Reference equations for exhaled nitric oxide-what is needed?

Standardisation is the road to improvement! If we all measure exhaled nitric oxide (NO) the same way, we will be successful in having data to make reference questions. Many research groups have published their reference equation, but most differ considerably. About 25 years ago, using the flow of 50 ml s-1was recommended and not using a nose clip. When collecting data worldwide, we still see publications that do not indicate what flow was used and that nose clip was utilised. Three things are needed: the analysing method, a flow recording and a filled-in nitric oxide questionnaire. The analysing method is because the techniques have different sensitivity, response times and calibration. The flow of 50 ml s-1is on the steep part of the NO output curve; therefore, we need to record the flow to analyse repeated measurements or compare results. The NO questionnaire controls individual factors that may influence the NO measurements, i.e. food intake, smoking and upper airway infection. An important tool in following old and new disease treatments, at home or in health care, is exhaled biomarkers. If we follow the standardisation we have agreed upon, we will be able to have data to say what a high or a low exhaled NO value is.

Exhaled Nitric Oxide Reflects the Immune Reactions of the Airways in Early Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) have altered levels of exhaled nitric oxide (NO) compared with healthy controls. Here, we investigated whether the clinical features of and immunological factors in RA pathogenesis could be linked to the NO lung dynamics in early disease. A total of 44 patients with early RA and anti-citrullinated peptide antibodies (ACPAs), specified as cyclic citrullinated peptide 2 (CCP2), were included. Their exhaled NO levels were measured, and the alveolar concentration, the airway compartment diffusing capacity and the airway wall concentration of NO were estimated using the Högman-Meriläinen algorithm. The disease activity was measured using the Disease Activity Score for 28 joints. Serum samples were analysed for anti-CCP2, rheumatoid factor, free secretory component, secretory component containing ACPAs, antibodies against Porphyromonas gingivalis (Rgp) and total levels of IgA, IgA1 and IgA2. Significant negative correlations were found between the airway wall concentration of NO and the number of swollen joints (Rho -0.48, p = 0.004), between the airway wall concentration of NO and IgA rheumatoid factor (Rho -0.41, p = 0.017), between the alveolar concentration and free secretory component (Rho -0.35, p = 0.023) and between the alveolar concentration and C-reactive protein (Rho -0.36, p = 0.016), but none were found for anti-CCP2, IgM rheumatoid factor or the anti-Rgp levels. In conclusion, altered NO levels, particularly its production in the airway walls, may have a role in the pathogenesis of ACPA-positive RA.

Biomarkers of chronic airflow limitation and COPD identified by mass spectrometry.

Rationale: COPD affects 300 million people worldwide and is the third leading cause of death according to World Health Organization global health estimates. Early symptoms are subtle, and so COPD is often diagnosed at an advanced stage. Thus, there is an unmet need for biomarkers that can identify individuals at early stages of the disease before clinical symptoms have manifested. To date, few biomarkers are available for clinical diagnostic use in COPD. Methods: We evaluated a panel of serum biomarkers related to inflammation and infection for their ability to discriminate between 77 subjects with chronic airflow limitation (CAL) and 142 subjects with COPD, versus 150 healthy subjects (divided into two control groups that were matched with regards to age, gender and smoking to CAL and COPD). Healthy subjects and CAL were from Burden of Obstructive Lung Disease (BOLD), a population-based study. CAL was defined by post-bronchodilatory forced expiratory volume in 1 s/forced vital capacity ratio <0.7 in the BOLD population. COPD subjects were from Tools for Identifying Exacerbations (TIE), a COPD patient cohort. Quantification of 100 biomarker candidates was done by liquid chromatography-tandem mass spectrometry. Results: Several protein-derived peptides were upregulated in CAL, compared to controls; most notably peptides representing histidine-rich glycoprotein (HRG), α1-acid glycoprotein (AGP1), α1-antitrypsin (α1AT) and fibronectin. Out of these, HRG-, AGP1- and α1AT-specific peptides were also elevated in the COPD cohort. Conclusion: HRG, AGP1 and α1AT biomarkers distinguish subjects with CAL and COPD from healthy controls. HRG and AGP1 represent novel findings.

