Rationale: Postbronchodilator spirometry is used for the diagnosis of chronic obstructive pulmonary disease. However, prebronchodilator reference values are used for spirometry interpretation. Objectives: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using preor postbronchodilator reference values generated within SCAPIS (Swedish CArdioPulmonary bioImage Study) when interpreting postbronchodilator spirometry in a general population. Methods: SCAPIS reference values for postbronchodilator and prebronchodilator spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or postbronchodilator reference values, with respiratory burden in the SCAPIS general population (28,851 individuals). Measurements and Main Results: Bronchodilation resulted in higher predicted medians and lower limits of normal (LLNs) for FEV1/FVC ratios. The prevalence of postbronchodilator FEV1/FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV1/FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV1/FVC ratio, and this group hadmore respiratory symptoms, emphysema (13.5% vs. 4.1%; P < 0.001), and self-reported physician-diagnosed chronic obstructive pulmonary disease (2.8% vs. 0.5%, P < 0.001) than subjects with a postbronchodilator FEV1/FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV1/FVC ratio. Use of postbronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using postbronchodilator reference values when interpreting postbronchodilator spirometry might enable the identification of individuals with mild disease and be clinically relevant.

Early identification of subjects running an increased risk of contracting COPD enables focus on individual preventive measures. The slope of the alveolar plateau of the single-breath nitrogen washout test (N 2 -slope) is a sensitive measure of small-airway dysfunction. However, its role remains unexplored in predicting hospital admission or death related to COPD, i.e. incident COPD events, in relation to the presence of various respiratory symptoms. A random population sample of 625 men, aged 50 (n=218) or 60 years (n=407), was followed for 38 years for incident COPD events. At baseline, a questionnaire on respiratory symptoms and smoking habits was collected, spirometry and the single-breath nitrogen test were performed, and the N 2 -slope was determined. Proportional hazard regression (Cox regression) analysis was used for the prediction model. The N 2 -slope improved the prediction of COPD events significantly beyond that of respiratory symptoms weighted all together and other covariates (hazard ratio 1.63, 95% CI 1.20–2.22; p<0.005), a prediction applicable to subjects without (p=0.001) and with (p<0.05) airway obstruction. Dyspnoea and wheezing were the most predictive symptoms. The combination of the N 2 -slope and number of respiratory symptoms notably resulted in an effective prediction of incident COPD events even in nonobstructive subjects, as evidenced by a predicted incidence of ∼70% and ∼90% for a very steep N 2 -slope combined with many respiratory symptoms in subject without and with airway obstruction, respectively. The alveolar N 2 -slope should be considered in the critical need for further research on early diagnosis of COPD.

Exhaled droplets are composed of water, salts and organic material and the physical designation is particles. These particles vary in size from 0.01 µm to very large, e g produced during coughing. The respiratory tract lining fluid (RTLF) is the main source of the particles. Large and small exhaled particles are produced in central airways, vocal cords and mouth whereas small particles (< about 5 µm) are produced also in small airways, generated during inspiration by the airway closure/opening mechanism. These particles are composed mainly of surfactant. Exhaled small particles may carry virus and cause airborne transmission and infection, which may be an important transmission route indoors. Ventilation, concentration of people, activities and face mask occurrence influence the risk of infection. Outdoor transmission is in addition influenced by outdoor pollution and wind speed.

IntroductionRespiratory tract lining fluid of small airways mainly consists of surfactant that can be investigated by collection of the particles of exhaled aerosol (PExA) method. This offers an exciting prospect to monitor small airway pathology, including subjects with asthma and smokers.AimTo explore the influence of anthropometric factors and gender on phospholipids, surfactant protein A (SP-A) and albumin of the lining fluid of small airwaysand to examine the association with asthma and smoking. Furthermore, to examine if the surfactant components can predict lung function in terms of spirometry variables.MethodThis study employs the population-based cohort of the European Community Respiratory Health Survey III, including participants from Gothenburg city, Sweden (n=200). The PExA method enabled quantitative description and analytical analysis of phospholipids, SP-A and albumin of the lining fluid of small airways.ResultsAge was a significant predictor of the phospholipids. The components PC14:0/16:0, PC16:0/18:2 (PC, phosphatidylcholine) and SP-A were higher among subjects with asthma, whereas albumin was lower. Among smokers, there were higher levels particularly of di-palmitoyl-di-phosphatidyl-choline compared with non-smokers. Most phospholipids significantly predicted the spirometry variables.ConclusionThis non-invasive PExA method appears to have great potential to explore the role of lipids and proteins of surfactant in respiratory disease.

