Device comparison study to measure nasal nitric oxide in relation to primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic respiratory disease characterized by chronic cough, recurrent respiratory infections, and rhinosinusitis. The measurement of nasal nitric oxide (nNO) against resistance has been suggested as a sensitive screening method. However, current recommendations argue for the use of expensive, chemiluminescence devices to measure nNO. This study aimed to compare nNO measurement using three different devices in distinguishing PCD patients from healthy controls and cystic fibrosis (CF) patients and to evaluate their diagnostic precision. The study included 16 controls, 16 PCD patients, and 12 CF patients matched for age and sex. nNO measurements were performed using a chemiluminescence device (Eco Medics CLD 88sp), and two devices based on electrochemical sensors (Medisoft FeNO+ and NIOX Vero) following standardized guidelines. Correlation estimation, Bland-Altman, ROC curve, and one-way ANOVA were used to assess device differences and diagnostic performance. Significantly lower nNO output values were observed in PCD and CF patients compared to controls during exhalation against resistance. The correlation analysis showed high agreement among the three devices. ROC curve analysis demonstrated 100% sensitivity and specificity at different cut-off values for all devices in distinguishing PCD patients from controls (optimal cut-offs: EcoMedics 73, Medisoft 92 and NIOX 87 (nl min-1)). Higher nNO output values were obtained with the Medisoft and NIOX devices as compared to the EcoMedics device, with a bias of-19 nl min-1(95% CI: -73-35) and -21 nl min-1(-73-31) accordingly. These findings indicate that all three tested devices can potentially serve as diagnostic tools for PCD if device specific cut-off values are used. This last-mentioned aspect warrants further studies and consideration in defining optimal cut-offs for individual device.

Risk Factors for the Absence of Diagnosis of Asthma Despite Disease Symptoms: Results from the Swedish GA2LEN Study.

BACKGROUND: Asthma is a common chronic disease presenting with airway symptoms such as wheezing, chest tightness and attacks of breathlessness. Underdiagnosis of asthma is common and correlates to negative outcomes such as a lower quality of life and reduced work capacity. PURPOSE: This study aims to identify factors for not being diagnosed with asthma if presenting with asthma symptoms. PATIENTS AND METHODS: A questionnaire was sent to 45,000 subjects (age 16-74 years) in Sweden. Subjects who reported both wheeze and breathlessness and wheeze when not having a cold were defined as having asthma-related symptoms. Data on demographics, educational level, smoking, physical activity, comorbidities, symptoms and asthma were collected. Logistic regression was used to identify risk factors for not being diagnosed with asthma. RESULTS: Of the 25,391 who responded to the survey, 6.2% reported asthma-related symptoms. Of these, 946 had been diagnosed with asthma previously, while 632 had not. Independent risk factors for not being diagnosed with asthma were higher age (OR (95% CI) (2.17 (1.39-3.40))), male sex (1.46 (1.17-1.81)), current smoking (2.92 (2.22-3.84)), low level of education (1.43 (1.01-2.01)), low physical activity (1.36 (1.06-1.74)), and hypertension (1.50 (1.06-2.12)). CONCLUSION: Men, smokers, older subjects, and those with low educational level or low physical activity are less likely to be diagnosed with asthma despite presenting asthma-related symptoms.

Cross-sectional study on exhaled nitric oxide in relation to upper airway inflammatory disorders with regard to asthma and perennial sensitization.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a well-known marker of type-2 inflammation. FeNO is elevated in asthma and allergic rhinitis, with IgE sensitization as a major determinant. OBJECTIVE: We aimed to see whether there was an independent association between upper airway inflammatory disorders (UAID) and FeNO, after adjustment for asthma and sensitization, in a multi-centre population-based study. METHODS: A total of 741 subjects with current asthma and 4155 non-asthmatic subjects participating in the second follow-up of the European Community Respiratory Health Survey (ECRHS III) underwent FeNO measurements. Sensitization status was based on measurement of IgE against airborne allergens; information on asthma, UAID and medication was collected through interview-led questionnaires. Independent associations between UAID and FeNO were assessed in adjusted multivariate regression models and test for interaction with perennial sensitization and asthma on the relation between UAID and FeNO were made. RESULTS: UAID were associated with higher FeNO after adjusting for perennial sensitization, asthma and other confounders: with 4.4 (0.9-7.9) % higher FeNO in relation to current rhinitis and 4.8 (0.7-9.2) % higher FeNO in relation to rhinoconjunctivitis. A significant interaction with perennial sensitization was found in the relationship between current rhinitis and FeNO (p = .03) and between rhinoconjunctivitis and FeNO (p = .03). After stratification by asthma and perennial sensitization, the association between current rhinitis and FeNO remained in non-asthmatic subjects with perennial sensitization, with 12.1 (0.2-25.5) % higher FeNO in subjects with current rhinitis than in those without. CONCLUSIONS & CLINICAL RELEVANCE: Current rhinitis and rhinoconjunctivitis was associated with higher FeNO, with an interaction with perennial sensitization. This further highlights the concept of united airway disease, with correlations between symptoms and inflammation in the upper and lower airways and that sensitization needs to be accounted for in the relation between FeNO and rhinitis.

