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Background Long-time data of peanut allergy over time is sparse. We aimed to study the longitudinal development of sensitization to peanut extract and storage protein allergen molecules and associations with asthma status, airway and systemic inflammation markers. Methods The Swedish birth cohort BAMSE followed 4089 participants with questionnaires, clinical investigations and blood sampling between 0 and 24 years. Information on (i) background factors at 2 months, (ii) peanut allergy symptoms and IgE data (ImmunoCAP) at 4, 8, 16, and 24 years, and (iii) IgE to storage proteins, lung function data including exhaled nitric oxide (FENO) as well as systemic inflammatory markers at 24 years of age were collected. Results The prevalence of peanut extract sensitization, defined as IgE ≥ 0.35 kUA/L, was 5.4%, 8.0%, 7.5%, and 6.2% at 4, 8, 16, and 24 years of age, respectively. Between 8 and 24 years of age, (33/1565) participants developed IgE-ab to peanut extract (median 1,4, range 0.7–2.6 kUA/L), and among those 85% were also sensitized to birch. Only six individuals developed sensitization to Ara h 2 (≥0.1 kUA/L) between 8 and 24 years of age, of whom three had an IgE-ab level between 0.1–0.12 kUA/L. Storage protein sensitization was associated with elevated FENO, blood eosinophils and type 2 inflammation-related systemic proteins. Conclusion Sensitization to peanut extract after 4 years of age is mainly induced by birch cross-sensitization and IgE to Ara h 2 rarely emerges after eight years of age. Storage protein sensitization is associated with respiratory and systemic inflammation.

Background: The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type-2 (T2) cytokine biology which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood. Objectives: To explore airway pathology in T2 biomarker-high and -low severe asthma. Methods: T2 biomarker-high severe asthma (T2-high, n=17) was compared to biomarker-intermediate (T2-intermediate, n=21) and biomarker-low (T2-low, n=20) severe asthma, and healthy controls (n=28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD2 and LTE4 measurements. Results: Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodeling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared to health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5, and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD2 and LTE4, were increased in T2-high and T2-intermediate asthma compared to healthy controls. Conclusions: Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodeling persists, and may be important for residual disease expression beyond eosinophilic exacerbations.

Aim To update obstetric care providers about asthma management. Summary Asthma is the most frequent comorbid chronic illness in pregnancy. Convincing evidence shows that uncontrolled asthma magnifies the risk of maternal, fetal and neonate complications. Unfortunately, one in four women take no inhaler during pregnancy, and it is likely that decreased adherence, rather than changes in pathology, explains uncontrolled maternal asthma. Patient surveys reveal a need for information and reassurance. Although some molecules are preferred in pregnancy, there is currently no basis to withhold any asthma medication – old or new. Biomarkers such as blood eosinophils and fractional exhaled nitric oxide are an effective way to assess the risk of asthma attacks and the likelihood of responding to inhaled steroids. Furthermore, practice-changing trials in mild asthma show that switching reliever-only regimens to as-needed ‘controller-and-reliever’ therapy is effective. We suggest that applying these changes can alleviate women’s concerns and improve outcomes.

