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We found significant differences in 3-year change in pulmonary function among pulmonary function phenotypes and races, but no difference between sexes.
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Correspondence to Dr Michelle Sharp, Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA; [email protected]
WHAT IS ALREADY KNOWN ON THIS TOPIC
Sarcoidosis is a disease with heterogeneous presentation and unpredictable clinical course. Significant race and sex-based differences in clinical outcomes have been reported in sarcoidosis. We aimed to determine whether 3-year longitudinal change in pulmonary function differed between pulmonary function phenotypes, races and sexes.
WHAT THIS STUDY ADDS
We found significant differences in longitudinal changes in pulmonary function between the various pulmonary function phenotypes and between races. Additionally, we identified a group of individuals who experienced more rapid decline in pulmonary function.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study can inform future prospective studies to further explore pulmonary function phenotypes of sarcoidosis and the determinants of racial differences in pulmonary function over time in sarcoidosis.
Introduction
The heterogeneity of sarcoidosis manifestations and course is a challenging aspect of the disease.1 There are ongoing attempts to identify clinical phenotypes in sarcoidosis2–4 and to identify individuals who will have disease progression versus stable disease.5 Although pulmonary involvement is found in up to 90% of individuals with sarcoidosis,6 variability in disease manifestations results in different pulmonary function phenotypes.7–9 Identification of clinical, physiological, molecular and immunological phenotypes has the potential to mitigate the challenges resulting from the heterogeneity in sarcoidosis with hope of leading to progress in disease understanding and clinical therapeutics.
Given the heterogeneity, predicting the disease course of patients with sarcoidosis remains a challenge. Approximately half of patients with sarcoidosis will develop progressive disease which requires long-term disease monitoring necessary to help identify potential organ dysfunction.10 In pulmonary sarcoidosis, both pulmonary function and chest imaging have been used to assess for disease progression. Chest imaging has been less sensitive at determining disease progression compared with pulmonary function5 and often the chest imaging findings are not well correlated with pulmonary function.5 11
Significant race and sex differences in pulmonary function have been reported in sarcoidosis.7 12 These cross-sectional studies have reported worse lung function in black individuals and females when compared with white individuals and males, respectively7 12; however, little information is available regarding whether longitudinal changes in lung function differ by race or sex. The purpose of this study was to determine whether the 3-year change in pulmonary function differed between pulmonary function phenotypes and whether there were differential longitudinal changes by race and sex.
Methods
Study population
The study population was drawn from an established cohort of individuals with a diagnosis of sarcoidosis based on criteria from the 2020 American Thoracic Society Statement.1 Patients were seen in the Johns Hopkins Sarcoidosis Clinic between 2005 and 2015 and had available pulmonary function tests (PFTs) within 1 year of their first clinic visit.7 The study population included individuals with pulmonary involvement based on the Organ Assessment Tool (OAT) used in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study13 and additional pulmonary function measurement within 3 years of entry into the cohort.
Data
For each individual, PFTs including spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO), sarcoidosis organ involvement defined by OAT, Charlson Comorbidity Index, time since sarcoidosis diagnosis, race, sex, age, medicines prescribed for sarcoidosis defined as corticosteroids or steroid-sparing agents (such as methotrexate, azathioprine or mycophenolate), tobacco use and chest imaging results were abstracted from medical charts. Medicines were abstracted at each time the PFTs were abstracted and therefore were a time-varying covariate. Chest imaging was abstracted (from the official radiology report) by the lead author (MS) with a preference for CT of the chest over chest radiographs and included if imaging occurred within 1 year of the first PFT. The chest imaging was described as hilar or mediastinal lymph node involvement (yes/no), parenchymal involvement (yes/no) and fibrocystic disease (yes/no). Chest imaging was then classified as normal (no to all variables), lymph node only, lymph node and parenchymal, parenchymal only or fibrocystic disease, which conforms to the widely used Scadding Stage for chest radiographs but includes preferentially chest CT as well.