The influence of individual characteristics and non-respiratory diseases on blood eosinophil count.

BACKGROUND: Blood eosinophil (B-Eos) count is an emerging biomarker in the management of respiratory disease but determinants of B-Eos count besides respiratory disease are poorly described. Therefore, we aimed to evaluate the influence of non-respiratory diseases on B-Eos count, in comparison to the effect on two other biomarkers: fraction of exhaled nitric oxide (FeNO) and C-reactive protein (CRP), and to identify individual characteristics associated with B-Eos count in healthy controls. METHODS: Children/adolescents (<18 years) and adults with complete B-Eos data from the US National Health and Nutritional Examination Surveys 2005-2016 were included, and they were divided into having respiratory diseases (n = 3333 and n = 7,894, respectively) or not having respiratory disease (n = 8944 and n = 15,010, respectively). After excluding any respiratory disease, the association between B-Eos count, FeNO or CRP, and non-respiratory diseases was analyzed in multivariate models and multicollinearity was tested. After excluding also non-respiratory diseases independently associated with B-Eos count (giving healthy controls; 8944 children/adolescents and 5667 adults), the independent association between individual characteristics and B-Eos count was analyzed. RESULTS: In adults, metabolic syndrome, heart disease or stroke was independently associated with higher B-Eos count (12%, 13%, and 15%, respectively), whereas no associations were found with FeNO or CRP. In healthy controls, male sex or being obese was associated with higher B-Eos counts, both in children/adolescents (15% and 3% higher, respectively) and adults (14% and 19% higher, respectively) (p < 0.01 all). A significant influence of race/ethnicity was also noted, and current smokers had 17% higher B-Eos count than never smokers (p < 0.001). CONCLUSIONS: Non-respiratory diseases influence B-Eos count but not FeNO or CRP. Male sex, obesity, certain races/ethnicities, and current smoking are individual characteristics or exposures that are associated with higher B-Eos counts. All these factors should be considered when using B-Eos count in the management of respiratory disease.

Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study.

Rationale: New approaches are needed to guide personalized treatment of asthma.Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11ß-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers.Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).

Inflammatory patterns in fixed airflow obstruction are dependent on the presence of asthma.

RATIONALE: Fixed airflow obstruction (FAO) can complicate asthma. Inflammation is a proposed underlying mechanism. OBJECTIVE: Our aim in this cross-sectional investigation was to evaluate the blood leucocyte pattern and level of exhaled nitric oxide in asthmatics and non-asthmatics with or without FAO. METHODS: A total of 11,579 individuals aged ≥20 years from the US National Health and Nutrition Examination Survey were included. They were grouped as: controls without asthma and FAO (n = 9,935), asthmatics without FAO (n = 674), asthmatics with FAO (n = 180) and non-asthmatics with FAO (n = 790). FAO was defined as post-bronchodilator FEV1/FVC < lower limit of normal. Exhaled nitric oxide ≥ 25ppb, blood eosinophil levels ≥300 cells/µL, and blood neutrophil levels ≥5100 cells/µL were defined as elevated. Stratified analyses for smoking and smoking history were performed. RESULTS: Elevated blood eosinophil levels were more common in all groups compared to the controls, with the highest prevalence in the group with asthma and fixed airflow obstruction (p<0.01). In a multiple logistic regression model adjusted for potential confounders including smoking, the asthma groups had significantly higher odds ratios for elevated B-Eos levels compared to the control group (odds ratio 1.4, (confidence interval: 1.1-1.7) for the asthma group without fixed airflow obstruction and 2.5 (1.4-4.2) for the asthma group with fixed airflow obstruction). The group with fixed airflow obstruction without asthma had higher odds ratio for elevated blood neutrophil levels compared to the controls: 1.4 (1.1-1.8). Smoking and a history of smoking were associated to elevated B-Neu levels. CONCLUSION: Fixed airflow obstruction in asthma was associated with elevated blood eosinophil levels, whereas fixed airflow obstruction without asthma was associated with elevated blood neutrophil levels.

