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Chronic obstructive pulmonary disease: clinical phenotyping, mortality and causes of death
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.ORCID iD: 0000-0003-0473-9227
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Chronic obstructive pulmonary disease (COPD) is common. The estimated prevalence is about 10% among adults, but varies largely dependent on the major risk factors age and smoking. Under-diagnosis of COPD is substantial and is related to disease severity. Thus, subjects with mild to moderate COPD are underrepresented in medical registers among health care providers as well as in national registers. Post- bronchodilator (BD) spirometry is mandatory for the diagnosis of COPD, but not sufficient to assess and manage COPD. Phenotyping based on spirometry and clinical manifestations can make it easier to apply individual assessment of subjects with COPD. COPD is a systemic disease with pulmonary and extra-pulmonary manifestations and comorbidities are common. Comorbidities most probably contribute to the observed increased mortality among subjects with COPD, however, the impact of comorbidities on mortality and causes of death among subjects with mild to moderate COPD is unclear. Furthermore, there seems to be sex-dependent differences with regard to susceptibility to risk factors, clinical manifestation and outcomes.

Aim

The overall aim of this thesis was to identify and characterize clinical relevant COPD phenotypes in population-based studies, using spirometry together with clinical characteristics such as respiratory symptoms, exacerbations, and comorbidities, and their impact on mortality and further, also cause of death.

Methods

This thesis is based on data from the Obstructive Lung Disease in Northern Sweden (OLIN) COPD study. The study population was recruited in the years 2002-2004, when all 993 individuals with (FEV1/VC<0.70) were identified after examinations of population-based cohorts, together with age- and sex-matched non-obstructive referents (n=in total 1,986). In this thesis, cross-sectional data from recruitment were used together with mortality data from the Swedish Tax Agency from the date of recruitment in 2002-2004 and onwards. Data on cause of death was collected from the Swedish National Board for Health and Welfare register for all deaths until 31 December 2015. Spirometry was used to identify the following spirometric groups, in paper I: Non-COPD (FEV1/VC≥0.70); COPD (pre- BD FEV1/VC<0.70); in paper II: Non- obstructive (FEV1/VC≥0.70), Pre- not post-BD obstructive (pre- not post-BD FEV1/VC<0.70); COPD (post-BD FEV1/VC<0.70); In paper III: Normal Lung Function (NLF, FEV1/VC≥0.7 & FVC≥80% predicted), COPD (post BD FEV1/VC<0.70) and Lower Limit of Normal COPD (LLN-COPD, the LLN criterion applied among those with COPD); in paper IV: NLF and COPD defined as in paper III, and Restrictive Spirometric pattern (RSP, FEV1/VC≥0.70 & FVC<80% predicted). The OLIN-COPD study and collection of data on causes of death were approved by the regional ethical committee at Umeå University.

Results

Paper I: Subjects with COPD had more productive cough than non-COPD, and men more than women. Productive cough increased the risk for exacerbations in COPD and non-COPD and productive cough was associated with worse survival in both groups. In adjusted models (HR;95%CI) the increased risk for death associated with productive cough among those with COPD persisted (1.48;1.13-1.94) when compared with non-COPD without productive cough, significantly so also among men with COPD (1.63;1.17-2.26), but not among women (1.23;0.76-1.99).

Paper-II: Pre-BD spirometry misclassified every fourth subject as having COPD. Subjects with pre- but not post-BD obstruction were similar to subjects with COPD regarding reported ‘any respiratory symptoms’, asthma before the age of 40, exacerbations, and comorbidities. The cumulative mortality among subjects with pre- not post-BD obstruction was similar to among subjects in the non-obstructive group, still, the survival was better than among those with COPD. The increased risk for death for COPD persisted also in an adjusted model (1.24; 1.04-1.49) when compared with the non-obstructive group, and the pattern was similar among men and women (1.27; 1.00-1.60 and1.24; 0.92-1.13).

Paper III: Men with COPD had more CVD and DM compared to women, while anxiety/depression (A/D) was more common among women than men in all spirometric groups. Men had a higher cumulative mortality than women in all groups. However, CVD seemed to have a greater impact on mortality among women than men, while anxiety/depression increased the risk for death similarly in both sexes. The use of the LLN criterion did not change the observed pattern.

Paper IV: CVD was the most common cause of death in all spirometric groups, NLF, RSP and COPD, followed by cancer. Those with COPD and RSP had a similar and higher cumulative mortality than those with NLF. RSP and COPD had an increased risk for CVD death and respiratory death, independent of age, sex, smoking habits and BMI-category, however, the increased risk for CVD death did not reach statistical significance in RSP. In all the groups, the risk for deaths due to cancer was similar, however, lung cancer was more common in COPD than in NLF and RSP. The pattern was fairly similar among men and women. 