Determining if reproductive failures in ewes at the semiarid region in the state of Bahia are related to the consumption of the species Cenostigma pyramidale (Tul.) Gagnon & G.P. Lewis, and this study was developed using pregnant ewes divided into six groups: G1, G2, G3, G4 with six animals each, G5 and G6 with ten animals. Each group received fence leaves in the proportion of 1%, 2%, 0.5%, and 0.25% of live weight (LW) respectively; G5 and G6, with ten animals each, receiving 0.25% and 0.5% of the LW, respectively, and the Control Group, comprising 16 ewes, were grass feeding (Cynodon dactylon). Ewes from G1 to G4 were the same, except for two, and started ingestion of the plant four days after ending of natural mating on the 80th day of gestation, while those regarding from G5 to G6 groups started ingestion on the 26th day of gestation ending on the 98 day. The ultrasonographic test was performed weekly. In G1 ewes (1%), there was an embryonic loss on the 32nd and 39th days of gestation and abortion on the 46th day. In G2 (2%), the embryo loss was earlier (on the 26th day of gestation), and abortion on the 46th day of gestation. In G3 group (0.5%), there was an embryonic loss around the 40th day of gestation. In G4 group (0.25%), it was observed the occurrence of one death lamb with bone malformations. In G6 (0.5%), abortion occurred later (108 days), followed by retained placenta. This was also verified in G5 group (0.25%). The presence of fetal malformation was found in death lambs born in G4 group, born alive from G5 and G6 groups, and one aborted from G6. In G5 and G6 groups, there were also genetic alterations on surviving lambs. In addition to these results, recurrent estrus was observed without gestation in G1, G2, G3, and G4 ewes. From the Control Group, 13 normal lambs were born without genetic alterations; furthermore, concerning a quadruple birth, three lambs were born dead. The results infer that species of C. pyramidale in low doses causes reproductive losses in pregnant ewes, therefore it is not recommended for sheep diet over the first 60 days of gestation. RESUMO: Para determinar se falhas reprodutivas em ovelhas na região semiárida da Bahia estão relacionadas ao consumo de Cenostigma pyramidale (Tul.) Gagnon & G.P. Lewis, foi realizado um estudo utilizando-se ovelhas prenhes divididas em seis grupos e dois Grupos Controle. Os grupos G1, G2, G3 e G4 com seis animais cada. Cada grupo recebeu folhas fenadas na proporção de 1%, 2%, 0,5% e 0,25% do peso vivo (PV) respectivamente; G5 e G6, com 10 animais cada, que receberam 0,25% e 0,5% do PV respectivamente. Os Grupos Controle foram alimentados com ração e capim (Cynodon dactylon). Ovelhas dos grupos 1 a 4 iniciaram ingestão da planta quatro dias após monta natural com término aos 80 dias de gestação, enquanto as dos grupos 5 a 6 iniciaram ingestão no 26º dia de gestação com término aos 98 dias. Avaliação ultrassonográfica foi realizada semanalmente. Nos animais do G1 (1%), verificou-se perda embrionária aos 32 e 39 dias de gestação, e aborto aos 46 dias. Nos do G2 (2%) a perda embrionária foi mais precoce (26 dias), e aborto aos 46 dias. No G3 (0,5%), houve perda embrionária em torno dos 40 dias. No G4 (0,25%), verificou-se ocorrência de natimorto com malformações aos 150 dias de gestação. No G6 (0,5%) o aborto ocorreu mais tardiamente (108 dias), seguido de retenção de placenta. Essa ocorrência também foi verificada no G5 (0,25%). A presença de malformação fetal foi encontrada em fetos natimorto do G4, nascidos vivos do G5 e G6, e um abortado do G6. No G5 e G6 também foram observadas alterações de aprumos em cordeiros sobreviventes. Do Grupo Controle nasceram 13 borregos normais, porém uma ovelha apresentou gestação quádrupla com três natimortos. Os resultados inferem que C. pyramidale fenada em baixas doses causa perdas reprodutivas em ovelhas gestantes, não sendo por isso recomendada para a dieta de ovelhas durante os primeiros 60 dias de gestação.

Acute respiratory disorder is a common sub-clinical condition affecting elite cyclists. Monitoring the perturbations of the immunological cells in the respiratory tract, indicative of a likely proinflammatory state, during an International Cycling Union world tour is a challenging task. The aim of this study was to follow up on the sign and symptoms of upper way respiratory infections with or without asthma, using non-invasive methods, during a 21-day race (100° Giro d’Italia, 2017). Nine male elite cyclists of the Bahrain Merida Team were evaluated before the training season and daily during the race. Clinical history, skin prick and spirometric test, acute respiratory symptoms were measured using validated questionnaires, and values of fraction of exhaled nitric oxide were collected longitudinally. Four of the 9 athletes had allergies with/or consistent abnormal spirometric curves before the race. During the race, 5 athletes had a fraction of exhaled nitric oxide values >20 ppb which correlated with respiratory symptoms collected through questionnaires. These were related to the environmental characteristics of the places travelled through in the race. The athletes with a predisposition to chronic respiratory inflammation in the pre-competitive season were more likely to develop acute respiratory symptoms during the race.