Different baseline characteristics are associated with incident wheeze in female and male adolescents.

AIM: To investigate the independent relationships between baseline characteristics and incident wheeze in adolescents, with particular regard to gender. METHODS: Adolescents (N = 959), aged 12-15 years, answered a standardised respiratory questionnaire and underwent height and weight measurements at baseline. Four years later, 96% of the subjects completed a similar questionnaire. The present study included the adolescents without self-reported wheeze at baseline (n = 795; 394 girls). RESULTS: The proportion of adolescents with obesity was higher among subjects with incident wheeze than among subjects who never reported wheeze: 19.1% vs 8.3%. When stratifying for gender, this difference was only found in girls. In stepwise logistic regression models (odds ratios [95% confidence interval]), obesity (2.84 [1.17-6.86]) and rhinitis (3.04 [1.53-6.03]) at baseline and current smoking (2.60 [1.16-5.82]) at follow-up were associated with incident wheeze in girls. For boys, FEV1 <-1.65 standard deviation (3.20 [1.04-9.79]), family asthma (3.16 [1.46-6.86]) and seasonal allergic symptoms (5.61 [2.56-12.27]) at baseline were independently associated with incident wheeze. CONCLUSION: Data stratified by gender showed that obesity in girls and an atopic constitution in boys were independently associated with increased risk of developing wheeze within four years.

The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms.

BACKGROUND: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations. METHODS: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (ß-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-ß-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0-10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions. RESULTS AND CONCLUSIONS: Only ß-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-ß-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-ß-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

Comparison of hypothesis- and data-driven asthma phenotypes in NHANES 2007-2012: the importance of comprehensive data availability.

BACKGROUND: Half of the adults with current asthma among the US National Health and Nutrition Examination Survey (NHANES) participants could be classified in more than one hypothesis-driven phenotype. A data-driven approach applied to the same subjects may allow a more useful classification compared to the hypothesis-driven one. AIM: To compare previously defined hypothesis-driven with newly derived data-driven asthma phenotypes, identified by latent class analysis (LCA), in adults with current asthma from NHANES 2007-2012. METHODS: Adults (≥ 18 years) with current asthma from the NHANES were included (n = 1059). LCA included variables commonly used to subdivide asthma. LCA models were derived independently according to age groups: < 40 and ≥ 40 years old. RESULTS: Two data-driven phenotypes were identified among adults with current asthma, for both age groups. The proportions of the hypothesis-driven phenotypes were similar among the two data-driven phenotypes (p > 0.05). Class A < 40 years (n = 285; 75%) and Class A ≥ 40 years (n = 462; 73%), respectively, were characterized by a predominance of highly symptomatic asthma subjects with poor lung function, compared to Class B < 40 years (n = 94; 25%) and Class B ≥ 40 years (n = 170; 27%). Inflammatory biomarkers, smoking status, presence of obesity and hay fever did not markedly differ between the phenotypes. CONCLUSION: Both data- and hypothesis-driven approaches using clinical and physiological variables commonly used to characterize asthma are suboptimal to identify asthma phenotypes among adults from the general population. Further studies based on more comprehensive disease features are required to identify asthma phenotypes in population-based studies.

Fixed airflow obstruction relates to eosinophil activation in asthmatics.