Small airways are difficult to access. Exhaled droplets, also referred to as particles, provide a sample of small airway lining fluid and may reflect inflammatory responses. We aimed to explore the effect of smoking on the composition and number of exhaled particles in a smoker-enriched study population. We collected and chemically analyzed exhaled particles from 102 subjects (29 never smokers, 36 former smokers and 37 current smokers) aged 39 to 83 years (median 63). A breathing maneuver maximized the number exhaled particles, which were quantified with a particle counter. The contents of surfactant protein A and albumin in exhaled particles was quantified with immunoassays and the contents of the phospholipids dipalmitoyl- and palmitoyl-oleoyl- phosphatidylcholine with mass spectrometry. Subjects also performed spirometry and nitrogen single breath washout. Associations between smoking status and the distribution of contents in exhaled particles and particle number concentration were tested with quantile regression, after adjusting for potential confounders. Current smokers, compared to never smokers, had higher number exhaled particles and more surfactant protein A in the particles. The magnitude of the effects of current smoking varied along the distribution of each PEx-variable. Among subjects with normal lung function, phospholipid levels were elevated in current smokers, in comparison to no effect of smoking on these lipids at abnormal lung function. Smoking increased exhaled number of particles and the contents of lipids and surfactant protein A in the particles. These findings might reflect early inflammatory responses to smoking in small airway lining fluid, also when lung function is within normal limits.

The Global Lung Function Initiative (GLI) has recently published international reference values for diffusing capacity of the lung for carbon monoxide (DLCO). Lower limit of normal (LLN), i.e. the 5th percentile, usually defines impaired D-LCO. We examined if the GLI LLN for D-LCO differs from the LLN in a Swedish population of healthy, never-smoking individuals and how any such differences affect identification of subjects with respiratory burden. Spirometry, D-LCO, chest high-resolution computed tomography (HRCT) and questionnaires were obtained from the first 15 040 participants, aged 50-64 years, of the Swedish CArdioPulmonary bioImage Study (SCAPIS). Both GLI reference values and the lambda-mu-sigma (LMS) method were used to define the LLN in asymptomatic never-smokers without respiratory disease (n=4903, of which 2329 were women). Both the median and LLN for D-LCO from SCAPIS were above the median and LLN from the GLI (p<0.05). The prevalence of D-LCO GLI LLN but GLI LLN but GLI LLN and >SCAPIS LLN). No differences were found with regard to physician-diagnosed asthma. The GLI LLN for D-LCO is lower than the estimated LLN in healthy, never-smoking, middle-aged Swedish adults. Individuals with D-LCO above the GLI LLN but below the SCAPIS LLN had, to a larger extent, an increased respiratory burden. This suggests clinical implications for choosing an adequate LLN for studied populations.

INTRODUCTION:Particles in exhaled air (PEx) provide samples of respiratory tract lining fluid from small airways containing, for example, Surfactant protein A (SP-A) and albumin, potential biomarkers of small airway disease. We hypothesized that there are differences between morning, noon, and afternoon measurements and that the variability of repeated measurements is larger between days than within days. METHODS:PEx was obtained in sixteen healthy non-smoking adults on 11 occasions, within one day and between days. SP-A and albumin were quantified by ELISA. The coefficient of repeatability (CR), intraclass correlation coefficient (ICC), and coefficient of variation (CV) were used to assess the variation of repeated measurements. RESULTS:SP-A and albumin increased significantly from morning towards the noon and afternoon by 13% and 25% on average, respectively, whereas PEx number concentration and particle mean mass did not differ significantly between the morning, noon and afternoon. Between-day CRs were not larger than within-day CRs. CONCLUSIONS:Time of the day influences the contents of SP-A and albumin in exhaled particles. The variation of repeated measurements was rather high but was not influenced by the time intervals between measurements.