Nowadays, there are a number of respiratory illnesses that directly affect children. Exhaled nitric oxide measurement (FeNO) is one of the modern methods of investigation used for diagnosing and controlling allergic eosinophilic airway inflammation. It is a simple, painless and time-saving method for the patient. Because of its non-invasiveness and simplicity, it is a valuable diagnostic method, especially in younger children. Measurement of FeNO is a recognized biomarker and an accurate quantitative indicator in the detection, assessment and monitoring of airway inflammation, including asthma. However, only a few studies assess the relationship between FeNO and level of air pollution. The aim of our study is to determine the relationship between FeNO in third-grade students of primary schools and the level of air pollution in Ruzomberok. 146 children aged 8-10 years were included in the research. This is the first stage of a wider research project involving FeNO measurements in children at different times of the year. The goal of the research is to determine the concentration of FeNO in the studied group of children in the autumn when air pollution is lower than in second stage which is observed in winter. The study showed elevated values of FeNO>20ppb in 11% of the tested children and correct values 3and for NO2 – from 28 to 44 μg/m3. The study shows that the significant majority of children have normal levels of nitric oxide in the exhaled air when air pollution is low. Analysis of the second phase of FeNO measurements in winter, when air pollution was higher, will allow to compare the results and assess the correlation between the FeNO value and air pollution.

Fractional exhaled nitric oxide (FeNO) is a breath-related biomarker of eosinophilic asthma. The aim of this study was to investigate FeNO variations due to environmental or occupational exposures in respiratory healthy subjects. Overall, 14 hairdressers and 15 healthcare workers in Oslo were followed for 5 workdays. We registered the levels of FeNO after commuting and arriving at the workspace and after ≥3 h of work, in addition to symptoms of cold, commuting method, and hair treatments that were performed. Both short- and intermediate-term effects after exposure were evaluated. Environmental assessment of daily average levels of air quality particulate matter 2.5 (PM2.5), particulate matter 10 (PM10), nitrogen dioxide (NO2), sulphur dioxide (SO2), and ozone (O3) indicated a covariation in ozone and FeNO in which a 35–50% decrease in ozone was followed by a near 20% decrease in FeNO with a 24-h latency. Pedestrians had significantly increased FeNO readings. Symptoms of cold were associated with a significant increase in FeNO readings. We did not find any FeNO increase of statistical significance after occupational chemical exposure to hair treatments. The findings may be of clinical, environmental and occupational importance.

Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10−8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= −0.015, p = 2.53 × 10−9) and nominally associated in nasal samples (coefficient = −0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes.