BACKGROUND: Some asthmatics develop irreversible chronic airflow obstruction, for example, fixed airflow obstruction (fixed-AO). This is probably a consequence of airway remodelling, but neither its relation to inflammation nor which asthma biomarkers can be clinically useful are elucidated. We hypothesized that the presence of type 2 inflammation relates to fixed-AO. OBJECTIVES: To evaluate the presence of four markers for type 2 inflammation in fixed airflow obstruction among asthmatics. METHODS: This was a cross-sectional study of 403 participants with asthma, aged 17-75 years, from three Swedish centres. Fixed airflow obstruction was defined as forced expiratory volume during the first second (FEV1 ) over forced vital capacity (FVC) being below the lower limit of normal (LLN). The following type 2 inflammation markers were assessed: exhaled nitric oxide (FeNO), serum periostin, serum eosinophil cationic protein (S-ECP), and urinary eosinophil-derived neurotoxin (U-EDN). RESULTS: Elevated U-EDN (values in the highest tertile, ≥65.95 mg/mol creatinine) was more common in subjects with fixed-AO vs. subjects without fixed-AO: 55% vs. 29%, P < 0.001. Elevated U-EDN related to increased likelihood of having fixed-AO in both all subjects and never-smoking subjects, with adjusted (adjusted for sex, age group, use of inhaled corticosteroids last week, atopy, early-onset asthma, smoking history, and packyears) odds ratios (aOR) of 2.38 (1.28-4.41) and 2.51 (1.04-6.07), respectively. In a separate analysis, having both elevated S-ECP (>20 µg/L) and U-EDN was related to having the highest likelihood of fixed-AO (aOR (95% CI) 6.06 (2.32-15.75)). Elevated serum periostin or FeNO did not relate to fixed-AO. CONCLUSIONS AND CLINICAL RELEVANCE: These findings support that type 2 inflammation, and in particular eosinophil inflammation, is found in asthma with fixed-AO. This could indicate a benefit from eosinophil-directed therapies. Further longitudinal studies are warranted to investigate causality and relation to lung function decline.

Exhaled NO reference limits in a large population-based sample using the Lambda-Mu-Sigma method.

Absolute values are used in the interpretation of the fraction of exhaled nitric oxide (FeNO), but it has been suggested that equations to calculate reference values may be a practical and clinically useful approach. We hypothesize that the application of the Lambda-Mu-Sigma (LMS) method may improve FeNO reference equations and their interpretation. Our aims were to develop FeNO reference equations with the LMS method and to describe the difference between this method and the absolute fixed cut-offs of the current recommendations. We utilized the United States National Health and Nutrition Examination Surveys 2007-2012 and included healthy individuals with no respiratory diseases and blood eosinophils <300/mm3 ( n = 8,340). Natural log-transformed FeNO was modeled using the LMS method, imbedded in the generalized additive models for location, scale, and shape models. A set of FeNO reference equations was developed. The explanatory variables were sex, age, height, smoking habits, and race/ethnicity. A significant proportion of individuals with normal FeNO given by the equations were classified as having intermediate levels by the current recommendations. Further lower predicted FeNO compared with previous linear models was seen. In conclusion, we suggest a novel model for the prediction of reference FeNO values that can contribute to the interpretation of FeNO in clinical practice. This approach should be further validated in large samples with an objective measurement of atopy and a medical diagnosis of asthma and rhinitis. NEW & NOTEWORTHY Novel reference equations and fraction of exhaled nitric oxide (FeNO)-predicted values to improve interpretation of FeNO in clinical practice are presented. These may increase the accuracy of ruling out airway inflammation in patients with asthma or suspected asthma.

Associations between self-rated health, sickness behaviour and inflammatory markers in primary care patients with allergic asthma: a longitudinal study.