Background There is low diagnostic accuracy of the proxy restrictive spirometric pattern (RSP) to identify true pulmonary restriction. This knowledge is based on patients referred for spirometry and total lung volume determination by plethysmograpy, single breath nitrogen washout technique or gas dilution and selected controls. There is, however, a lack of data from general populations analyzing whether RSP is a valid proxy for true pulmonary restriction. We have validated RSP in relation to true pulmonary restriction in a general population where we have access to measurements of total lung capacity (TLC) and spirometry. Methods The data was from the Swedish CArdioPulmonary bioImage Study (SCAPIS Pilot), a general population-based study, comprising 983 adults aged 50–64. All subjects answered a respiratory questionnaire. Forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were obtained before and after bronchodilation. TLC and residual volume (RV) was recorded using a body plethysmograph. All lung function values are generally expressed as percent predicted (% predicted) or in relation to lower limits of normal (LLN). True pulmonary restriction was defined as TLC < LLN 5 defined as a Z score < − 1.645, i e the fifth percentile. RSP was defined as FEV 1 /FVC ≥ LLN and FVC < LLN after bronchodilation. Specificity, sensitivity, positive and negative likelihood ratios were calculated, and 95% confidence intervals (CIs) were calculated. Results The prevalence of true pulmonary restriction was 5.4%, and the prevalence of RSP was 3.4%. The sensitivity of RSP to identify true pulmonary restriction was 0.34 (0.20–0.46), the corresponding specificity was 0.98 (0.97–0.99), and the positive likelihood ratio was 21.1 (11.3–39.4) and the negative likelihood ratio was 0.67 (0.55–0.81). Conclusions RSP has low accuracy for identifying true pulmonary restriction. The results support previous observations that RSP is useful for ruling out true pulmonary restriction.

To identify pathological changes in the composition of the lining fluid of small airways, it is important to know what factors that may influence it, also in healthy individuals. The aim of the present study was to 1) identify determinants of Albumin, Surfactant Protein A (SP-A) and the profile of phospholipids in PEx in healthy subjects, and 2) to explore if the composition is altered in asthma and smokers in a small number of subjects. Methods: 166 non-smoking healthy individuals, 17 current smokers and 16 subject reporting asthma-symptoms within the last year, from the European Community Respiratory Health Survey III, was examined with the PExA® method, i.e. sampling of droplets of lining fluid from small airways in breath. PEx samples were analyzed with ELISA (Albumin and SP-A) and the di-palmitoyl-phosphatidylcholine (DPPC), palmitoyl-oleoyl-glycero-phosphocholine (POPC), PC14:0/16:0 and PC16:0/18:2 with LC-MS-MS. Concentrations of all biomarkers in PEx are expressed as weight percent (wt%). statistical analysis: Spearmann correlations and quantile regression were used. Results: Increasing age was associated with an increase in albumin (rs =0.23, p=0.001). The levels of DPPC and POPC in PEx were decreasing with age (rs=-0.35, p=0.006 and rs =-0.28, p=0.008, respectively, and not in women. In asthma, albumin was significantly lower in PEx than in healthy subjects. In females with asthma, PC14:0/16:0 was also lower and PC16:0/18:2 higher, but not in men. The levels of SP-A were not different from that in healthy subjects. Smokers had higher levels of DPPC, POPC as well as SP-A, but lower levels of albumin in PEx. Conclusion: Age and gender, but also smoking and asthma, seem to significantly influence surfactant composition.

Surfactant protein A (SP-A) is considered a potential biomarker of small airway inflammation. In the present study we aimed to assess within- and between-day variation of SP-A and albumin in exhaled particles (PEx) and define the expected maximal normal variation in healthy individuals. 16 healthy non-smoking subjects were examined with PExA®, in the morning, noon and afternoon during three non-consecutive days. SP-A and albumin were quantified by ELISA and expressed as weight % in PEx (wt%). The differences on the same time points between different days were assessed and the coefficient of repeatability (CR) and 95% CI of limits of agreement (LoA) was calculated. Diurnal variation was tested with repeated two-way ANOVA. The variation of SP-A between days was low and non-significant (p = 0.75), whereas albumin in PEx varied more (p < 0.01). SP-A and albumin had the lowest values during morning and increased towards the noon (p < 0.05): 12 % variation in SP-A, and 24% in albumin (Figure). The mean difference (95 % CI of LoA) was 0.07 ± 2.06 for SP-A and 0.32 ± 2.57 for albumin. CR for SP-A and albumin were 2.1 (wt%) and 2.6 (wt%), respectively. Our findings show that there is a rather small diurnal variation of SP-A in PEx. We also describe the maximal normal variation of these biomarkers over time, which may be of importance in clinical settings, when assessing the effect of exposure challenge and medical intervention.

