median start date in the same cohort: 31 December 1989 in the Hordaland county and Sauda municipality cohort 1988–1990 (n = 100) and 5 October 1998 in the Oslo and Hordaland counties cohort 1998–1999 (n = 4).
The cohort members were followed until death or censored at the date of emigration or end of follow-up on 31 December 2016, whichever came first. For some people that emigrated (n = 231), we did not have a date of emigration, but only an interval. These cases were censored at the mid-point of the interval [6]. We did not impute missing values for other variables.
We pooled the four cohorts and analyzed the association of symptom scores of breathlessness on effort, cough or/and phlegm and attacks of breathlessness or/and wheeze with cause-specific mortality. We used Cox proportional hazards analysis, with age as the dependent variable [21]. We also repeated the analysis replacing the respiratory symptom scores with a variable with no respiratory symptom = 0, any respiratory symptom = 1. These analyses were prepared using shared frailty for study cohort, i.e. incorporating cluster-specific random effects to account for within-cluster homogeneity in outcomes [22].
All analyses were multivariable, adjusting for sex, education (<10, 11–13, ≥14 years), smoking habits (never, ex-, current-smoker) and occupational exposure (dust/fume vs. none). The results are presented as hazard ratios (HR) of death with 95% confidence intervals (CI).
Finally, we conducted analyses in strata of the pooled sample (men, women, never smokers, those without a history of cardiopulmonary disease) according to death from lung cancer, COPD and pneumonia using the same approach and the same covariates. For other causes of death, we did not conduct stratified analyses because of few events.
The proportional hazards assumption was checked graphically using log-log plots and was considered acceptable. We chose a significance level of 0.05 using two-sided tests. Stata version 16.1 (StataCorp, College Station, TX, USA) was used for all statistical analyses.
Results
Among the 103,881 individuals (response rate 64%), 78% were men, and mean baseline age was 46.8 years (range 15–92 years). Altogether 43,731 (42%) had died as of 31 December 2016 and had a specified cause of death. In total 5,949 persons (14% of all deaths) had a pulmonary death; lung cancer 2,442 (41%), COPD 1,717 (28%), and pneumonia 1348 (23%) including 40 cases of influenza deaths (Table 2). In addition, 147 (2.5%) died from interstitial pneumonia, 119 from asthma (2.0%) and 176 due to other pulmonary causes (3.0%).
The prevalence of baseline symptom scores and the distribution of symptoms according to the principal causes of death is shown in S3 Table.
Respiratory mortality
The overall crude mortality rate (MR) of respiratory diseases was 243 per 100,000 person-years. In total, 6.1% of men (4971/81510) and 4.4% of women (978/22371) died from respiratory causes. Among individuals with pulmonary deaths, 87% were ever smokers (Table 3).
The hazard of death due to pulmonary disease was higher in men compared with women, in those with only compulsory education compared with university education and in smokers versus never smokers (Table 4). Scores on breathlessness, cough and phlegm and attacks of breathlessness and ever wheezing were strongly associated with increased hazard of respiratory mortality. However, breathlessness showed a stronger association with pulmonary mortality than cough and phlegm did.
The pattern of associations was similar in subgroups, except that associations for phlegm and cough were weaker and non-significant in women and never-smokers, as well as for attacks of breathlessness/wheeze in men and never-smokers (Table 5).
Multivariable proportional hazards regression analysis.
Lung cancer
The crude MR of lung cancer was 100 per 100,000 person-years. Ex-smokers had fourfold and current smokers tenfold increased hazard of lung cancer death relative to never smokers. Breathlessness, cough and phlegm were also associated with an increased risk of lung cancer death, with an increased risk occurring from a score of 1 to 2 on both symptom scales (Table 4). Attacks of breathlessness and ever wheeze did not increase the risk for lung cancer deaths. Identical trends for risks of respiratory symptoms for lung cancer deaths were observed in stratified analyses of men, women, never smokers and in those without self-reported cardiopulmonary diseases (S4 Table).