Fungi exposure has been significantly linked to respiratory illness. However, numerous fungi taxa that are potentially allergenic still undocumented and leave a barrier to establishing a clear connection between exposure and health risks. This study aimed to evaluate the association of fungi composition in settled dust with fractional exhaled nitric oxide (FeNO) levels among school children with doctor-diagnosed asthma. A cross-sectional study was undertaken among secondary school students in eight schools in the urban area of Hulu Langat, Selangor, Malaysia. A total of 470 school children (aged 14 years old) were randomly selected and their FeNO levels were measured and allergic skin prick tests were conducted. The settled dust samples were collected and analysed by using metagenomic technique to determine the fungi composition. The general linear regression with complex sampling was employed to determine the interrelationship. In total, 2645 fungal operational taxonomic units (OTUs) were characterised from the sequencing process which belongs to Ascomycota (60.7 %), Basidiomycota (36.4 %), Glomeromycota (2.9 %) and Chytridiomycota (0.04 %). The top five mostly abundance in all dust samples were Aspergillus clavatus (27.2 %), followed by Hyphoderma multicystidium (12.2 %), Verrucoconiothyrium prosopidis (9.4 %), Ganoderma tuberculosum (9.2 %), and Heterochaete shearii (7.2 %). The regression results indicated that A. clavatus, Brycekendrickomyces acaciae, Candida parapsilosis, Hazslinszkyomyces aloes, H. multicystidium, H. shearii, Starmerella meliponinorum, V. prosopidis were associated in increased of FeNO levels among the asthmatic group at 0.992 ppb (95 % CI = 0.34-1.68), 2.887 ppb (95 % CI = 2.09-3.76), 0.809 ppb (95 % CI = 0.14-1.49), 0.647 ppb (95 % CI = 0.36-0.94), 1.442 ppb (95 % CI = 0.29-2.61), 1.757 ppb (95 % CI = 0.59-2.87), 1.092 ppb (95 % CI = 0.43-1.75) and 1.088 ppb (95 % CI = 0.51-1.62), respectively. To our knowledge, this is a new finding. The findings pointed out that metagenomics profiling of fungi could enhance our understanding of a complex interrelation between rare and unculturable fungi with airway inflammation.

Introduction: Biologic drugs have dramatically improved severe eosinophilic asthma (SEA) outcomes. Our aim was to evaluate the long-term efficacy of biological therapy in SEA in a real-life setting and to identify the predictors for switching to another biological drug in patients with poor asthma control. The outcomes for efficacy were decreased annual exacerbations (AE) and improved asthma control test (ACT). Methods: In 90 SEA patients being treated with a biological drug, clinical examination, ACT, blood eosinophils count and spirometry were assessed before (T0) and after 6 (T1), 12 (T2), 24 (T3) and 36 (T4) months from the start of biological therapy. Patients were considered responders (R) or non-responders (NR) to biologics depending on whether or not they had less than two AE and a 20% increase in the ACT after 12 months of treatment. Results: 75% of the patients were R, 25% NR. In R patients, biological therapy add-on was followed by significant improvement in AE and ACT throughout the whole follow-up period. The percentage of patients on oral corticosteroids (OCS) dropped from 40% to 12%. By contrast, the NR patients were shifted to another biological drug after 12 months of therapy, as they still had high AE and nearly unchanged ACT; 40% of them still needed OCS treatment. The predictors of switching to another biological drug were three or more AE, ACT below 17, nasal polyposis and former smoking (p < 0.05). In NR, the shift to another biological drug was followed by a significant decrease in AE and an increase in the ACT. Discussion: This real-life study confirms the long-term efficacy of biologics in most SEA patients and indicates that even in non-responders to a first biological drug, it is worth trying a second one. It is hoped that the availability of additional biologics with different targets will help improve the personalization of SEA therapy.