Allergic asthma is a chronic inflammatory disorder associated with elevated levels of immunoglobulin E (IgE), serum eosinophilic cationic protein (S-ECP), plasma eosinophil-derived neurotoxin (P-EDN) and fraction of exhaled nitric oxide (FENO). Poor self-rated health and sickness behaviour has repeatedly been associated with inflammatory markers, but the nature of this relationship in chronic inflammatory disease is not known. Likewise, such findings largely rely on cross-sectional investigations. Self-rated health (How would you rate your general state of health?), sickness behaviour (mean rating of satisfaction with energy, sleep, fitness, appetite and memory), IgE, S-ECP, P-EDN, and FENO were assessed in 181 non-smoking primary care patients with asthma in a 1-year longitudinal study. Associations between repeated measurements were calculated using mixed regression models and Spearman's correlations for change scores. Poor self-rated health was associated with high levels of seasonal IgE (p = 0.05) and food IgE (p = 0.04), but not total IgE or inflammatory markers. An increase over 1 year in perennial IgE was associated with a worsening of self-rated health (ρ = 0.16, p = 0.04). Poor self-rated health was associated with more pronounced sickness behaviour (p < 0.001), and a worsening in sickness behaviour was associated with a worsening of self-rated health over time (ρ = 0.21, p = 0.007). The study corroborates the importance of sickness behaviour as a determinant of self-rated health by showing that these factors co-vary over a 1-year period in a group of patients with allergic asthma. The importance of specific IgE for perceived health in primary care patients with mild to moderate asthma needs further investigation.

Longitudinal co-variations between inflammatory cytokines, lung function and patient reported outcomes in patients with asthma.

BACKGROUND: Asthma is a chronic inflammatory respiratory disorder associated with reduced lung function and poor quality of life. The condition is also associated with poor self-rated health, a major predictor of objective health trajectories. Of biological correlates to self-rated health, evidence suggests a role for inflammatory cytokines and related sickness behaviours. However, this is mainly based on cross-sectional data, and the relation has not been investigated in patients with chronic inflammatory conditions. OBJECTIVE: To investigate inflammatory cytokines, lung function, sickness behaviour and asthma-related quality of life as determinants of self-rated health in patients with asthma, and to investigate if these variables co-vary over time. METHODS: Plasma cytokines (IL-5, IL-6), lung function (FEV1), sickness behaviour, asthma-related quality of life and self-rated health were assessed in 181 patients with allergic asthma aged 18-64 years in a one-year longitudinal study. Mixed effect regression models and Spearman's correlation were performed to analyse the associations between repeated measurements. RESULTS: More sickness behaviour and poorer asthma-related quality of life were associated with poorer self-rated health (p's<0.001). In men, both low and high levels of interleukin (IL)-6 and poorer lung function were related with poorer self-rated health (p's<0.05). Over the year, improved asthma-related quality of life was associated with better self-rated health (Spearman's rho = -0.34 women,-0.36 men, p's<0.01). Further, if sickness behaviour decreased, self-rated health improved, but only in women (Rho = -0.21, p<0.05). Increased FEV1 in men was associated with an increase in IL-6 (Rho = 0.24, p<0.05) as well as improved self-rated health (Rho = -0.21, p<0.05) and asthma-related quality of life (Rho = 0.29, p<0.01) over the year. CONCLUSION: The study highlights the importance of subjectively perceived sickness behaviour and asthma-related quality of life together with lung function as determinants of self-rated health in asthmatic patients. The importance of inflammatory activation for patient reported outcomes in chronic inflammatory conditions need further investigation.

Differential effect of cigarette smoke exposure on exhaled nitric oxide and blood eosinophils in healthy and asthmatic individuals.

BACKGROUND: Tobacco smoking affects both the fraction of exhaled nitric oxide (FeNO) and blood eosinophil (B-Eos) count, two clinically useful biomarkers in respiratory disease that represent local and systemic type-2 inflammation, respectively. OBJECTIVE: We aimed to study the influence of objectively measured smoke exposure on FeNO and B-Eos in a large population of subjects with and without asthma. METHODS: We utilized the US National Health and Nutrition Examination Surveys 2007-2012 and included 10 669 subjects aged 6-80 years: 9869 controls and 800 asthmatics. Controls were defined as having no respiratory disease, no hay fever in the past year, and B-Eos count ≤0.3 × 109 l-1. Asthma was defined as self-reported current asthma and at least one episode of wheezing or an asthma attack in the past year, but no emphysema or chronic bronchitis. Tobacco use was collected via questionnaires and serum cotinine was measured with mass spectrometry. RESULTS: Increasing cotinine levels were associated with a progressive reduction in FeNO in both controls and asthmatics. FeNO remained significantly higher in asthmatics than controls except in the highest cotinine decile, equivalent to an average reported consumption of 13 cigarettes/day. B-Eos count increased with cotinine in controls, but was unchanging in asthmatics. Interestingly, B-Eos count was significantly higher in presently non-exposed (cotinine below detection limit) former smokers than never smokers. CONCLUSION: Smoke exposure decreases FeNO and increases B-Eos count. These effects should be considered in the development of normalized values and their interpretation in clinical practice. The persistence of elevated B-Eos in former smokers warrants further studies.