Chronic obstructive pulmonary disease
The MR was 70 for COPD per 100,000 person-years. The pattern of adjusted HR for COPD with regard to sex and attained education was almost identical to the HR for lung cancer, but with lower HRs with regard to smoking habits (Table 4). The HR with increasing breathlessness on effort was higher for COPD than for other pulmonary causes of death.
The risk trends of respiratory symptoms for COPD deaths were similar for men, women, never smokers and for those without cardiopulmonary diagnosis (S5 Table).
Pneumonia
The MR of pneumonia was 55 per 100,000 person-years. The MR of pneumonia increased markedly for those aged ≥60 years at baseline compared with younger individuals (Table 3). There was no clear association between smoking habits and death due to pneumonia. There was a dose-response relationship between breathlessness score and pneumonia deaths, while this was not so obvious for cough and phlegm score (Table 4).
Associations between symptom burden and pneumonia deaths were not prominent in women. Attacks of breathlessness and wheeze score was negatively associated with deaths due to pneumonia in men (S6 Table).
Rare causes
Asthma was a rare cause of death with MR of 5 per 100,000 person-years, which was only 7% that of COPD deaths. The risk of asthma deaths showed the same pattern as COPD with regard to respiratory symptoms. However, higher attacks of breathless and wheeze score increased the risk of asthma mortality more than any other pulmonary causes of death (Table 4).
Interstitial pneumonia had a MR of 6 per 100,000 person-years. The risk pattern was similar for sex and education as for other pulmonary causes of deaths. The risk was lower in ex-smokers than in never smokers. An increased hazard of death from interstitial pneumonia was observed in those with breathlessness on effort (Table 4).
Occupational exposure to air pollution
There was a slightly increased crude rate of pulmonary death in those with occupational exposure to gas or dust. However, no increased risk was evident in multivariable models. It was rather the opposite trend with a higher risk of deaths in those without occupational exposure to dust and gases compared with those with occupational exposure, except for death from interstitial pneumonia (Table 4).
Any respiratory symptom
The presence of any respiratory symptom increased the HR (95%CI) for pulmonary death to 2.0 (1.9–2.1), lung cancer death to 1.7 (1.5–1.8), COPD death to 4.3 (3.8–4.8) and pneumonia to 1.4 (1.2–1.5) after adjustment for sex, education, smoking and occupational exposure (Fig 1).
Multivariable hazard ratios with 95% confidence intervals for any respiratory symptom (0 = no, 1 = yes), sex, education, smoking and occupational exposure to air pollution according to all pulmonary deaths, lung cancer, COPD or pneumonia. All subjects in pooled sample with available covariates (n = 107,136).
Discussion
This study has shown that respiratory symptoms were associated with respiratory deaths due to lung cancer, COPD, pneumonia and asthma. The scores of breathlessness, cough and phlegm had a dose-response relationship for specific causes of pulmonary deaths. These associations were stronger for deaths due to lung cancer and COPD than for pneumonia.
The burden of respiratory symptoms increased the risk of death due to lung disease, independent of subset of symptoms, although the subsets of respiratory symptoms were associated with different mortality risks. Breathlessness on effort was associated with a higher risk than cough and phlegm.
This study comprises a very large pooled cohort with a very long follow-up period, enabling us to present new data on cause-specific deaths. This is a strength of the present study and would not be possible or meaningful in smaller cohorts and explains why there is little previous information on the association between respiratory symptoms and the less common causes of respiratory deaths.
The study supports and extends the previous findings in one of the four cohorts with 30 years of follow up [12], which showed a strong association of respiratory symptoms with deaths due to obstructive lung disease and a weak association with pneumonia. We are aware of few other comparable studies with sub-classified respiratory death as outcomes. The Busselton study investigated the association between respiratory symptoms and respiratory deaths, except lung cancer which was grouped with cancers, with 20–26 years of follow-up. The study dichotomized the respiratory symptoms, whereas the present study had graded responses. The Busselton study included forced expiratory volume in 1 second (FEV1) and several cardiovascular risk factors in the analysis of about 4,300 subjects, in contrast to the present study with >100,000 subjects that included occupational exposure and education in the analysis, but no spirometry variable. The present study was far larger and had longer observation time than that study, which enabled the analysis of subgroups of respiratory deaths, such as lung cancer, COPD, pneumonia, and less common respiratory diseases as causes of death.