Pulmonary function phenotypes
Pulmonary function impairment phenotypes were based on our previously used definitions7 which included: restriction as forced vital capacity (FVC) Primary outcomes The % predicted measurements for FVC, FEV1 and DLCO were determined using Global Lung Function Initiative reference equations calculated by assigning race to the race-composite set of equations with the designation ‘other’14 15 using absolute values of lung function parameters for each individual. Statistical analysis Demographic and clinical characteristics of the study population were summarised and compared between white and black participants using Mann-Whitney U tests for continuous variables and χ2 square or Fisher’s exact tests for categorical variables. Linear mixed models with subject-specific random intercepts were used to determine whether the longitudinal 3-year rate of change of each pulmonary function parameter (FVC% predicted, FEV1% predicted and DLCO% predicted) differed between pulmonary function phenotypes. These models included an interaction term for pulmonary function phenotype by time, in addition to the following covariates: time since sarcoidosis diagnosis, race, sex, tobacco use and medication use. The reference group for these analyses was the normal pulmonary function phenotype. We further evaluated potential race and sex differences in pulmonary function changes using similar linear mixed models which included pulmonary function phenotype and a race×time or sex×time interaction term, respectively. Results of all models are presented as the average 3-year changes in pulmonary function parameters with corresponding 95% CIs. Analyses were repeated for raw FVC and FEV1 change over time. Sensitivity analyses repeated the previously described analyses and included only those individuals with chest imaging classifications. Finally, we categorised individuals into quartiles of rate of change and compared characteristics of the individuals in the highest quartile of rate of decline with the other three quartiles. A p<0.05 was considered statistically significant. All analyses were performed using Stata V.15 (STATA Corp, College Station, Texas, USA). Results Participants A total of 291 individuals met inclusion criteria, of which 135 (46%) were white and 156 (54%) were black. 10 individuals who had race documented as ‘other’ in the medical chart were excluded since we were unable to adequately categorise into an appropriate racial category. A majority of the cohort was female (173 (59%)), had two or more organ involvement with their sarcoidosis (178 (61%)) and was ever on immunosuppression treatment for sarcoidosis (189 (65%)). Participant demographic and disease characteristics are presented in table 1. Demographic and clinical characteristics of participants at baseline, overall and for black and white participants P values based on Mann-Whitney U tests for continuous variables and χ2 or Fisher’s exact tests for categorical variables. *Treatment for sarcoidosis was abstracted at each PFT and the variable included in the table is ever prescribed treatment. DLCO, diffusing capacity for carbon monoxide; PFT, pulmonary function test. Pulmonary function phenotype differences Results of regression analyses evaluating the association of pulmonary function phenotype and the 3-year rate of change of each pulmonary function parameter are presented in table 2. Individuals with a restrictive pulmonary function phenotype had a 3-year rate of FVC% predicted change that was −3.88 (95% CI: −7.38 to −0.38) compared with individuals with normal pulmonary function phenotype. No significant differences in FVC% predicted change were found for the obstructive, combined or isolated reduction in DLCO pulmonary function phenotypes. The 3-year change in FEV1% predicted was −4.17 (95% CI: −7.85 to −0.49) among those with a restrictive pulmonary function phenotype. No significant differences in FEV1% predicted change were found for the obstructive, combined or isolated reduction in DLCO pulmonary function phenotypes. No differences in change in DLCO% predicted were observed for the obstructive, restrictive, mixed or the isolated DLCO impairment pulmonary function phenotypes compared with the normal phenotype. The combined phenotype had significant decline in FEV1/FVC over 3 years (online supplemental table 1). Similar results were found using absolute values for FVC and FEV1, but the FVC was no longer statistically significantly for the restrictive phenotype (online supplemental table 2). A sensitivity analysis was performed excluding individuals with an obstructive phenotype which revealed no changes to the FVC% predicted model. However, all other phenotypes significantly declined compared with normal in the FEV1% predicted model and the restrictive phenotype significantly declined compared with normal in the DLCO% predicted model. Three-year rate of change in pulmonary function parameters by pulmonary function phenotype Bold values have statistical significance. *Multivariable linear mixed models which included pulmonary function phenotype×time interaction in addition to time since sarcoidosis