Exposure to the air pollutant particulate matter (PM) is associated with increased risks of respiratory diseases and enhancement of airway inflammation in children. In the context of large scale air pollution studies, it can be challenging to measure fractional exhaled nitric oxide (FeNO) as indicator of lung inflammation. Urinary CC16 (U-CC16) is a potential biomarker of increased lung permeability and toxicity, increasing following short-term PM2.5 exposure. The single nucleotide polymorphism (SNP) CC16 G38A (rs3741240) affects CC16 levels and respiratory health. Our study aimed at assessing the use of U-CC16 (incl. CC16 G38A from saliva) as potential alternative for FeNO by investigating their mutual correlation in children exposed to PM. Samples from a small-scale study conducted in 42 children from urban (n = 19) and rural (n = 23) schools examined at two time points, were analysed. When considering recent (lag1) low level exposure to PM2.5 as air pollution measurement, we found that U-CC16 was positively associated with FeNO (8 = 0.23; 95% CI [-0.01; 0.47]; p = 0.06) in an adjusted analysis using a linear mixed effects model. Further, we observed a positive association between PM2.5 and FeNO (8 = 0.56; 95% CI [0.02; 1.09]; p = 0.04) and higher FeNO in urban school children as compared to rural school children (8 = 0.72; 95% CI [0.12; 1.31]; p = 0.02). Although more investigations are needed, our results suggest that inflammatory responses evidenced by increased FeNO are accompanied by potential increased lung epithelium permeability and injury, evidenced by increased U-CC16. In future large scale studies, where FeNO measurement is less feasible, the integrated analysis of U-CC16 and CC16 G38A, using noninvasive samples, might be a suitable alternative to assess the impact of air pollution exposure on the respiratory health of children, which is critical for policy development at population level. The authors would like to thank the Belgian Federal Science Policy Office (BELSPO) and Sciensano who funded this research through respectively the project PMOLLUGENIX-V2 (BELSPO, BR/165/PI/ PMOLLUGENIX) and the research project Respikid (Sciensano PJ/RP). They would like to thank the colleagues from the department of Transversal Activities of Applied Genomics at Sciensano for their help during the field study, including the sampling and measurements. They would also like to thank all the participating Belgian schools and the associated ‘pupil guidance centers (CLBs) for their enthusiastic collaboration during the field study. Finally, the authors would also like to thank Irceline and Leefmilieu Brussel-BIM (Het Brussels Instituut voor Milieubeheer) for making pollutant data publicly available.

Diagnostic tests are widely used in medicine, especially in the clinical setting. The doctor’s decision regarding the treatment process is mostly based on the result of the diagnostic test. The value of the test is expressed by its accuracy. It is easier to verify the accuracy of a diagnostic test in a clinical setting in comparison to an epidemiological setting. Moreover, a very good test may not work in epidemiological settings in the same effective way as in a clinical setting, especially because the accuracy is affected by the prevalence of the disease. The aim of the study is to assess the accuracy of FeNO measurement in different respiratory disorders or symptoms, including their prevalence, in a childhood population. The secondary aim is to suggest the optimal FeNO cut-off for epidemiological screening for respiratory diseases and symptoms. Methods: The cross-sectional study included 447 children (50.8% boys and 49.2% girls) aged 6–9 years. An adapted version of the ISAAC questionnaire was used for the assessment of the respiratory status. FeNO was measured with an electrochemical device (Niox Mino) according to ERS/ATS recommendations. For interpretation, the FeNO cut-off values of 20 parts per billion (ppb), 25 ppb and 35 ppb were applied taking the real-life prevalence of the disease or symptoms into consideration and also for simulated prevalences of 20%, 30%, 40%, 50% for the interpretation of the accuracy of the test. The accuracy was calculated according to the following formula: Accuracy = (Prevalence) (Sensitivity) + (1- Prevalence) (Specificity). The area under the curve was calculated based on logistic regression. Results: For all respiratory outcomes, FeNO accuracy decreased with increasing prevalence, and in general the area under the curve (AUC) was low. The highest FeNO accuracy was found for any asthma diagnosis (with possible coexisting diseases/symptoms), i.e., 78.6%, 92.8% and 88.5% for FeNO cut-offs >19 ppb, >24 ppb and >34 ppb, respectively. The AUC was 0.628. For the same FeNO cut-offs, the accuracy of an asthma diagnosis without any coexisting diseases and symptoms was 81.2%, 87.5%, 92.9%, respectively, with an AUC of 0.757. Conclusion: FeNO accuracy decreases with increasing prevalence of the respiratory disease and symptoms. The best accuracy for the FeNO cut-off in the screening of asthma for epidemiological purposes is 35 ppb. For isolated asthma, the best accuracy for FeNO was 92.9%.