In a sample of the population of Copenhagen, Denmark, chronic respiratory symptoms were associated with deaths in individuals with normal spirometry and without known airway disease [8]. In another follow up study, dyspnoea was associated with all-cause mortality after adjustment for lung function, but specific pulmonary mortality was not analysed [23]. In a large primary care study, breathlessness was an early marker of chronic respiratory and cardiac disease, and it was associated with all-cause mortality, death from COPD as well as ischemic heart disease [24].
We did not find an association between symptoms of attacks of breathlessness/wheeze and death from lung cancer. In contrast, a recent study reported a possible association between asthma symptom control and the incidence of lung cancer [25].
Our findings are robust given that the pattern of associations between respiratory symptoms and cause-specific mortality was similar in strata of men and subjects without cardiopulmonary diseases, and the total pooled sample. In stratified analysis of women only and never-smokers, the effects were smaller or disappeared, in particular for cough and phlegm.
Strengths of the present study include a large population-based cohort study with randomly selected individuals with high response rate of the target population and with a long and complete follow-up. The outcome of respiratory-specific deaths is highly relevant in a clinical setting. Furthermore, the respiratory symptoms were self-reported and not biased by observers [4]. The items on respiratory symptoms were identical in all these sub-cohorts, and they were administered by postal questionnaires. All studies had the same primary investigator.
In the present population-based study, it is unlikely that we have missed individuals with substantial symptoms, but more likely that we have included more individuals with mild symptoms. Nevertheless, individuals with mild symptoms will only dilute an association and reduce the risk estimates. There was a clear dose-response relationship between respiratory symptoms and outcomes of death like lung cancer and COPD.
Some limitations of the study should be noted. In this large, pooled sample, we had access to only a limited number of common/harmonized covariates. It is possible that covariates such as cardiovascular risk factors, body mass index, genetic factors, more detailed history of allergy or infections may, or other variables may be confounders in the relationship between respiratory symptoms and the specific respiratory deaths. During such a long observation time, covariates may also change over time, however, this study only had available covariates at baseline.
Spirometry would have been a useful supplement to subjective perceptions of respiratory symptoms, but that was only available for a fraction of the participants in the pooled sample. However, spirometry is more resource-consuming than assessment of simple respiratory symptoms in clinical practice.
The largest sub-cohort included mostly only men, hence the pooled sample had relatively few women and may represent a bias, although we adjusted for sex in the analysis. In a previous report, however, we have shown a similar pattern of association between respiratory symptoms and all-cause mortality for men and women in stratified analyses [6].
As in any survey, there is a risk of non-participation bias; however, it is hard to delineate how this would impact the association between respiratory symptoms and the studied outcome. The response rate in the surveys in this study ranged 67–89%, which is higher than what would probably be achievable today, as survey response rates to epidemiological studies have decreased over the past decades [26]. However, response rates depend on the topic and length of the questionnaire, target population, and whether incentives are used [26–28].
Another potential limitation is that ICD codes are reported by medical doctors, and there will be misclassifications. A validity study of the European short list of respiratory death certificate and autopsy showed a very high agreement for lung cancer, intermediate for COPD but only fairly for pneumonia [29]. This type of misclassification is likely to be non-differential and would bias toward the null [30, 31], and cannot explain our positive results.
Pneumonia is a difficult outcome based on cause of death coding, and there might be different predisposing conditions. It is possible that deaths coded as pneumonia as underlying cause of death could reflect unrevealed chronic lung diseases, or be related to other covariates than those that were available in the pooled sample in these cohorts.
Occupational exposure to air pollution was not a significant predictor of deaths for lung cancer, COPD and pneumonia in the pooled cohorts in this study. On the contrary, we observed a reduced risk for lung cancer mortality as well as COPD mortality in those with occupational exposure to dust and gas. This can be due to the healthy worker effect, i.e. a selection of relatively healthier individuals into occupations with dusty exposures. Paradoxically, in 1985 we found that a positive answer to the same question on occupational exposure was associated with an increased risk of respiratory symptoms [32]. Further explanations for this reduced risk could be information biases with greater reduction in smoking, improved socioeconomic status or less obesity in the follow up of the occupational exposure subset of the population compared with the rest of the population, or possibly better health care or other health-promoting factors for those with occupational exposure.