Conclusions

Simple diagnostic procedures like history of respiratory symptoms, exacerbations, and comorbidity can, together with spirometry, contribute with important clinical classification of prognostic importance. Productive cough increased the risk for exacerbations in both COPD and non-COPD. The highest risk for exacerbations and death was observed among subjects with COPD and productive cough. It was impossible to distinguish COPD from those with pre- not post-BD obstruction based on the history of respiratory symptoms, asthma, exacerbations and comorbidities. Still, COPD was associated with an increased risk for death while pre- not post-BD obstruction had better survival than COPD but similar as non-obstructive. There were sex-dependent differences regarding comorbidities and mortality. CVD was less common among women but had a greater impact on mortality compared to among men while A/D, less common among men, increased the risk for death similarly in both sexes. CVD and cancer were the most common causes of death in all spirometric groups. RSP had a similar and higher mortality as COPD when compared with NLF. The risk for cancer-related death was similar in all groups, while the results indicated that COPD and RSP had an increased risk for CVD and respiratory death.

Abstract [sv]

Introduktion

Kronisk obstruktiv lungsjukdom (KOL) är en folksjukdom som förekommer hos cirka 10% i den vuxna befolkningen. Förekomsten (prevalensen) varierar dock och är framförallt beroende av ålder och rökning. Underdiagnostiken av KOL är betydande och är relaterad till sjukdomens svårighetsgrad. Upp till 70 % av dem med KOL är inte identifierade inom hälso- och sjukvården. Även feldiagnostik är vanligt, nästan lika vanlig som underdiagnostik. Personer med lindrig till måttligt svår KOL är särskild sårbara för under- och feldiagnostik. Det förefaller finnas betydelsefulla könsskillnader vad gäller känslighet för riskfaktorer som rökning samt kliniska sjukdomsuttryck och prognos vid KOL. Det krävs lungfunktionsmätning (spirometri) efter luftrörsvidgande läkemedel (bronkdilatation (BD)) för att påvisa kvarstående luftrörsförträngning (luftvägsobstruktion) vid diagnostik av KOL. Spirometri görs i allt för liten omfattning hos personer med misstänkt KOL, och vid undersökning med spirometri, det är inte ovanlig att den genomförs utan luftrörsvidgande mediciner. Det krävs mer än enbart spirometri för korrekt handläggning (utredning och behandling) av personer med KOL. Kliniska sjukdomsuttryck (fenotyper), baserade på spirometri och kliniska uppgifter om exempelvis luftvägssymtom och uppgift om försämringsperioder (exacerbationer) kan underlätta bedömning av KOL och tillämpning av individualiserad handläggning vid KOL. Enkel klinisk fenotypning skulle vara tillämpningsbar i det daglig kliniska arbetet. Samsjuklighet (komorbiditeter) är vanliga vid KOL och bland dem är hjärt- och kärlsjukdomar vanligast. Komorbiditet bidrar förmodligen till den ökade dödligheten som har observerats hos personer med KOL, men det är oklart vilken betydelse komorbiditeter har för mortalitet framförallt bland personer med lindrig och måttligt svår KOL samt vilka som är de vanligaste dödsorsakerna.

Syfte

Det övergripande syftet med denna avhandling var att identifiera och karakterisera kliniska fenotyper av KOL i en befolkningsbaserad studie med hjälp av spirometri och enkla kliniska uppgifter såsom förekomst av luftvägssymtom, exacerbationer och komorbiditet, samt värdera deras betydelse i relation till mortalitet och dödsorsaker. 