Introduction: We recently suggested a novel model for prediction of reference FeNO values, by applying the Lambda-Mu-Sigma (LMS) regression models, that may help interpreting FeNO in clinical practice. Aim: To describe the effect of smoking and atopy in two large groups of healthy individuals with the LMS models, and to evaluate the consistency of the results in the two samples. Methods: Caucasian healthy subjects (age 24-75 years) from US NHANES and a Swedish cohort were analysed. Smoking was defined as non-smokers (including former smokers) and current smokers. Atopy was defined by a positive Phadiatop in the Swedish data, and self-reported hay fever symptoms in the past 12 months in the US data. Models were created with the LMS method, imbedded in the Generalized Additive Models for Location, Scale, and Shape (GAMLSS) models, for each sex and corrected for age and height. Results: A total of 6,723 subjects were included, 2,157 from NHANES and 4,566 from Sweden. In NHANES there were 15.5% current smokers, and 15.6% atopics. Current smoking decreased FeNO by 62.5% and 55.1%, whereas atopy increased FeNO by 15.8% and 8.5%, in males and females, respectively. In the Swedish cohort, there were 15.2% current smokers, and 23.2% atopics. The results were similar: current smoking decreased FeNO by 41.8% and 35.0%, whereas atopy increased FeNO by 20.1% and 8.5%, in males and females, respectively. Conclusion: We show consistent effects of active smoking and atopy in large samples of healthy individuals from the US and Europe. These effects seem to be constant and should be accounted for in the interpretation of FeNO in clinical practice.

The particles in exhaled breath provide a promising matrix for the monitoring of pathological processes in the airways, and also allow exposure to exogenous compounds to be to assessed. The collection is easy to perform and is non-invasive. The aim of the present study is to assess if an exogenous compound-methadone-is distributed in the lining fluid of small airways, and to compare two methods for collecting methadone in particles in exhaled breath. Exhaled particles were collected from 13 subjects receiving methadone maintenance treatment. Two different sampling methods were applied: one based on electret filtration, potentially collecting exhaled particles of all sizes, and one based on impaction, collecting particles in the size range of 0.5-7 μm, known to reflect the respiratory tract lining fluid from the small airways. The collected samples were analyzed by liquid chromatography mass spectrometry, and the impact of different breathing patterns was also investigated. The potential contribution from the oral cavity was investigated by rinsing the mouth with a codeine solution, followed by codeine analysis of the collected exhaled particles by both sampling methods. The results showed that methadone was present in all samples using both methods, but when using the method based on impaction, the concentration of methadone in exhaled breath was less than 1% of the concentration collected by the method based on filtration. Optimizing the breathing pattern to retrieve particles from small airways did not increase the amount of exhaled methadone collected by the filtration method. The contamination from codeine present in the oral cavity was only detected in samples collected by the impaction method. We conclude that methadone is distributed in the respiratory tract lining fluid of small airways. The samples collected by the filtration method most likely contained a contribution from the upper airways/oral fluid in contrast to the impaction method.

Background Breathlessness is associated with major adverse health outcomes and is twice as common in women as men in the general population. We evaluated whether this is related to their lower absolute lung volumes. Methods Cross-sectional analysis of the population-based Swedish CardioPulmonarybioImage Study (SCAPIS) Pilot, including static spirometry and diffusing capacity (n = 1,013; 49% women). Breathlessness was measured using the modified Medical Research Council (mMRC) scale and analyzed using ordinal logistic regression adjusting for age, pack-years of smoking, body mass index, chronic airway limitation, asthma, chronic bronchitis, depression and anxiety in all models. Results Breathlessness was twice as common in women as in men; adjusted odds ratio (OR) 2.20 (95% confidence interval, 1.32−3.66). Lower absolute lung volumes were associated with increased breathlessness prevalence in both men and women. The sex difference in breathlessness was unchanged when adjusting for lung function in %predicted, but disappeared when controlling for absolute values of total lung capacity (OR 1.12; 0.59−2.15), inspiratory capacity (OR 1.26; 0.68−2.35), forced vital capacity (OR 0.84; 0.42−1.66), forced expiratory volume in one second (OR 0.70; 0.36−1.35) or lung diffusing capacity (OR 1.07; 0.58−1.97). Conclusion In the general population, the markedly higher prevalence of breathlessness in women is related to their smaller absolute lung volumes.