diagnosis, race, sex, tobacco use and medication use. The reference group for all models were individuals having a normal pulmonary function phenotype. DLCO, diffusing capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity. Race and sex differences in longitudinal changes in pulmonary function The 3-year longitudinal changes in FVC% predicted, FEV1% predicted and DLCO% predicted for white and black individuals are presented in figure 1. Black individuals had worse pulmonary function at entry into the cohort measured by FVC% predicted, FEV1% predicted and DLCO% predicted compared with white individuals. The 3-year change in FVC% and FEV1% predicted in white individuals was 3.34 and 3.23, which was significantly greater than in black individuals which was 0.06 and −0.06, respectively. White individuals had a higher DLCO% predicted change of 0.56 (95% CI −2.17 to 3.31) compared with black individuals DLCO% predicted change of −2.07 (95% CI −4.58 to 0.44), but the difference in changes was not significant. Similar results were found using absolute values for FVC and FEV1, but the FVC was no longer statistically significantly (online supplemental table 3). There were no significant differences in 3-year longitudinal changes in FVC% predicted, FEV1% predicted and DLCO% predicted between males and females. No significant interactions between race and sex were found for any of the longitudinal lung function parameters. Figure 1. Race difference in lung function over time in sarcoidosis. (A) FVC% predicted over the 3-year period among white individuals within the cohort by pulmonary function phenotype. (B) FVC% predicted over the 3-year period among black individuals within the cohort by pulmonary function phenotype. (C) FEV 1 % predicted over the 3-year period among white individuals within the cohort by pulmonary function phenotype. (D) FEV 1 % predicted over the 3-year period among black individuals within the cohort by pulmonary function phenotype. (E) DL CO % predicted over the 3-year period among white individuals within the cohort by pulmonary function phenotype. (F) DL CO % predicted over the 3-year period among black individuals within the cohort by pulmonary function phenotype. Multivariable linear mixed models which included pulmonary function phenotype×time interaction in addition to time since sarcoidosis diagnosis, sex, tobacco use and medication use. DL CO , diffusing capacity of the lungs for carbon monoxide; FEV 1 , forced expiratory volume over 1 s; FVC, forced vital capacity. Differences when including chest imaging in models Chest imaging was available for 220 (75.6%) individuals, of which 109 (50%) were white and 111 (50%) were black. Characteristics of these participants are presented in online supplemental table 4. After further adjustment for presence or absence of hilar/mediastinal adenopathy, parenchymal disease or fibrocystic disease on CT imaging, the 3-year change in FEV1% predicted was 4.51 (95% CI: −8.97 to −0.05) lower among those with a restrictive pulmonary function phenotype compared with the normal pulmonary phenotype; however, the FVC% predicted 3-year change did not differ between these groups (table 3). Of note, black individuals were more likely to have fibrocystic changes on chest imaging compared with white individuals. Differences in longitudinal changes in pulmonary function between black and white individuals were similar in direction and magnitude of the entire cohort but did not significantly differ in the subgroup (online supplemental figure 1). Three-year rate of change in pulmonary function parameters by pulmonary function phenotype, adjusted for chest imaging Bold values have statistical significance. *Multivariable linear mixed models which included pulmonary function phenotype×time interaction in addition to time since sarcoidosis diagnosis, race, sex, tobacco use, chest imaging and medication use. The reference group for all models were individuals having a normal pulmonary function phenotype. DLCO, diffusing capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume over 1 s; FVC, forced vital capacity. Characteristics of highest decliners We examined the characteristics of those in the quartile with the greatest FVC% predicted and FEV1% predicted decline in the 3-year follow-up (online supplemental tables 5 and 6). The median 3-year FVC change in mL in the quartile with the greatest FVC decline was −156 mL. The proportion of black individuals and the restrictive and combined restrictive obstructive phenotypes were greater in the highest decline quartile compared with the lowest three quartiles. There were no significant differences in organ involvement, diagnosis duration, sex, age, prescribed treatment for sarcoidosis or tobacco use. The median 3-year FEV1 change in mL in the quartile of the highest FEV1 decline was −121 mL. Individuals with restrictive and combined restrictive obstructive phenotypes were more likely to have the highest rates of FEV1 decline compared with the other quartiles. There were no significant differences in organ involvement, diagnosis duration, race, sex, age, prescribed treatment for sarcoidosis or