Metod

Avhandlingen utgår från en befolkningsstudie i norra Sverige där en långtidsuppföljning av personer med och utan KOL pågår inom ramen för det epidemiologiska forskningsprogrammet Obstruktiv Lungsjukdom i Norrbotten  (OLIN) studierna; OLINs KOL-studie. Efter kliniska undersökningar av populationsbaserade kohorter under åren 2002-2004 identifierades alla (n=993) individer med luftvägsobstruktion (FEV1/VC <0.70) tillsammans med lika många ålders- och könsmatchade referenspersoner utan luftvägsobstruktion, totalt n=1986. Tvärsnittsdata från undersökningstillfället vid rekryteringen under åren 2002-04 har använts i samtliga fyra delarbeten, tillsammans med mortalitets data från Skatteverkets folkbokföringsregister. Dödsorsakuppgifter har erhållits från Socialstyrelsens dödsorsaksregister för alla som avlidit fram till den 31 december 2015. Följande spirometriska grupper har identifierats; delarbete I: Ej KOL (FEV1/VC≥0,70); KOL (pre-BD FEV1/VC<0,70), delarbete II: Icke obstruktiv; obstruktiv före men inte efter BD (pre- not post BD obstruktiv); KOL (post-BD FEV1/VC<0.70), delarbete III: Normal lungfunktion (NLF, FEV1/VC≥ 0,70 & FVC≥80% av förväntat värde), KOL (post-BD FEV1/VC<0,70) och KOL enligt Lower limit of normal (KOL enligt LLN; femte percentilen av normalvärde för post-BD FEV1/VC<0,70), delarbete IV: NLF och KOL definierat som i delarbete III, Restriktivt spirometriskt mönster (RSP, FEV1/VC≥0,70 & FVC<80% av förväntat värde). KOL-studien och inhämtande av uppgifter om dödsorsaker från dödsorsaksregistret är godkända av den Etiska kommittén vid Umeå universitet. 

Resultat

Delarbete I: Produktiv hosta var mer vanlig förekommande bland personer med KOL än bland dem som inte hade KOL, och framförallt bland män. Produktiv hosta ökade risken för exacerbationer hos både personer med och utan KOL och i båda könen.  Produktiv hosta var även förknippat med sämre överlevnad bland både dem med och utan KOL.

Den ökade risken för död (HR;95%CI) bland dem med KOL och produktiv hosta jämfört med dem utan KOL och utan produktiv hosta, kvarstod oberoende av kön, ålder, rökvanor och förekomst av hjärtsjukdom (1,48;1,13-1,94). Den förhöjda risken var signifikant bland män med KOL (1,63;1,17–2,26), men inte bland kvinnor med KOL (1,23;0,76–1,99).  

Delarbete II: Spirometri utan bronkodilatation medför att varje fjärde person fel-klassificeras som obstruktiv. Personer med luftvägsobstruktion före men inte efter BD kunde inte skiljas från personer med KOL, vad gäller förekomsten av några luftvägssymtom, astmadiagnos före 40 års ålder, exacerbationer och förekomsten av komorbiditeter. Dock hade de hade bättre överlevnad i jämförelse med dem med KOL och överlevnaden var på samma nivå som hos dem utan KOL. De med KOL hade 24 % ökad risk för död, jämfört med dem utan KOL, oberoende av ålder, kön, rökvanor, BMI och komorbiditet och detta riskmönster var likartat bland män och kvinnor.  

Delarbete III: Hjärtkärlsjukdomar var en större riskfaktor för död bland kvinnor, trots att de var mer vanligt förekommande bland män. Ångest/depression var vanligare hos kvinnor än hos män i alla spirometriska grupper, men det var en lika stark riskfaktor för död bland män och kvinnor. Män hade dock genomgående sämre överlevnad än kvinnor i alla spirometriska grupper. Mönstret var likartat också när KOL definierades enlig LLN-kriterierna.  

Delarbete IV: Hjärtkärlsjukdomar var den vanligaste dödsorsaken i alla spirometriska grupper, NLF, RSP och KOL, följt av cancersjukdomar. Personer med KOL och RSP hade en likartad och ökad mortalitet, jämfört med dem i NLF-gruppen. Personer med RSP och KOL hade en ökad risk för att dö av sjukdomar i andningsorganen jämfört med dem i NLF-gruppen, oberoende av ålder, kön, rökvanor och BMI. De med KOL och RSP hade också en ökad risk för död i hjärtkärlsjukdomar där dock riskökningen för dem i RSP inte nådde statistisk signifikans. Risk att dö till följd av cancersjukdomar var lika stor i alla spirometriska grupper. I analyser genomförda separat bland män och kvinnor var mönstren likartade. 

Slutsatser

Enkla kliniska uppgifter om luftvägssymptom, exacerbationer och komorbiditet kan tillsammans med spirometri användas vid klinisk fenotypning av prognostisk betydelse hos män och kvinnor med KOL.

Produktiv hosta ökade risken för exacerbationer hos män och kvinnor, både med och utan KOL.  Den största risken för exacerbationer och död observerades hos personer med samtidig KOL och produktiv hosta.