Exhaled and nasal nitric oxide in relation to lung function, blood cell counts and disease characteristics in cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) have similar or lower exhaled nitric oxide (FeNO) and lower nasal nitric oxide (nNO) levels than controls. There are divergent results on alveolar NO (CalvNO) concentrations in relation to CF. There are inconsistent results on correlation between different nitric oxide parameters and lung function and inflammation in CF. AIM: To compare FeNO, CalvNO and nNO levels between subjects with CF, asthma and healthy controls and to study whether these parameters are related to lung function, blood cell counts or clinical characteristics in CF patients. MATERIAL AND METHODS: Measurements of FeNO at multiple exhalation flow rates, nNO and spirometry were done in 38 patients (18 adults) with CF. Blood cell counts and CF clinical characteristics were recorded. Thirty-eight healthy controls and 38 asthma patients, gender- and age-matched, were included as reference groups. RESULTS: FeNO levels were lower in CF patients (7.2 [4.7-11.2] ppb) than in healthy controls (11.4 [8.3-14.6] ppb) and asthma patients (14.7 [8.7-24.7] ppb) (both p < 0.005). These differences were consistent in adults. No difference in CalvNO was seen between the groups. nNO levels in CF patients (319 [193-447] ppb) were lower than in healthy controls (797 [664-984] ppb) and asthma patients (780 [619-961] ppb) (both p < 0.001). FeNO positively related to FEV1 (rho = 0.51, p = 0.001) in CF patients and this was consistent in both adults and children. A negative correlation was found between FeNO and blood neutrophil counts (rho = -0.37, p = 0.03) in CF patients. CONCLUSION: CF patients have lower FeNO and nNO and similar CalvNO levels as healthy controls and asthma patients. Lower FeNO related to lower lung function in both adults and children with CF. Furthermore, in CF, lower FeNO also related to higher blood neutrophil counts.

Lin- CD34hi CD117int/hi FcεRI+ cells in human blood constitute a rare population of mast cell progenitors.

Mast cells are rare tissue-resident immune cells that are involved in allergic reactions, and their numbers are increased in the lungs of asthmatics. Murine lung mast cells arise from committed bone marrow-derived progenitors that enter the blood circulation, migrate through the pulmonary endothelium, and mature in the tissue. In humans, mast cells can be cultured from multipotent CD34(+) progenitor cells. However, a population of distinct precursor cells that give rise to mast cells has remained undiscovered. To our knowledge, this is the first report of human lineage-negative (Lin(-)) CD34(hi) CD117(int/hi) FcεRI(+) progenitor cells, which represented only 0.0053% of the isolated blood cells in healthy individuals. These cells expressed integrin ß7 and developed a mast cell-like phenotype, although with a slow cell division capacity in vitro. Isolated Lin(-) CD34(hi) CD117(int/hi) FcεRI(+) blood cells had an immature mast cell-like appearance and expressed high levels of many mast cell-related genes as compared with human blood basophils in whole-transcriptome microarray analyses. Furthermore, serglycin, tryptase, and carboxypeptidase A messenger RNA transcripts were detected by quantitative reverse transcription-polymerase chain reaction. Altogether, we propose that the Lin(-) CD34(hi) CD117(int/hi) FcεRI(+) blood cells are closely related to human tissue mast cells and likely constitute an immediate precursor population, which can give rise to predominantly mast cells. Furthermore, asthmatics with reduced lung function had a higher frequency of Lin(-) CD34(hi) CD117(int/hi) FcεRI(+) blood mast cell progenitors than asthmatics with normal lung function.

Application of nitric oxide measurements in clinical conditions beyond asthma.

Fractional exhaled nitric oxide (FeNO) is a convenient, non-invasive method for the assessment of active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid diagnosis and monitoring in several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory, infectious, and/or immunological conditions. In this short review, we provide an overview of several clinical studies and discuss the status of potential applications of NO measurements in clinical conditions beyond asthma.

Setting reference values for exhaled nitric oxide: a systematic review.