tobacco use. Discussion There has been a recognised need to identify clinical phenotypes to improve disease understanding that goes beyond expert opinion.2 16 We compared the pulmonary function changes over time between the pulmonary function phenotypes within a cohort of individuals in which 65% were on treatment in order to identify potential higher-risk phenotypes with greater likelihood of pulmonary function decline. We found that the restrictive pulmonary function phenotype had significantly greater decline in 3-year rate of FVC% predicted and FEV1% predicted change compared with normal and was more commonly seen among the highest decliners in the cohort suggesting that this phenotype may be a higher-risk phenotype requiring closer monitoring. Interestingly, the obstructive pulmonary function phenotype had a positive 3-year change in FVC% predicted, although not significant compared with normal, which may suggest that there is more reversibility for this phenotype. Further work is needed to understand whether pulmonary function phenotypes can be used to inform management strategies to prevent progression of disease. Pulmonary function and chest imaging in sarcoidosis have been shown to be associated in some cohorts2 17; however, discordance between the two has been seen in up to 50% of cases in other cohorts.18 19 Although pulmonary function has been more closely associated with disease activity in sarcoidosis compared with chest imaging,18–20 in a large population-based cohort, chest imaging drove medication change and not pulmonary function.21 While the restrictive phenotype had significantly greater reduction of pulmonary function compared with normal in the overall cohort, when accounting for chest imaging (which included ~75% of the overall cohort), the change over time pattern was similar, but change in FVC% was no longer significantly different. One explanation for this finding may be that restrictive lung disease is associated with irreversible fibrosis, in this context. The loss of significance of the FVC% predicted rate of change when adjusting for chest imaging in our cohort may suggest that scarring was present in some individuals resulting in a lack of improvement over time. Although statistical significance was lost, individuals with a restrictive PFT phenotype did experience decline in lung function over the 3-year follow-up period. An alternative explanation for this loss of statistical significance may be a reduction in sample size when analysing the smaller subgroup of patients for whom imaging was available. While our study begins to explore high-risk phenotypes for disease progression through lung function phenotypes, use of chest imaging and other parameters such as health-related quality of life measures is likely also important in identifying high-risk phenotypes in sarcoidosis. Sarcoidosis is a disease that can be marked by its chronicity and potential for progression over time. Therefore, small changes over a smaller time period may reflect a more clinically meaningful difference over the course of these patients’ lifetimes. Furthermore, we identified a cohort of patients who experienced rapid decline in lung function with median loss of FVC of 156 mL/3 years and FEV1 of 121 mL/3 years which is higher than the population expected rate of lung function decline of 30 mL/year.22 These individuals, named highest decliners, represent a particularly high-risk group of patients in our cohort and warrant further investigation to understand what may drive their rapid rate of lung function decline. Potential drivers include challenges in access to medications, difficulty with medication adherence, as well as environmental factors that may be associated with lung function decline. Additionally, identifying if these patients fit into a particular phenotype of disease may be telling. Understanding this group of patients could potentially highlight a high-risk group of patients for whom more targeted intervention may be beneficial. Similarly, we found that individuals with a restrictive phenotype tended to have more significant decline in lung function which raises the question of the utility of target treatment such as anti-fibrotic therapy among individuals with this phenotype. Racial differences in pulmonary function have been reported in sarcoidosis with black individuals having significantly worse lung function compared with white individuals.7 12 23 The difference has been attributed to the findings that black individuals have more advanced disease based on imaging compared with white individuals, whereas differences in change in FVC% predicted or FEV1% predicted over time have not been previously observed.23 In contrast to these findings, we found that while black individuals in our cohort not only start with lower pulmonary function across all parameters compared with white individuals, their FVC% predicted and FEV1% predicted rates of decline were higher compared with the white individuals in the cohort. It is likely that methodological differences and population differences contributed to these contrasting observations. For example, the previous study