ERS technical standard: Global Lung Function Initiative reference values for exhaled nitric oxide fraction (F ENO50 ).

BACKGROUND: Elevated exhaled nitric oxide fraction at a flow rate of 50 mL·s-1 (F ENO50 ) is an important indicator of T-helper 2-driven airway inflammation and may aid clinicians in the diagnosis and monitoring of asthma. This study aimed to derive Global Lung Function Initiative reference equations and the upper limit of normal for F ENO50 . METHODS: Available individual F ENO50 data were collated and harmonised using consensus-derived variables and definitions. Data collected from individuals who met the harmonised definition of "healthy" were analysed using the generalised additive models of location, scale and shape (GAMLSS) technique. RESULTS: Data were retrospectively collated from 34 782 individuals from 34 sites in 15 countries, of whom 8022 met the definition of healthy (19 sites, 11 countries). Overall, height, age and sex only explained 12% of the between-subject variability of F ENO50 (R2=0.12). F ENO device was neccessary as a predictor of F ENO50 , such that the healthy range of values and the upper limit of normal varied depending on which device was used. The range of F ENO50 values observed in healthy individuals was also very wide, and the heterogeneity was partially explained by the device used. When analysing a subset of data in which F ENO50 was measured using the same device and a stricter definition of health (n=1027), between-site heterogeneity remained. CONCLUSION: Available F ENO50 data collected from different sites using different protocols and devices were too variable to develop a single all-age reference equation. Further standardisation of F ENO devices and measurement are required before population reference values might be derived.

Allergic sensitisation and type-2 inflammation is associated with new-onset and persistent allergic disease.

BACKGROUND: Allergic disease is common. The aim of this study was to look at the change in asthma and rhinitis over time and to characterise factors contributing to remission and persistence of disease. METHODS: This cohort study included 255 individuals with or without asthma and or rhinitis that participated in a population survey and a follow-up 10 years later. The participants were tested for allergic sensitisation, total IgE, multiplex allergen component analysis and type-2 inflammatory markers: exhaled nitric oxide (FE NO), eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN). RESULTS: Of the 132 healthy individuals, 112 remained healthy, 16 developed rhinitis, 4 asthma and rhinitis over the 10 years. Out of 82 subjects with rhinitis, 26 went into remission, 53 remained unchanged and 3 developed asthma in addition to rhinitis. None of the 41 participants with asthma and rhinitis went into remission. Subjects with persistent rhinitis and asthma had higher levels of total IgE (odds ratio [OR] 95% confidence interval [CI]: 6.16 [3.05-12.5]) at baseline and after 10 years, and FE NO and ECP at baseline (OR per log unit increase, 95% CI 5.21 [1.20-22.7] and 6.32 [1.52-26.4], respectively), compared with those that remained healthy. Subjects with persistent rhinitis were more likely to be sensitised to grass pollen and had higher total IgE levels than those that went into remission. Individuals with persistent asthma were more likely to be sensitised to tree pollen and furry animals than those with only persistent rhinitis (OR 95% CI: 3.50 [1.29-9.49] and 6.73 [2.00-22.6], respectively). CONCLUSION: IgE sensitisation and total IgE levels are associated with the persistence of rhinitis and asthma. Participants with persistent allergic disease had higher levels of allergen sensitisation and type 2 inflammation markers at baseline than those who remained healthy.

Burden and risk factors of chronic respiratory diseases in Nepal, 1990-2019: An analysis of the global burden of diseases study.