Chronic obstructive pulmonary disease (COPD) develops in small airways. Severity of small airway pathology relates to progression and mortality. The present study evaluated the prediction of COPD of a validated test for small airway disease, i.e. a slope of the alveolar plateau of the single breath nitrogen test (N-2-slope). The N-2-slope, spirometry, age, smoking habits, and anthropometric variables at baseline were obtained in a population-based sample (n = 592). The cohort was followed for first COPD events (first hospital admission of COPD or related conditions or death from COPD) during 38 years. During follow-up, 52 subjects (8.8%) had a first COPD event, of which 18 (3.0%) died with a first COPD diagnosis. In the proportional hazard regression analysis adjusted for age and smoking habits, the cumulative COPD event incidence increased from 5% among those with high forced expired volume in one second (FEV1) to 25% among those with low FEV1, while increasing from 4% among those with the lowest N-2-slope to 26% among those with the highest. However, combining the N-2-slope and FEV1 resulted in considerable synergy in the prediction of first COPD event and even more so when taking account of smoking habits. The cumulative COPD event incidence rate was 75% among heavy smokers with the highest N-2-slope and lowest FEV1, and less than 1% among never smokers with the lowest N-2-slope and highest FEV1. Thus, combining the results of the single breath N-2-slope and FEV1 considerably improved the prediction of COPD events as compared to either test alone.

Exhaled particles constitute a micro-sample of respiratory tract lining fluid. Inhalations from low lung volumes generate particles in small airways by the airway re-opening mechanism. Forced exhalations are assumed to generate particles in central airways by mechanisms associated with high air velocities. To increase knowledge on how and where particles are formed, different breathing manoeuvres were compared in 11 healthy volunteers. Particles in the 0.41-4.55 mu m diameter range were characterised and sampled. The surfactant lipid dipalmitoylphosphatidylcholine (DPPC) was quantified by mass spectrometry.The mass of exhaled particles increased by 150% (95% CI 10-470) for the forced exhalation and by 470% (95% CI 150-1190) for the airway re-opening manoeuvre, compared to slow exhalations. DPPC weight percent concentration (wt%) in particles was 2.8 wt% (95%CI 1.4-4.2) and 9.4 wt% (95%CI 8.0-10.8) for the forced and the airway re-opening manoeuvres, respectively.In conclusion, forced exhalation and airway re-opening manoeuvres generate particles from different airway regions having different DPPC concentration.

BACKGROUNDParticles in exhaled air (PEx) provide samples of respiratory tract lining fluid from small airways and offer a new opportunity to monitor pathological changes. The exhaled particles are produced by reopening of closed small airways and contain surfactant. The amount of PEx varies by orders of magnitude among subjects. A standardized breathing pattern reduces the variation, but it remains large and the reasons are unknown. The aim of the present study was to assess to what extent sex, age, body size, and spirometry results explain the interindividual variation of PEx among healthy middle-aged subjects.METHODSThe PExA® instrument was used to measure PEx in 126 healthy middle-aged nonsmoking subjects participating in the European Respiratory Community Health Survey (ERCS-III). The subjects performed a standardized breathing maneuver involving expiration to residual volume, a breath-hold of 3 seconds, a full inspiration, and then a full expiration into the PExA instrument. PEx number concentrations were expressed per exhalation and per exhaled liter. Age and anthropometric and spirometric variables were analyzed as potential predictors.RESULTSPEx/L was consistently and negatively associated to lung size-related variables and accordingly lower in men than in women. PEx/Exhalation was similar in women and men. Increasing age was associated with increasing PEx. Reference equations are presented based on age, weight, and spirometry variables and independent of sex. These predictors explained 28%-29% of the interindividual variation.CONCLUSIONSThe interindividual variation of PEx after a standardized breathing maneuver is large and the considered predictors explain a minor part only.

Fractional exhaled nitric oxide (FENO) is used to assess of airway inflammation; diagnose asthma and monitor adherence to advised therapy. Reliable and accurate reference values for FENO are needed for both non-smoking and current smoking adults in the clinical setting. The present study was performed to establish reference adult FENO values among never-smokers, former smokers and current smokers.