Background: Northern China has severe air pollution, especially in winter. Fractional exhaled nitric oxide (FeNO) is an established biomarker of airway inflammation. Aim: To study associations between ambient temperature, air pollution and FeNO in university students in northern China. Methods: We performed a panel study in 67 university students without asthma diagnosis in the city of Taiyuan. FeNO was measured 6 times, over one heating season. Outdoor PM10, PM2.5, SO2, NO2 and O-3 were measured at a fixed location in the campus. SO2, NO2 and O-3 were measured 7 days (24 h/day) before the FeNO test. PM2.5 and PM10 were measured at different lag times (lag 1 day to lag 7 days). Temperature and carbon monoxide (CO) data were collected from a nearby monitoring station (lag 7). Linear mixed models were applied to study associations between exposure and FeNO, adjusting for gender, age, current smoking, height and furry pet or pollen allergy. Results: The overall geometric mean (GM) of FeNO was 17.2 ppb. GM of FeNO was lowest (12.9 ppb) in January and highest (20.0 ppb) in April. The range of lag 7 pollution was 105.0-339.0 mu g/m(3) for PM10, 72.0-180.0 mu g/m(3) for PM2.5, 36.0-347.0 mu g/m(3) for SO2, 26.0-69.0 mu g/m(3) for NO2, 31.0-163.0 mu g/m(3) for O-3 and 0.93-3.14 mg/m(3) for CO. The lag 7 temperature ranged from -4.5 to 20.1 degrees C. FeNO was consistently higher at higher outdoor temperature (p < 0.001). In multi-pollutant models with temperature adjustment, PM10, PM2.5 and SO2 were associated with FeNO (all p-values

The measurement of the exhaled nitric oxide (FeNO) is a recognized biomarker in the detection and monitoring of airway inflammatory infections, this including asthma. Due to its simplicity, and noninvasiveness, it is more and more widely used in diagnostics of children. Few studies indicate the relationship between FeNO and atmospheric air pollution. The goal of the following study was the measuring of FeNO for 8-9year old children in Krakow and Ruzomberok and relating the results of these measurements to the level of air pollution in the PM10 and PM2,5 range. 250 children aged 8-9 (125 in Krakow and 125 in Ruzomberok) attending third grades of primary schools, have constituted the research group. The measurement has been taken in accordance with the applicable standards with the application of a MediSOFT Belgium analyzer with a disposable head with an antibacterial filter. The results of the measurements have been referred to the PM10 and PM2,5 concentration of particulate matter in the air. Within the group of 125 children participating in the study in Krakow, the FeNO levels were normal for 104 (83.2%) children and increased for 21 (16.8%) children. During the period of the study, the average PM10 concentration was 55,7µg/m3and PM2,5 was 37.0µg/m3. As far as the group of 125 children examined in Ruzomberok, the FeNO levels were correct (5-20 ppb) for 114 (91,2%) children and increased (21-55) for 11 child­ren (8.8%). During the period of the study, the average PM10 concentration was 24.1µg/m3and PM2,5 was 15.4µg/m3. As one can see from the comparison, 1.9 times more increased FeNO levels have been recorded in Krakow than in Ruzomberok (18.6 vs 8.8%), and, within the range of the heavily increased values (>50ppb), this difference was as much as 4 times greater (3.2% vs 0.8%). These results correlate with the PM10 and PM2,5 levels in Krakow, which are respectively 2.3 and 2.4 times higher than those in Ruzomberok.

Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.

Pulmonary sequelae as assessed by pulmonary function tests (PFTs) are often reported in patients infected by SARS-CoV-2 during the post-COVID-19 period. Little is known, however, about the status of pulmonary inflammation during clinical recovery after patients’ discharge from the hospitals. We prospectively measured PFTs coupled with the exhaled nitric oxide (NO) stemming from the proximal airways (FeNO) and the distal lung (CaNO) in 169 consecutive patients with varying degrees of the severity of COVID-19 six weeks to one year after acute infection by SARS-CoV-2. The proportions of patients with abnormal PFTs, defined as the presence of either obstructive/restrictive patterns or impaired lung gas transfer, or both, increased with the severity of the initial lung disease (15, 30, and 52% in patients with mild, moderate, and severe COVID-19). FeNO values remained within normal ranges and did not differ between the three groups of patients. CaNO, however, was significantly higher in patients with severe or critical COVID-19, compared with patients with milder forms of the disease. There was also an inverse relationship between CaNO and DLCO. We conclude that the residual inflammation of the distal lung is still present in the post-COVID-19 follow-up period, in particular, in those patients with an initially severe form of COVID-19. This long-lasting alveolar inflammation might contribute to the long-term development of pulmonary fibrosis and warrants the regular monitoring of exhaled NO together with PFTs in patients with COVID-19.