investigating this racial difference evaluated lung function over 10 years with less than 10% of the cohort following for 10 years, which may have resulted in selection bias in the longitudinal findings. Our cohort represents data for individuals over a 3-year time period so that differences in time frame between these two studies could also impact the results. We postulate that there may be several potential reasons or a combination of reasons for the racial differences in rates of lung function decline in our study. The observed racial differences seen in our study may stem from disproportionate burden related to social determinants of health experienced by minoritised populations that have been identified as contributors to health disparities more broadly. Environmental exposures are a possible determinant to explain our findings as there are significant racial differences in air pollution exposures in the USA. Black individuals are exposed to significantly higher particulate matter 2.5 and nitrogen dioxide when compared with non-Hispanic white individuals, and these disparities in exposure tend to remain across income levels.24 25 Air pollution has been shown to affect lung development over time.26 27 Our finding that black individuals in our cohort had lower lung function on entry into the cohort may partially reflect exposures over time, as well as possible delay in diagnosis and/or treatment due to presenting later in disease course. Air pollution exposure has been associated with lower lung function in children and adults in cohort studies of the general population and individuals with asthma and chronic obstructive pulmonary disease.26–30 While much research has been focused on possible environmental triggers in sarcoidosis, little is known about environmental exposures over time and how these exposures may affect the course of lung function. Another possibility explaining our findings of racial differences in lung function is that there may be differences in medication adherence and treatment effectiveness. Medical treatment was evaluated as a categorical variable (treatment yes/no) and this study was not designed to qualitatively evaluate the effectiveness of medical treatment with regard to the time, dose to type of treatment agent(s). Previous research has shown racial differences in medication adherence in sarcoidosis.31 While 65% of the cohort was prescribed treatment for sarcoidosis, we did not have medication adherence information about the cohort. More work is needed to understand the role of medication adherence and disease outcomes in sarcoidosis. Finally, we found a racial difference in chest imaging with black individuals having more fibrocystic disease compared with white individuals. One hypothesis for our findings could be reduced access to care for black individuals compared with white individuals may result in delayed diagnosis and delayed treatment leading to more advanced, irreversible lung fibrosis in pulmonary sarcoidosis. We did not find significant sex differences in change in pulmonary function over time despite our previous finding of sex differences at baseline.7 The present study included a small sample size, which may be why no differences were seen. Alternatively, the differences at baseline may suggest that access to care between the sexes may differ, but once within care the pulmonary function changes are similar. Similar findings were seen in a recent cardiac sarcoidosis cohort that reported females having more symptoms at presentations, but similar long-term outcomes.32 Given the higher percentages of black compared with white females in our cohort, we investigated if our findings of race differences were secondary to sex differences and found no interaction between race and sex. There are several important strengths of this study. First, we report a large longitudinal study in sarcoidosis. Second, our study is made up of a diverse population of individuals with sarcoidosis. Third, our cohort includes the prospective collection of data elements with a high proportion with complete demographic data, lung function data and imaging data. There are limitations to the present investigation. First, given the retrospective nature of our analyses, we were unable to assess patient-reported outcomes or patient-level measures such as socioeconomic status or education, which could have led to unmeasured confounding which could result in bias impacting effect sizes. We were also unable to assess the disease duration in our cohort as we only had access to the date of diagnosis. There are reported delays in diagnosis for patients with sarcoidosis and the delays were associated with worse lung function.33 Additionally, the study population is a clinical cohort from a tertiary, urban referral centre in the USA and results may not be generalisable to other subgroups of patients with sarcoidosis found in different geographical and ethnic populations. Our study was also limited in the ability to identify imaging phenotypes and the association with outcomes. Future prospective studies will be needed to determine whether identifying subsets of pulmonary