Rationale: Breathlessness is twice as common in women as men in the general population for unknown reasons. We tested the hypothesis that the higher prevalence of breathlessness in women is due to their lower absolute lung volumes. Methods: Cross-sectional analysis of the population-based Swedish CardioPulmonarybioImage Study (SCAPIS) Pilot, with data from questionnaire and on dynamic and static spirometry and diffusing capacity (n=1,013). Sex difference in breathlessness, measured using the modified Medical Research Council (mMRC) scale, was analyzed using ordinal logistic regression adjusting for age, pack-years of smoking, body mass index, chronic airway limitation, asthma, chronic bronchitis, depression and anxiety in all models. Results: Breathlessness (mMRC ≥ 1) was twice as common in women (12.0%) as in men (6.4%); adjusted odds ratio (OR) 2.20 (95% confidence interval 1.32 to 3.66). Lower absolute lung function was associated with higher rates of breathlessness overall and in men and women separately. The sex difference was unchanged when adjusting for lung function in %predicted in multivariable analysis, but became non-significant when controlling for absolute values of total lung capacity (OR 1.12; 0.59 to 2.15), inspiratory capacity (OR 1.26; 0.68 to 2.35), forced vital capacity (OR 0.84; 0.42 to 1.66), forced expiratory volume in one second (OR 0.70; 0.36 to 1.35) or lung diffusing capacity (OR 1.07; 0.58 to 1.97). Conclusions: In the general population, the markedly higher prevalence of breathlessness in women is explained by their smaller absolute lung volumes. People with smaller lungs may be at increased risk of developing more severe breathlessness.

Exhaled particles are produced by reopening of closed small airways and contain surfactant. However, the amount of exhaled particles varies by orders of magnitude between subjects. A standardized breathing pattern reduces the variation but it remains large and the reasons are unknown. The aim of the present study has been to assess to what extent sex, age, body size and spirometry results explain the inter-individual variation of exhaled particles of healthy subjects performing a standardized breathing maneuver. Methods: The PExA instrument was used to measure exhaled particles (PEx) in 126 healthy subjects of the European Respiratory Community survey (ERCHS-III). Subjects performed a standardized breathing maneuver involving expiration to residual volume, breath holding for three seconds prior to the measurement in order to maximize the amount of PEx. PEx number concentrations were expressed per exhaled liter. The distribution of PEx was skewed and were thus log transformed as InPEx. Multiple linear regression was used for futher analyses. Results: LnPEx was increased by age (4%/year) and decreased with 1% by weight in kg. Those with increased bronchial tone also had lower number of PEx (-5% per % ΔFEV1). At best 28 percent of the variation was explained. Conclusions: The inter-individual variation of exhaled particles among middle aged healthy subjects performing a standardized breathing maneuver is large and a minor part of the variation is explained by age, weight and spirometry variables. Number of exhaled particles increase with age, probably due to increasing airway closure.

A spirometric reference equation consists of a mathematical model with constants and coefficients optimized to fit a specific data set from healthy individuals. Commonly applied models are selected on statistical rather than physiological considerations. A predetermined model with constants and coefficients optimized to various populations would enable interpretable and interesting comparisons between populations. Lubinski and Golczewski recently presented a piecewise linear model with constants and coefficients claimed to be physiologically interpretable (Lubinski model). Three questions were addressed: Is the Lubinski model as useful clinically as other models: multiple linear, piecewise polynomial and exponential with splines? Will reference equations based on the Lubinski model and optimized to a Swedish and to a Polish population allow for interpretable comparisons? Are three well-known reference equations clinically useful in the Swedish adult population? A recent Swedish random population sample with high-quality spirometric measurements enabled the present analyses. When optimized to fit the Swedish population sample, the Lubinski model and two other models provided accurate predictive normal values. Interesting differences were demonstrated between the Polish and Swedish populations. The proportion of subjects below lower limit normal was adequate for the piecewise polynomial equations but too low and not clinically useful for the advocated exponential equations with splines. It is concluded that the Lubinski model is clinically as useful as other models, and it adds important value and is recommended for future spirometric reference equations for adults. The advocated exponential equations with splines are not recommended for Swedish adults because of too wide normal limits.