BACKGROUND: The values obtained when the fraction of exhaled nitric oxide (FeNO) is measured are affected by several factors that are specific to the individual patient, making interpretation difficult, especially in the initial assessment of patients with respiratory symptoms. METHODS: Systematic review of studies on FeNO reference values and individual-specific factors that influence them. RESULTS: From 3739 references, 15 studies were included. Four studies included children and adolescents. In nine studies, samples were selected from the general population. Most studies reported objective measures for atopy (nine studies), but not for smoking status (one). Significant determinants of FeNO values reported were age and height (seven studies), atopy (six), smoking (four), weight (four), sex (three) and race (three). Additional factors were included in eight studies. R2 was reported in only five studies. The logarithmic transformation of FeNO was inadequately described in seven studies. CONCLUSION: There are several equations for FeNO reference values that may be used in clinical practice, although the factors they include and the statistical methods they use vary considerably. We recommend the development of standard methods for the evaluation of normal FeNO data and that reference equations should be formulated based on a predetermined physiological model.

Measurement of nasal nitric oxide by hand-held and stationary devices.

BACKGROUND: Nasal nitric oxide (nNO) is assessed by nasal aspiration/insufflation via one nostril or by nasal silent exhalation through a facemask and is also measured during humming, a manoeuvre that results in increased nNO in the presence of a patent osteomeatal complex. Humming nNO peak is absent in primary ciliary dyskinesia (PCD) and in cystic fibrosis (CF). Hand-held devices are used successfully for exhaled or nNO analysis. No study compared nNO during silent and humming exhalation using hand-held and stationary analysers. METHODS: Thirty-eight subjects (14 PCD; 11 CF; 13 healthy individuals) measured nNO with a stationary and a hand-held analyser during silent and humming exhalations. RESULTS: No difference between nNO obtained from stationary or hand-held analyser during silent and humming exhalation was found (P > 0·05). Patients with PCD exhibited lower silent and humming nNO than CF or controls (P < 0·001). During both silent and humming exhalation, there was a significant correlation between nNO from the two analyzers both in the whole study population and within each group (r ≥ 0·7, P < 0·01). Bland-Altman plots confirmed this agreement. Using the hand-held device during humming, nNO values of 50, 81 and 21 ppb had sensitivity and specificity > 90% for discriminating PCD or CF from healthy subjects, and patients with PCD from patients with CF, respectively. CONCLUSIONS: The hand-held device is as effective as the stationary analyzer for assessing nNO during silent and humming exhalation. Its wider use might result in an increased number of subjects suspected to have PCD.

Use of tobacco products and gastrointestinal morbidity: an endoscopic population-based study (the Kalixanda study).

The impact of snus (smokeless tobacco or snuff) on gastrointestinal symptoms and pathological findings is largely unknown. The authors aimed to investigate whether the exposure to different forms of tobacco influences upper gastrointestinal symptoms, histology and frequency of Helicobacter pylori infection. A random sample (n = 2,860) of the adult population of two northern Swedish municipalities Kalix and Haparanda (n = 21,610) was surveyed between December 1998 and June 2001 using a validated postal questionnaire assessing gastrointestinal symptoms (response rate 74.2%, n = 2,122) (The Kalixanda Study). A random sub-sample (n = 1,001) of the responders was invited to undergo an esophagogastroduodenoscopy (participation rate 73.3%) including biopsies, Helicobacter pylori culture and serology and symptom assessment and exploration of present and past use of tobacco products. No symptom groups were associated with snus use. Snus users had a significantly higher prevalence of macroscopic esophagitis univariately but snus use was not associated with esophagitis in multivariate analysis. Snus use was associated with basal cell hyperplasia (OR = 1.74, 95% CI: 1.02, 3.00) and with elongation of papillae (OR = 1.79, 95% CI: 1.05-3.05) of the squamous epithelium at the esophago-gastric junction. Current smoking cigarettes was associated with overall peptic ulcer disease (OR = 2.32, 95% CI: 1.04, 5.19) whereas snus use was not. There were no significant association between current Helicobacter pylori infection and different tobacco product user groups. Snus significantly alters the histology of the distal esophagus but does not impact on gastrointestinal symptoms or peptic ulcer disease.