function phenotypes in sarcoidosis can lead to progress in disease understanding and improve clinical outcomes by assisting the process of monitoring and treating our patients. Conclusion Within a prevalence cohort of individuals with sarcoidosis from a tertiary referral centre, individuals with the restrictive phenotype had greater reduction of FEV1% predicted and FVC% predicted compared with normal. We identified a subset of individuals in the cohort, highest decliners, who had significant 3-year decline in lung function. Black individuals had worse lung function at entry into the cohort compared with white individuals, and black individuals’ lung function remained stable or declined over time, while white individuals’ lung function improved over time. Longitudinal prospective studies are necessary to further explore pulmonary function phenotypes of sarcoidosis and the determinants of racial differences in pulmonary function over time in sarcoidosis. Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information. Ethics statements Patient consent for publication Not applicable. Ethics approval This study involves human participants but the Johns Hopkins University Institutional Review Board (IRB00195158) exempted this study, as this was a retrospective study. Contributors MS had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and is the guarantor of the manuscript. MS, KJP, AMM, ESC, NWL, SCM, NAG, MNE, RAW, DRM and MCM contributed substantially to the study design, data analysis and interpretation, and/or the writing of the manuscript. Funding Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers T32HL007534, K23HL163313 and K23HL148527. Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Competing interests Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health to support AMM, NWL and MS, respectively. MS has been a co-investigator on grants with aTyr Pharma, Kinevant and Novartis without support. ESC has received grant support from aTyr Pharma, Kinevant and Novartis that does not pertain to the current manuscript. NAG has consulted for Kiniksa Pharmaceutical. SCM has consulted for Janssen, United Therapeutics and Merck. RAW has received grant funding from Sanofi, Chiesi and AstraZeneca, and has consulted for Galderma, AbbVie, AstraZeneca, Boehringer-Ingelheim, Contrafect, Savara, Kamada, Bristol Myers Squibb, Pulmonx, Scene Healthcare, Beyond Air and Puretech. DRM receives royalties from Taylor & Francis Group and is chairman and chief technical officer for Sarcoidosis Diagnostic Testing. MCM has received royalties from UpToDate for authorship and editorial work and has consulting relationships with Aridis, GlaxoSmithKline, NDD Medical Technologies, MCG Diagnostics and Boehringer Ingelheim. Provenance and peer review Not commissioned; externally peer reviewed. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. 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J Bras Pneumol 2013; 39: 539–46. doi:10.1590/S1806-37132013000500003 All White Black P value N=291 N=135 N=156 Age in years, median (IQR) 51 (44–58) 52 (44–59) 50 (44–57) 0.3338 Female sex, n (%) 173 (59) 60 (44) 113 (72) <0.0001 Organ involvement, n (%) 1 organ 113 (39) 66 (49) 47 (30) 2–4 organs 167 (57) 66 (49) 101 (65) 0.003 >5 organs 11(4) 3 (2) 8 (5) Diagnosis duration in years, median (IQR) 4 (1–12) 2 (0–7) 7 (1–18) <0.0001 Charlson Comorbidity Index, median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.5846 Pulmonary function phenotype, n (%) Normal 122 (42) 87 (64) 35 (22) Restrictive 76 (26) 8 (6) 68 (44) Obstructive 35 (12) 26 (19) 9 (6) <0.0001 Combination restrictive obstructive 33 (11) 9 (7) 24 (15) Isolated reduction in DLCO 25 (9) 5 (4) 21 (13) Ever prescribed treatment for sarcoidosis*, n (%) 189 (65) 78 (58) 111 (71) 0.017 Tobacco use, n (%) Never 170 (58) 89 (66) 81 (52) Former 96 (33) 41 (30) 55 (35) 0.006 Current 25 (9) 5 (4) 20 (13) Days in cohort, median (IQR) 790 (406–965) 749 (350–958) 805 (502–977) 0.2443 Number of PFTs during follow-up, median (IQR) 3 (2–4) 3 (2–4) 3 (2–4) 0.2112 FVC% predicted* FEV1% predicted* DLCO% predicted* Overall 1.53 (0.07 to 2.99) 1.42 (−0.10 to 2.93) −0.88 (−2.77 to 1.02) Pulmonary function phenotypes Normal (n=122) Ref Ref Ref Restrictive (n=76) −3.88 (−7.38 to −0.38) −4.17 (−7.85 to −0.49) −4.31 (−9.01 to 0.39) Obstructive (n=35) 2.09 (−1.92 to 6.10) 0.72 (−3.50 to 4.94) −0.72 (−6.12 to 4.68) Combined (n=33) −2.13 (−6.51 to 2.26) −3.09 (−7.70 to 1.53) −1.31 (−7.22 to 4.61) Isolated reduction in DLCO (n=25) −2.14 (−7.03 to 2.74) −4.61 (−9.76 to 0.54) −0.42 (−7.06 to 6.23) FVC% predicted* FEV1% predicted* DLCO% predicted* Overall 2.04 (0.29 to 3.80) 2.06 (0.27 to 3.86) −0.37 (−2.46 to 1.72) Pulmonary function phenotypes Normal (n=98) Ref Ref Ref Restrictive (n=54) −3.19 (−7.50 to 1.13) −4.51 (−8.97 to −0.05) −5.05 (−10.41 to 0.30) Obstructive (n=27) 1.09 (−3.62 to 5.79) −0.34 (−4.90 to 4.83) −2.06 (−7.90 to 3.77) Combined (n=21) −2.42 (−8.15 to 3.30) −4.34 (−10.26 to 1.59) 0.37 (−6.77 to 7.51) Isolated reduction in DLCO (n=20) −2.21 (−8.34 to 3.93) −5.52 (−11.91 to 0.87) −1.40 (−9.31 to 6.51)
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