Ayad Mohammed Salem,1 Noor Al Khathlan,2 Abdulelah Fawzi Alharbi,3 Turki Alghamdi,3 Saleh AlDuilej,3 Mohammed Alghamdi,3 Majed Alfudhaili,3 Ahmed Alsunni,1 Talay Yar,1 Rabia Latif,1 Nazish Rafique,1 Lubna Al Asoom,1 Hussein Sabit4 1Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 2Department of respiratory care, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 3College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 4Department of Genetics, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi ArabiaCorrespondence: Ayad Mohammed SalemDepartment of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, PO Box 2114, Dammam, 31451, Saudi ArabiaEmail ayadsalem@iau.edu.saBackground: The sequelae of COVID-19 pneumonia on pulmonary function and airways inflammation are still an area of active research.Objective: This research aimed to explore the long-term impact of COVID-19 pneumonia on the lung function after three months from recovery.Methods: Fifty subjects (age 18– 60 years) were recruited and classified into two groups: the control group (30 subjects) and the post-COVID-19 pneumonia group (20 patients). Pulmonary function tests, spirometry, body plethysmography [lung volumes and airway resistance (Raw)], diffusion capacity for carbon monoxide (DLCO), and fractional exhaled nitric oxide (FeNO), were measured after at least 3 months post-recovery.Results: Significant reduction in total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FEV, and diffusing capacity for carbon monoxide (DLCO) was observed in post-COVID-19 subjects compared to controls. Restrictive lung impairment was observed in 50% of post-COVID-19 cases (n = 10) compared to 20% in the control group (n = 6, P = 0.026). In addition, mild diffusion defect was detected in 35% (n = 7) of the post-COVID-19 group compared to 23.3% (n = 7) in the controls (P = 0.012).Conclusion: COVID-19 pneumonia has an impact on the lung functions in terms of restrictive lung impairment and mild diffusion defect after three months from recovery. Therefore, a long-term follow-up of the lung function in post-COVID-19 survivors is recommended.Keywords: COVID-19, pneumonia, PFT, DLCO, FeNO