Background and Aims: Chronic respiratory diseases (CRDs) substantially contribute to morbidity and mortality globally and in Nepal. However, there is a paucity of evidence on the trend and the burden of CRDs in Nepal. This study reports the trend of the burden and contribution of major risk factors to CRDs in Nepal from 1990 to 2019. Methods: This study is an observational study using publicly available data from Global Burden of Disease 2019 estimations for Nepal. The age-standardized and age-specific prevalence, incidence, mortality, disability-adjusted life years (DALYs), and risk factors for CRDs in Nepal were extracted to measure the burden and its trend. The data are presented as percentages or as rates per 100,000 population. Results: The age-standardized incidence rate of CRDs in Nepal in 2019 was 913.6 per 100,000 (95% uncertainty interval [UI]: 828.7-1000.1), which was an increase of 7.7% from 848.6 per 100,000 (95% UI: 780.2-918.2) in 1990. However, the age-standardized prevalence rate [4453/100,000 (4234.2-4671.8) in 1990; 4457.1/100,000 (4255.2-4666.8) in 2019] was almost stagnant. Most CRDs attributed to deaths and DALYs were due to chronic obstructive pulmonary disease. Conclusions: Air pollution and smoking are the main risk factors for DALYs due to CRDs in Nepal. This surging burden of the incidence rate of CRDs in Nepal calls for more effective actions to curb the risk factors and diseases.

Alveolar Nitric Oxide in Chronic Obstructive Pulmonary Disease-A Two-Year Follow-Up.

Chronic obstructive pulmonary disease (COPD) affects the airways and gas exchange areas. Nitric oxide (NO) production from the airways is presented as FENO50 and from the gas exchange areas as alveolar NO (CANO). We aimed to evaluate, over two years, the consistency of the CANO estimations in subjects with COPD. A total of 110 subjects (45 men) who completed the study were included from primary and secondary care settings. CANO was estimated using the two-compartment model. CANO increased slightly during the two-year follow-up (p = 0.01), but FENO50 remained unchanged (p = 0.24). Among the subjects with a low CANO (<1 ppb) at inclusion, only 2% remained at a low level. For those at a high level (>2 ppb), 29% remained so. The modified Medical Research Council dyspnoea scale (mMRC) score increased at least one point in 29% of the subjects, and those subjects also increased in CANO from 0.9 (0.5, 2.1) ppb to 1.8 (1.1, 2.3) ppb, p = 0.015. We conclude that alveolar NO increased slightly over two years, together with a small decline in lung function. The increase in CANO was found especially in those whose levels of dyspnoea increased over time.

MAIT cell counts are associated with the risk of hospitalization in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation associated with chronic inflammation in the airways. Mucosal-associated invariant T (MAIT) cells are unconventional, innate-like T cells highly abundant in mucosal tissues including the lung. We hypothesized that the characteristics of MAIT cells in circulation may be prospectively associated with COPD morbidity. METHODS: COPD subjects (n = 61) from the Tools for Identifying Exacerbations (TIE) study were recruited when in stable condition. At study entry, forced expiratory volume in 1 s (FEV1) was measured and peripheral blood mononuclear cells were cryopreserved for later analysis by flow cytometry. Patients were followed for 3 years to record clinically meaningful outcomes. RESULTS: Patients who required hospitalization at one or more occasions during the 3-year follow-up (n = 21) had lower MAIT cell counts in peripheral blood at study inclusion, compared with patients who did not get hospitalized (p = 0.036). In contrast, hospitalized and never hospitalized patients did not differ in CD8 or CD4 T cell counts (p = 0.482 and p = 0.221, respectively). Moreover, MAIT cells in hospitalized subjects showed a more activated phenotype with higher CD38 expression (p = 0.014), and there was a trend towards higher LAG-3 expression (p = 0.052). Conventional CD4 and CD8 T cells were similar between the groups. Next we performed multi-variable logistic regression analysis with hospitalizations as dependent variable, and FEV1, GOLD 2017 group, and quantity or activation of MAIT and conventional T cells as independent variables. MAIT cell count, CD38 expression on MAIT cells, and LAG-3 expression on both MAIT and CD8 T cells were all independently associated with the risk of hospitalization. CONCLUSIONS: These findings suggest that MAIT cells might reflect a novel, FEV1-independent immunological dimension in the complexity of COPD. The potential implication of MAIT cells in COPD pathogenesis and MAIT cells' prognostic potential deserve further investigation.

Exhaled nitric oxide in early rheumatoid arthritis and effects of methotrexate treatment.