Smoking might be a confounder of the association between respiratory symptoms and mortality outcomes. Although we controlled for smoking before inclusion in the study, the prevalence of smoking has changed during follow up. In a follow-up of men in a Norwegian work-force, 32% had quit smoking, and only 16% had started smoking over a period of 8 years [33]. In addition, the total proportion of daily smokers in Norway decreased from 42% to 9% during the follow up period [34]. As a considerable proportion of the persons who smoked and reported symptoms might have reduced their symptoms after quitting [35], our analysis probably underestimates rather than overestimates the relation between symptoms and cause-specific pulmonary mortality.
Our study does not elucidate why having respiratory symptoms increases the risk for mortality from lung cancer, COPD and pneumonia, or why self-reports of such symptoms at any time have such long lasting effect. This study was an epidemiological study and not designed to investigate physiological mechanisms, therefore we can only speculate on such mechanisms. Furthermore, we do not have data that can confirm why for instance, dyspnea was a powerful predictor of COPD death, but a weaker predictor of lung cancer and pneumonia death.
It possible that the dyspnea domain captures both deconditioning by pulmonary, cardiovascular disease or other comorbidities, as well as anxiety-related conditions which may be associated with gradually developing COPD and death from COPD, and that this is less relevant for lung cancer or pneumonia, which have more rapid onset. In contrast, cough and phlegm might be more related to smoking habits and it is possible that there may be residual confounding even after adjustment for smoking. In conclusion, scores of respiratory symptoms were associated with long-term deaths due to COPD and lung cancer. Health personnel should be encouraged to ask patients about their symptom burden, as this may be a simple and cost-effective way to map increased mortality risk also among those without known illness. Awareness of even common respiratory symptoms is important in detecting deadly underlying diseases.
Supporting information
S1 Table. Questions (Q) on respiratory symptoms and scores.
https://doi.org/10.1371/journal.pone.0260416.s002
(PDF)
S2 Table. Descriptive statistics for participants at different stages according to response to questionnaire.
https://doi.org/10.1371/journal.pone.0260416.s003
(PDF)
S3 Table. Prevalence of baseline symptoms and distribution of symptoms according to principal causes of respiratory death.
https://doi.org/10.1371/journal.pone.0260416.s004
(PDF)
S4 Table. Hazard ratios (HR) with 95% confidence intervals and p-values for lung cancer death according to subgroup, multivariable proportional hazards regression analysis.
https://doi.org/10.1371/journal.pone.0260416.s005
(PDF)
S5 Table. Hazard ratios (HR) with 95% confidence intervals and p-values for COPD death according to subgroup, multivariable proportional hazards regression analysis.
https://doi.org/10.1371/journal.pone.0260416.s006
(PDF)
S6 Table. Hazard ratios (HR) with 95% confidence intervals and p-values for death from pneumonia according to subgroup, multivariable proportional hazards regression analysis.
https://doi.org/10.1371/journal.pone.0260416.s007
(PDF)
References
- 1. Soriano JB, Kendrick PJ, Paulson KR, Gupta V, Abrams EM, Adedoyin RA, et al. Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020;8(6):585–96. pmid:32526187
- 2. Snell N, Strachan D, Hubbard R, Gibson J, Limb E, Gupta R, et al. Burden of lung disease in the UK; findings from the British Lung Foundation’s ’respiratory health of the nation’ project. Eur Respir J. 2016;48(suppl 60):PA4913.
- 3. Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204–22. pmid:33069326
- 4. Gulsvik A. Prevalence of respiratory symptoms in the city of Oslo. Scand J Respir Dis. 1979;60(5):275–85. Epub 1979/10/01. pmid:316574.
- 5. Janson C, Johannessen A, Franklin K, Svanes C, Schioler L, Malinovschi A, et al. Change in the prevalence asthma, rhinitis and respiratory symptom over a 20 year period: associations to year of birth, life style and sleep related symptoms. BMC Pulm Med. 2018;18(1):152. Epub 2018/09/14. pmid:30208969; PubMed Central PMCID: PMC6136212.