Spirometri utan bronkodilatation orsakade en betydande felklassificering av KOL. Uppgift om luftvägssymtom, exacerbationer och komorbiditet kan inte ersätta spirometri efter bronkodilatation för att ställa rätt diagnos. Dessutom har rätt diagnos prognostiskt betydelse, då endast de med KOL hade en ökad risk för död jämfört med dem utan KOL.

Trots att hjärtkärlsjukdomar var mindre vanliga bland kvinnor än bland män, föreföll de vara en starkare riskfaktor för död bland kvinnor. Ångest/depression var vanligare bland kvinnor än bland män, men ökade risken för död likvärdigt i båda könen. Hjärtkärlsjukdomar och cancer var de vanligaste dödsorsakerna i alla spirometriska grupper. Personer med RSP och KOL hade en likvärdig och högre mortalitet än dem med NLF. Resultaten indikerar att de med KOL och RSP hade en ökad risk för död av hjärtkärlsjukdomar och sjukdomar av andningsorganen jämfört med NLF, medan risken att dö av cancer var densamma i alla grupperna.

 

 

 

 

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2019. , p. 73
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2056
Keywords [en]
Phenotyping, chronic airflow obstruction, COPD, productive cough, pre- and postbronchodilator airway obstruction, co-morbidity, epidemiology, mortality, causes of death, sex
National Category
Clinical Medicine
Research subject
Lung Medicine
Identifiers
URN: urn:nbn:se:umu:diva-164172ISBN: 978-91-7855-127-9 (print)OAI: oai:DiVA.org:umu-164172DiVA, id: diva2:1361068
Public defence
2019-11-08, Konferenscentrum, Aulan, Sunderby Sjukhus, Sjukhusvägen 10, 954 42 Södra Sunderbyn, Luleå, 09:00 (Swedish)
Opponent
Supervisors
Projects
Obstruktiv Lungsjukdom i Norrbotten (OLIN) studiernaAvailable from: 2019-10-17 Created: 2019-10-15 Last updated: 2019-10-16Bibliographically approved
List of papers
1. Subjects with COPD and productive cough have an increased risk for exacerbations and death
Open this publication in new window or tab >>Subjects with COPD and productive cough have an increased risk for exacerbations and death
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2015 (English)In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 109, no 1, p. 88-95Article in journal (Refereed) Published
Abstract [en]

Background: Chronic bronchitis is related to worse general health status, exacerbations and mortality among subjects with COPD. Also less longstanding cough and phlegm may be related to worse prognosis in COPD but this has rarely been evaluated in population-based studies. Aim: To evaluate the relationship between productive cough, exacerbations and mortality among subjects with and without COPD. Method: All subjects with COPD (n = 993) were identified together with sex-and age matched reference subjects without obstructive lung function impairment from four population-based cohorts in 2002-04. Baseline spirometry and structured interview including data on exacerbations last 12 months were used in this study (n = 1986) together with mortality data collected until February 2012. Results: Productive cough was more common in COPD than non-COPD (42.8 vs. 23.5%, p < 0.001), more common in men than women, but associated to exacerbations in both sexes. COPD-subjects with productive cough had the highest risk for exacerbations in both sexes and they had a significantly increased risk for death (HR 1.48, 95% CI 1.13-1.94) also when adjusted for sex, age, BMI, smoking habits and heart disease. Conclusion: Productive cough was common and increased the risk for exacerbations in both sexes, in both COPD and non-COPD. COPD-subjects with productive cough had the highest risk for exacerbations and a significantly higher risk for death also after adjustment for common risk factors.

Keywords
COPD, Productive cough, Exacerbations, Mortality, Epidemiology
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-99368 (URN)10.1016/j.rmed.2014.12.001 (DOI)000347097100010 ()
Available from: 2015-03-04 Created: 2015-02-07 Last updated: 2019-10-15Bibliographically approved
2. Pre- and post-bronchodilator airway obstruction are associated with similar clinical characteristics but different prognosis - report from a population-based study
Open this publication in new window or tab >>Pre- and post-bronchodilator airway obstruction are associated with similar clinical characteristics but different prognosis - report from a population-based study
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2017 (English)In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 12, p. 1269-1277Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: According to guidelines, the diagnosis of COPD should be confirmed by post-bronchodilator (post-BD) airway obstruction on spirometry; however, in clinical practice, this is not always performed. The aim of this population-based study was to compare clinical characteristics and prognosis, assessed as mortality, between subjects with airway obstruction divided into pre- but not post-BD obstruction, post-BD airway obstruction (COPD), and subjects without airway obstruction.