Patients with established rheumatoid arthritis (RA) and disease modifying treatments have lower nitric oxide (NO) levels in the alveolar compartment (CANO) and in the airway wall (CawNO), but also higher diffusion capacities for NO in the airways (DawNO) compared to matched controls. The aim of the present study was to investigate the NO lung dynamics in patients with recent onset RA before and after immune suppression with methotrexate therapy. Patients with early RA and antibodies against anticitrullinated peptides (ACPA) were recruited. Measurement of exhaled NO and inflammatory markers in serum were performed. Clinical disease activity was evaluated with Disease Activity Score for 28 joints. Healthy individuals were used as matched controls. Data are presented as median (lower quartile, upper quartile) values. RA patients (n = 44) had lower exhaled NO (FENO50) 16 (10-24) ppb compared to controls 21 (15, 29) ppb, p = 0.013. In NO-dynamics, CANO was lower in RA patients 1.6 (1.0, 2.2) ppb compared to the control subjects 2.3 (1.3, 3.1) ppb, p = 0.007. CawNO was also lower in the RA patients 55 (24, 106) ppb compared to control subjects 124 (110, 170) ppb, p < 0.001, but DawNO was higher 17 (8, 30) mL/s and 9 (5, 11) mL/s respectively, p < 0.001. Methotrexate treatment for three months reduced disease activity, but did not change the NO dynamics. In conclusion, the altered NO dynamics of the lung in ACPA-positive RA patients are already present in the early stages of the disease before any treatments and do not change after methotrexate therapy suggesting a role in the pathogenesis.

Changes in critical inhaler technique errors in inhaled COPD treatment - A one-year follow-up study in Sweden.

BACKGROUND: Critical inhaler technique errors have been associated with lower treatment efficacy in chronic obstructive pulmonary disease (COPD). We aimed to assess and follow-up critical inhaler technique errors, and to investigate their association with COPD symptoms and exacerbations. METHODS: COPD-diagnosed primary and secondary care outpatients (n = 310) demonstrated inhaler technique with inhaler devices they were currently using. Critical errors in opening, positioning and loading the inhaler device, and exhalation through dry-powder inhalers were assessed and corrected, and the assessment was repeated one year later. COPD Assessment Test, the modified Medical Research Council dyspnoea scale and history of exacerbations were collected at both visits. RESULTS: The proportion of patients making ≥1 critical inhaler technique error was lower at follow-up in the total population (46% vs 37%, p = 0.01) and among patients with unchanged device models (46% vs 35%, p = 0.02), but not among patients with a new inhaler device model (46% vs 41%, p = 0.56). Not positioning the device correctly was the most common critical error at both visits (30% and 22%). Seventy-four percent of the patients had unchanged COPD treatment from baseline to follow-up. Treatment escalation, de-escalation, and switch was observed in 14%, 11%, and 1% of the patients, respectively. No association was found between critical errors and COPD symptoms or exacerbations. CONCLUSIONS: Assessment and correction of inhaler technique was associated with a decrease in critical inhaler technique errors. This effect was most pronounced in patients using the same device models throughout the follow-up period.

Swedish Registered Nurse Anesthetists' Understanding of Difficult Airway Algorithms.

PURPOSE: To explore Swedish registered nurse anesthetists' (RNAs') different ways of understanding difficult airway algorithms. DESIGN: A qualitative study design, using a phenomenographic approach, was chosen to describe variations in RNAs' understanding of difficult airway algorithms. METHODS: Individual interviews were conducted with eighteen RNAs working at three hospitals in Sweden. The data were analyzed using a qualitative method. FINDINGS: Three ways of understanding algorithms were identified: (1) Algorithms constitute a plan not communicated at the clinic; (2) Algorithms constitute a shared plan to improve teamwork; (3) Algorithms constitute a plan for how to think and work systematically. CONCLUSIONS: According to the RNAs, airway management algorithms should be discussed more openly at the workplace. RNAs expressed their desire to have a shared algorithm and to use it as a tool during team simulations. Airway algorithms were seen as constituting a plan for how to think and work systematically to improve patient safety.