- 6. Gulsvik A, Bakke PS, Brogger J, Nielsen R, Stavem K. Respiratory symptoms and mortality in four general population cohorts over 45 years. Respir Med. 2020;170:106060. Epub 2020/08/28. pmid:32843179.
- 7. Stavem K, Sandvik L, Erikssen J. Breathlessness, phlegm and mortality: 26 years of follow-up in healthy middle-aged Norwegian men. J Intern Med. 2006;260(4):332–42. Epub 2006/09/12. pmid:16961670.
- 8. Colak Y, Nordestgaard BG, Vestbo J, Lange P, Afzal S. Prognostic significance of chronic respiratory symptoms in individuals with normal spirometry. Eur Respir J. 2019;54(3). Epub 2019/06/30. pmid:31248954.
- 9. Rosengren A, Wilhelmsen L. Respiratory symptoms and long-term risk of death from cardiovascular disease, cancer and other causes in Swedish men. Int J Epidemiol. 1998;27(6):962–9. Epub 1999/02/19. pmid:10024189.
- 10. Vollmer WM, McCamant LE, Johnson LR, Buist AS. Respiratory symptoms, lung function, and mortality in a screening center cohort. Am J Epidemiol. 1989;129(6):1157–69. Epub 1989/06/01. pmid:2729254.
- 11. Frostad A. Association between respiratory symptom score and 30-year cause-specific mortality and lung cancer incidence. Clin Respir J. 2008;2 Suppl 1:53–8. Epub 2008/10/01. pmid:20298350.
- 12. Frostad A, Soyseth V, Haldorsen T, Andersen A, Gulsvik A. Respiratory symptoms and 30 year mortality from obstructive lung disease and pneumonia. Thorax. 2006;61(11):951–6. Epub 2006/07/01. pmid:16809414; PubMed Central PMCID: PMC2121183.
- 13. Puhan MA. Chronic respiratory symptoms but normal lung function: substantial disease burden but little evidence to inform practice. Eur Respir J. 2019;54(3). Epub 2019/09/21. pmid:31537654.
- 14. Gulsvik A, Humerfelt S, Bakke PS, Omenaas ER, Lehmann S. Norwegian population surveys on respiratory health in adults: objectives, design, methods, quality controls and response rates. Clin Respir J. 2008;2 Suppl 1:10–25. Epub 2008/10/01. pmid:20298346.
- 15. Eilertsen E, Sulheim O. [Smoking and coronary disease (3). The Bergen Investigation]. Lakartidningen. 1970;67(2):145–9. Epub 1970/01/07. pmid:5415737.
- 16. Gulsvik A, Bakke P, Humerfelt S, Omenaas E, Baste V. Measurements of respiratory symptoms and sample size to detect a given difference between treatment groups in obstructive lung disease. Eur Respir Rev. 1991;(1):436–43.
- 17. Brogger JC, Bakke PS, Gulsvik A. Comparison of respiratory symptoms questionnaires. Int J Tuberc Lung Dis. 2000;4(1):83–90. Epub 2000/02/02. pmid:10654649.
- 18. Bakke P, Gulsvik A, Eide GE, Hanoa R. Smoking habits and lifetime occupational exposure to gases or dusts, including asbestos and quartz, in a Norwegian community. Scand J Work Environ Health. 1990;16(3):195–202. Epub 1990/06/01. pmid:2382122.
- 19. Pedersen AG, Ellingsen CL. Data quality in the Causes of Death Registry. Tidsskr Nor Laegeforen. 2015;135(8):768–70. Epub 2015/05/08. pmid:25947599.
- 20.
European Shortlist for Causes of Death, 2012: Eurostat; 2012 [cited 2020]. Available from: http://ec.europa.eu/eurostat/ramon/nomenclatures/index.cfm?TargetUrl=LST_NOM_DTL_LINEAR&IntCurrentPage=2&StrNom=COD_2012&StrLanguageCode=EN.