MATERIALS AND METHODS: In 2002-2004, four adult population-based cohorts were reexamined with spirometry and structured interview. Subjects with airway obstruction, with a ratio of forced expiratory volume in 1 s to (forced) vital capacity <0.70 (n=993), were identified together with sex- and age-matched referents (n=993). These subjects were further divided into subjects with pre- but not post-BD airway obstruction (pre- not post-BD obstruction) and subjects with post-BD airway obstruction (COPD). Mortality data were collected until December 31, 2014.

RESULTS: Out of 993 subjects with airway obstruction, 736 (74%) had COPD and 257 (26%) pre- not post-BD obstruction. Any respiratory symptoms, allergic rhinitis, asthma, exacerbations, and comorbidities were equally common among subjects with COPD and pre- not post-BD obstruction, but less common among nonobstructive subjects. Mortality was highest among subjects with COPD and higher in men than in women. In both sexes, COPD, but not pre- not post-BD obstruction, was associated with an increased risk for death compared to those without airway obstruction. When COPD was divided into Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, GOLD 2 and 3-4 had an increased risk for death when compared to the nonobstructive group, also when adjusted for common confounders and comorbidities such as heart disease, diabetes, and anxiety/depression.

CONCLUSION: Even though subjects with COPD and pre- not post-BD obstruction had fairly similar presentation of clinical characteristics, only those with COPD, specifically GOLD stage ≥2, had increased risk for death when compared with nonobstructive subjects.

Keywords
chronic airflow obstructions, epidemiology, mortality, spirometry
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:umu:diva-135016 (URN)10.2147/COPD.S127923 (DOI)000399981100001 ()28490870 (PubMedID)
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2019-10-15Bibliographically approved
3. The impact of comorbidities on mortality among men and women with COPD: report from the OLIN COPD study
Open this publication in new window or tab >>The impact of comorbidities on mortality among men and women with COPD: report from the OLIN COPD study
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2019 (English)In: Therapeutic Advances in Respiratory Disease, ISSN 1753-4658, Vol. 13, article id 1753466619860058Article in journal (Refereed) Published
Abstract [en]

Background: Comorbidities probably contribute to the increased mortality observed among subjects with chronic obstructive pulmonary disease (COPD), but sex differences in the prognostic impact of comorbidities have rarely been evaluated in population-based studies. The aim of this study was to evaluate the impact of common comorbidities, cardiovascular disease (CVD), diabetes mellitus (DM), and anxiety/depression (A/D), on mortality among men and women with and without airway obstruction in a population-based study.

Methods: All subjects with airway obstruction [forced expiratory volume in 1 second (FEV1)/(forced) vital capacity ((F)VC) <0.70, n = 993] were, together with age- and sex-matched referents, identified after examinations of population-based cohorts in 2002-2004.

Spirometric groups: normal lung function (NLF) and COPD (post-bronchodilator FEV1/(F)VC <0.70) and additionally, LLN-COPD (FEV1/(F)VC <lower limit of normal). Mortality data was collected until December 2015. Results: In COPD, the prevalence of CVD and DM was higher in men, whereas the prevalence of A/D was higher in women. The cumulative mortality was significantly higher in COPD than NLF, and higher in men than women in both groups. Among women with COPD, CVD and A/D but not DM increased the risk of death independent of age, body mass index, smoking habits, and disease severity, whereas among men DM and A/D but not CVD increased the risk for death. When the LLN criterion was applied, the pattern was similar.

Conclusion: There were sex-dependent differences regarding the impact of comorbidities on prognosis in COPD. Even though the prevalence of CVD was higher in men, the impact of CVD on mortality was higher in women, and despite higher prevalence of A/D in women, the impact on mortality was similar in both sexes. The reviews of this paper are available via the supplemental material section.

Place, publisher, year, edition, pages
Sage Publications, 2019
Keywords
chronic airflow obstruction, co-morbidity, epidemiology, mortality, sex
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-162339 (URN)10.1177/1753466619860058 (DOI)000478856400001 ()31291820 (PubMedID)
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-10-15Bibliographically approved
4. Mortality by cause of death and spirometric pattern in a population based study: more than 10 years follow-up of the OLIN COPD study
Open this publication in new window or tab >>Mortality by cause of death and spirometric pattern in a population based study: more than 10 years follow-up of the OLIN COPD study
Show others...
(English)Manuscript (preprint) (Other academic)
Keywords
Airway obstruction, COPD, restrictive spirometric pattern, causes of death
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-164177 (URN)
Available from: 2019-10-15 Created: 2019-10-15 Last updated: 2019-10-15

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