Community-based management of chronic obstructive pulmonary disease in Nepal-Designing and implementing a training program for Female Community Health Volunteers.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in Nepal. Female community health volunteers (FCHVs) have proven effective in the delivery of reproductive, maternal, and child health services in Nepal and recently in the prevention and management of hypertension and type 2 diabetes. Evidence on their roles in COPD management is not yet available. The aim of this study was to develop, implement, and evaluate a training program for FCHVs regarding COPD prevention and management. The training program was part of a cluster-randomized trial of a 12-month intervention to improve COPD outcomes in a semi-urban area of Western Nepal. A six-day workshop consisting of thirty hours of training was developed for FCHVs. Training materials incorporated introduction to COPD, risk factors and symptoms, COPD status assessment guide for FCHVs, guidance on breathing techniques, and exercises for people living with COPD. Pre- and post-test questionnaires were administered to assess the change in knowledge of FCHVs, post training skills assessment followed by semi-structured interviews assessed FCHVs' satisfaction with the training program. The findings of the pre- and post- test assessments showed a significant improvement in FCHVs' COPD-related knowledge from a median (interquartile range) score of 12 (3-16) before to 21 (21-22) (p<0.001) after the training program. The qualitative assessment revealed the feasibility of FCHVs' training on COPD and their acceptability to deliver the intervention package within the community. It also indicated that implementing future training with an extended period and a few days break in-between could enhance the effectiveness. Training of FCHVs in COPD management is feasible and leads to improvement in knowledge. The motivation shown by FCHVs to deliver the intervention could inform and guide community programs and policies for COPD prevention and management in Nepal and similar settings.

Alveolar Nitric Oxide and Peripheral Oxygen Saturation in Frequent Exacerbators with Asthma: A Pilot Study.

INTRODUCTION: Asthmatics can experience recurrent exacerbations (AEs), irrespectively of asthma severity. Airway inflammatory monitoring could be fundamental to optimize the asthma management. The present study evaluated whether exhaled NO concentrations in proximal and distal respiratory compartments are different in AE-prone patients in combination with T2 blood biomarkers and resting oxygen saturation (SpO2). METHODS: In this observational cross-sectional study, 91 mild-to-severe asthmatics were enrolled. Clinical characteristics, blood and lung function parameters including SpO2, and FENO were evaluated. On 50 randomly selected patients, CANO and JawNO were also analyzed. Then, patients were stratified in frequent exacerbators (FEs) or non-frequent exacerbators (nFEs), according to AE frequency in the previous year (phase I). Chart data were re-evaluated through a 12-month follow-up period post exhaled NO measurement to detect occurrence of novel AE (phase II). RESULTS: FE asthmatics had poorer asthma control and required higher therapeutic intensity (p < 0.05). FENO, CANO, and JawNO were similar between FE and nFE. FE exhibited higher total serum IgE levels and residual volume values but reduced SpO2 than nFE (p < 0.05); SpO2<96.5% characterized the FE patient (odds ratio = 2.94). In phase II, CANO was higher in the group with novel AE at 1-month post-NO measurement (p < 0.05), but not afterward. A higher prevalence of CANO >6 ppb was detected in asthmatics who developed AE within 1 month, suggesting its potential clinical use as biomarker in predicting near-future AE (RR = 11.20). CONCLUSION: AE-susceptible asthmatics are characterized by air trapping and distal airway inflammation in conjunction with lower oxygen saturation. CANO and SpO2 could exert specific roles, respectively, in predicting AE and monitoring FE asthmatics.