- 21. Korn EL, Graubard BI, Midthune D. Time-to-event analysis of longitudinal follow-up of a survey: choice of the time-scale. Am J Epidemiol. 1997;145(1):72–80. Epub 1997/01/01. pmid:8982025.
- 22. Austin PC. A Tutorial on Multilevel Survival Analysis: Methods, Models and Applications. Int Stat Rev. 2017;85(2):185–203. Epub 2018/01/09. pmid:29307954; PubMed Central PMCID: PMC5756088.
- 23. Leivseth L, Nilsen TI, Mai XM, Johnsen R, Langhammer A. Lung function and respiratory symptoms in association with mortality: The HUNT Study. COPD. 2014;11(1):59–80. Epub 2013/07/24. pmid:23875716.
- 24. Chen Y, Hayward R, Chew-Graham CA, Hubbard R, Croft P, Sims K, et al. Prognostic value of first-recorded breathlessness for future chronic respiratory and heart disease: a cohort study using a UK national primary care database. Br J Gen Pract. 2020;70(693):e264–e73. Epub 2020/02/12. pmid:32041768; PubMed Central PMCID: PMC7015162.
- 25. Jiang L, Sun YQ, Langhammer A, Brumpton BM, Chen Y, Nilsen TI, et al. Asthma and asthma symptom control in relation to incidence of lung cancer in the HUNT study. Sci Rep. 2021;11(1):4539. Epub 2021/02/27. pmid:33633205.
- 26. Galea S, Tracy M. Participation rates in epidemiologic studies. Ann Epidemiol. 2007;17(9):643–53. Epub 2007/06/08. pmid:17553702.
- 27. Guo Y, Kopec JA, Cibere J, Li LC, Goldsmith CH. Population Survey Features and Response Rates: A Randomized Experiment. Am J Public Health. 2016;106(8):1422–6. Epub 2016/05/20. pmid:27196650; PubMed Central PMCID: PMC4940641.
- 28. Harrison S, Alderdice F, Henderson J, Redshaw M, Quigley MA. Trends in response rates and respondent characteristics in five National Maternity Surveys in England during 1995–2018. Arch Public Health. 2020;78:46. Epub 2020/06/09. pmid:32509303; PubMed Central PMCID: PMC7249643.
- 29. Gulsvik AK, Henriksen AH, Svendsen E, Humerfelt S, Gulsvik A. Validity of the European short list of respiratory diseases: a 40-year autopsy study. Eur Respir J. 2015;45(4):953–61. Epub 2014/11/02. pmid:25359344.
- 30. McGarvey LP, Magder S, Burkhart D, Kesten S, Liu D, Manuel RC, et al. Cause-specific mortality adjudication in the UPLIFT(R) COPD trial: findings and recommendations. Respir Med. 2012;106(4):515–21. Epub 2011/11/22. pmid:22100536.
- 31. Drummond MB, Wise RA, John M, Zvarich MT, McGarvey LP. Accuracy of death certificates in COPD: analysis from the TORCH trial. COPD. 2010;7(3):179–85. Epub 2010/05/22. pmid:20486816; PubMed Central PMCID: PMC4802970.
- 32. Bakke P, Eide GE, Hanoa R, Gulsvik A. Occupational dust or gas exposure and prevalences of respiratory symptoms and asthma in a general population. Eur Respir J. 1991;4(3):273–8. Epub 1991/03/01. pmid:1864342.
- 33. Stavem K, Aaser E, Sandvik L, Bjornholt JV, Erikssen G, Thaulow E, et al. Lung function, smoking and mortality in a 26-year follow-up of healthy middle-aged males. Eur Respir J. 2005;25(4):618–25. Epub 2005/04/02. pmid:15802334.
- 34.
Tobakk i Norge. Appendix table B1. Oslo, Norway: Norwegian Institute of Public Health; 2020. Available from: https://www.fhi.no/contentassets/4354197c0c964778b2c53472af8a796e/vedleggstabeller-til-tobakk-i-norge-2020.pdf.
- 35. Eagan TM, Gulsvik A, Eide GE, Bakke PS. Remission of respiratory symptoms by smoking and occupational exposure in a cohort study. Eur Respir J. 2004;23(4):589–94. Epub 2004/04/16. pmid:15083759.