Community-based intervention for prevention and management of chronic obstructive pulmonary disease in Nepal (COBIN-P trial): study protocol for a cluster-randomized controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide and the commonest of non-communicable diseases (NCDs) in Nepal. Risk factors like indoor and outdoor air pollution, a high prevalence of smoking, and the lack of awareness of COPD make it a serious public health concern. However, no attempt has been made in Nepal to estimate its burden and address the disease at the community level. METHOD: This study aims to evaluate the effect of a community-based health educational intervention administered by Female Community Health Volunteers (FCHVs) on the prevention and management of COPD. An open-label, two-group, community-based, cluster-randomized controlled trial will be implemented in the semi-urban area of Pokhara Metropolitan city (former Lekhnath Municipality) located in the Kaski district of Nepal. The estimated sample size of the intervention will be 1143. The unit of randomization is the ward (administrative unit) of the study area. The follow-up survey will be conducted immediately after 12 months of FCHVs-led interventions. The difference in the rate of decline of forced expiratory volume in 1 s (FEV1) and FEV1/FVC (forced vital capacity) ratio are the primary outcomes and the change in the proportion of modifiable risk factors of COPD, health-related quality of life scores, and change in knowledge of COPD will be secondary outcomes. DISCUSSION: This study will estimate the burden of COPD, the magnitude of risk factors and generate evidence to mobilize community health workers for COPD prevention and management at the community level in Nepal. TRIAL REGISTRATION: ClinicalTrials.gov NCT03797768 . Registered on January 9, 2019.

Health-Related Quality of Life of People Living with COPD in a Semiurban Area of Western Nepal: A Community-Based Study.

Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality in Nepal. It is a progressive lung disease and has a significant impact on the quality of life of patients. Health-related quality of life (HRQOL) reflects the health- and disease-related facets of quality of life. Limited studies have assessed the impact of COPD on HRQOL and associated factors in Nepal. This study is based on a cross-sectional household survey data from a semiurban area of Western Nepal. A validated Nepali version of St George's Respiratory Questionnaire (SGRQ) was used to measure the HRQOL. COPD was defined together with post-bronchodilator airflow obstruction and the presence of respiratory symptoms. Post-bronchodilator airflow obstruction was defined as Forced Expiratory Volume in 1st second (FEV1) to Forced Vital Capacity (FVC) ratio < 0.70. COPD was diagnosed in 122 participants, and their median (IQR) total score of HRQOL was 40 (26 - 69); the score of symptoms, activity, and impact area were 53 (37 - 74), 57 (36 - 86), and 26 (13 - 62), respectively. The overall HRQOL was significantly different in terms of age, occupational status, physical activity, and comorbidities. Disease severity and the presence of respiratory symptoms had a significant difference in HRQOL (p = 0.0001). Appropriate measures to improve conditions and addressing the associated factors like respiratory symptoms and enhancing physical activity are necessary and important.

Differences in nitric oxide airway diffusion after maximum oxygen uptake test in asthmatic and nonasthmatic elite junior cross-country skiers.

Asthma is common in cross-country skiers and is often treated with ß2-agonists and inhaled corticosteroids (ICS). Exhaled nitric oxide (NO) is often used to guide ICS treatment in asthma. This study investigated the change in pulmonary NO dynamics before and after a maximum oxygen uptake (V'O2 max) test. An extended NO analysis was performed among Swedish elite junior cross-country skiers (n=25), with and without declared asthma, before and after a V'O2 max test using roller skis. Asthma was declared by six boys and two girls among whom five occasionally used ICSs. There were no differences in baseline NO parameters between those with and without declared asthma. The median (interquartile range) diffusion capacity over airway wall (D awNO) was 21 (17-25) mL·s-1, which is much increased for this age group. After the V'O2 max test, there were statistically significant differences from the baseline fraction of exhaled NO (F ENO50 ), NO flux from airways, D awNO and alveolar NO values; but not in the NO content in airway wall (C awNO) for all subjects together as one group. However, in the asthma group, differences were only seen in F ENO50 and C awNO. Interestingly, a majority of the subjects had an increase in the D awNO. An increase in D awNO has been found with allergic asthma together with elevated C awNO. The skiers did not have elevated C awNO, which indicates an absence of inflammation in the airway wall. Modelling of lung NO production clearly shows that the asthma among our skiers is distinct from the allergic asthma in nonathletes.

Critical inhaler technique errors in Swedish patients with COPD: a cross-sectional study analysing video-recorded demonstrations.

A correct use of inhaler devices is essential in chronic obstructive pulmonary disease (COPD) treatment. Critical errors were studied by analysing 659 video-recorded demonstrations of inhaler technique from 364 COPD patients using six different inhaler device models. The majority of the included patients used two (55%) or more (20%) device models. Overall, 66% of the patients made ≥1 critical error with at least one device model. The corresponding numbers for patients using 1, 2 and ≥3 device models were 43%, 70% and 86%, respectively. The only factor associated with making ≥1 critical error was simultaneous use of two (adjusted odds ratios (aOR) 3.17, 95% confidence interval (95% CI) 1.81, 5.64) or three or more (aOR 8.97, 95% CI 3.93, 22.1) device models. In conclusion, the proportion of patients making critical errors in inhaler technique was substantial, particularly in those using several different device models. To obtain optimal COPD treatment, it is important to assess a patient's inhaler technique and to minimise the number of inhaler device models.

Neutrophil-to-lymphocyte ratio, blood eosinophils and COPD exacerbations: a cohort study.

BACKGROUND: Blood neutrophil-to-lymphocyte ratio (NLR) and blood eosinophils (B-Eos) are emerging biomarkers in COPD. This study examined whether they could predict acute exacerbations of COPD (AECOPDs), and determined their longitudinal stability. METHODS: In this closed cohort study, Swedish subjects with spirometry-verified COPD attended three yearly visits in a stable phase of the disease. Blood cell counts, spirometry and questionnaire-assessed AECOPD-history (worsening of COPD leading to an unscheduled visit and/or use of antibiotics and/or oral corticosteroids) were collected at each visit. RESULTS: Of 466 included subjects 57% were female. Baseline mean±sd forced expiratory volume in 1 s was 58±17% predicted. High NLR (≥3.0) was more common in subjects with previous AECOPDs than in those without (33.5% versus 20.4%, p=0.002). In two-level mixed-effects logistic regression models adjusted for confounders, NLR as a continuous variable (OR 1.20, 95% CI 1.04-1.38) and B-Eos ≥300 cells·µL-1 (OR 1.54, 95% CI 1.06-2.24) were associated with future AECOPDs. In 386 subjects with blood cell data available at all three visits, the intraclass correlation coefficient for NLR was 0.61 (95% CI 0.56-0.66) and for B-Eos 0.69 (95% CI 0.64-0.73). NLR was persistently ≥3.0 in 10.6% and B-Eos was persistently ≥300 cells·µL-1 in 15.3%. CONCLUSIONS: Stable phase NLR and B-Eos were associated with future AECOPDs. NLR on its own is probably not useful to predict AECOPDs but might be included in a risk scoring index. A minority of subjects with COPD had persistently elevated stable-phase NLR or B-Eos, and the biomarkers showed fair longitudinal reliability.

Commonly used clinical chemistry tests as mortality predictors: Results from two large cohort studies.

BACKGROUND: The normal ranges for clinical chemistry tests are usually defined by cut-offs given by the distribution in healthy individuals. This approach does however not indicate if individuals outside the normal range are more prone to disease. METHODS: We studied the associations and risk prediction of 11 plasma and serum biomarkers with all-cause mortality in two population-based cohorts: a Swedish cohort (X69) initiated in 1969, and the UK Biobank (UKB) initiated in 2006-2010, with up to 48- and 9-years follow-up, respectively. RESULTS: In X69 and in UKB, 18,529 and 425,264 individuals were investigated, respectively. During the follow-up time, 14,475 deaths occurred in X69 and 17,116 in UKB. All evaluated tests were associated with mortality in X69 (P<0.0001, except bilirubin P<0.005). For calcium, blood urea nitrogen, bilirubin, hematocrit, uric acid, and iron, U-shaped associations were seen (P<0.0001). For leukocyte count, gamma-glutamyl transferase, alkaline phosphatases and lactate dehydrogenase, linear positive associations were seen, while for albumin the association was negative. Similar associations were seen in UKB. Addition of all biomarkers to a model with classical risk factors improved mortality prediction (delta C-statistics: +0.009 in X69 and +0.023 in UKB, P<0.00001 in both cohorts). CONCLUSIONS: Commonly used clinical chemistry tests were associated with all-cause mortality both in the medium- and long-term perspective, and improved mortality prediction beyond classical risk factors. Since both linear and U-shaped relationships were found, we propose to define the normal range of a clinical chemistry test based on its association with mortality, rather than from the distribution.