الملخص: أهداف البحث: تهدف هذه الدراسة إلى مقارنة السيتوكينات للخلايا التائية المساعدة (1 و 2) بين الأشخاص المصابين بالسمنة العامة وسمنة البطن والأفراد غير البدينين، وربطها بالعلامات الحيوية لالتهاب الشعب الهوائية والتكوينات المختلفة للجسم. طرق البحث: تم تقسيم ثمانين شخصًا إلى مجموعتين مجموعة الوزن الطبيعي وتشمل 37 شخصا (مؤشر كتلة الجسم أقل من 25) و43 مشاركا في مجموعة من الوزن الزائد / السمنة (مؤشر كتلة الجسم أكبر من أو يساوي 25). تم تصنيف جميع المشاركين أيضا وفقا لمحيط الخصر إلى مجموعة السمنة البطنية (32 شخصا) والمجموعة بدون سمنة بطنية (48 شخصا). تم قياس مستويات سيتوكينات الخلايا التائية المساعدة 1 وتشمل (إنترفيرون غاما، وعامل نخر الورم ألفا، وإنترلوكين-2)، وكذلك سيتوكينات الخلايا التائية المساعدة 2 وتشمل (إنترلوكين-4، وإنترلوكين-5، وإنترلوكين-13) في الدم باستخدام تقنية الأليزا المتعددة. تم تقييم التهاب الشعب الهوائية عن طريق قياس مستوى أكسيد النيتريك في هواء الزفير. وقد تم قياس تكوينات الجسم باستخدام محلل تكوين الجسم الكهربائي الحيوي. النتائج: تم تسجيل ارتفاع في تركيز إنترلوكين-5 وعامل نخر الورم ألفا بشكل ملحوظ في الأشخاص المصابين بالسمنة العامة وسمنة البطن مقارنة بالأشخاص غير البدينين. كما أظهر إنترلوكين-5 علاقة إيجابية مع مؤشر التهاب الشعب الهوائية. كما ارتبط مؤشر كتلة الجسم ونسبة الدهون الكلية بشكل إيجابي مع إنترلوكين-5 وعامل نخر الورم ألفا، بينما ارتبط محيط الخصر ونسبة الدهون الحشوية مع مستوى إنترلوكين-5 وإنترلوكين-4. الاستنتاجات: تؤكد هذه الدراسة ارتفاع بعض السيتوكينات الخاصة بالخلايا التائية المساعدة 1 و 2 في الأشخاص المصابين بالسمنة العامة وسمنة البطن. كما ارتبط إنترلوكين-5 ارتباطا إيجابيا مع مستوى أكسيد النيتريك في هواء الزفير، وهذا قد يربط السمنة مع التهاب الشعب الهوائية. Abstract: Objectives: This study aims to compare the Th1/Th2 cytokines of subjects with general/abdominal obesity and non-obese individuals, and to correlate them with the biomarker of airways inflammation and different body compositions. Methods: Eighty subjects were divided into 37 normal weight (BMI >25) and 43 overweight/obese groups (BMI ≥25). All participants were further categorised by waist circumference (WC) into an abdominal obesity group (n = 32) and a group without abdominal obesity (n = 48). Serum levels of Th1 cytokines (INF-γ, TNF-α, IL-2,) and Th2 cytokines (IL-4, IL-5, IL-13) were measured using a multiplex ELISA technique. The fractional exhaled nitric oxide (FeNO) was used as a biomarker for airways inflammation. Different body compositions were assessed using a bioelectrical body composition analyser. Results: Serum IL-5 and TNF-α were significantly increased in groups with general or abdominal obesity compared to control groups. IL-5 showed a significant positive correlation with FeNO. BMI and total fat percentage were positively correlated to IL-5 and TNF-α, whereas WC and visceral fat percentage were correlated with the levels of IL-5 and IL-4. Conclusion: This study confirms the elevation of certain Th1 and Th2 cytokines in subjects with general and abdominal obesity. IL-5 was positively correlated with FeNO, which may link obesity to airways inflammation.

PURPOSE OF REVIEW Fractional concentration of Nitric Oxide in the exhaled air (FeNO) is a moderately good biomarker of type-2 airway inflammation, and its measurement is feasible also in children. The available evidence is still not enough to support the routine use of FeNO to diagnose or manage asthma in every patient in clinical practice. However, its role in identifying asthma with eosinophilic inflammation is of particular interest in the management of severe asthma. RECENT FINDINGS In healthy subjects, FeNO levels increase with age and height, particularly in males, and are also influenced by ethnicity. FeNO measurement can support asthma diagnosis and help in predicting asthma development later in life in young children with recurrent wheezing. FeNO-guided asthma management is effective in reducing asthma exacerbations but may result in a higher daily dose of inhaled corticosteroids. FeNO can also be used as a marker to evaluate adherence to asthma treatment and predict response to different biologicals, especially Omalizumab and Dupilumab. SUMMARY This review outlines recent data on the application of FeNO in childhood-onset asthma diagnosis and management, as well as in phenotyping subjects with severe asthma who may benefit from monoclonal antibodies administration.

Josep Darbà,1 Meritxell Ascanio,2 Jörgen Syk,3– 5 Kjell Alving4 1Department of Economics, Universitat de Barcelona, Barcelona, Spain; 2BCN Health Economics & Outcomes Research, S.L., Barcelona, Spain; 3Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; 4Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden; 5Academic Primary Health Care Centre, Stockholm, SwedenCorrespondence: Josep DarbàDepartment of Economics, Universitat de Barcelona, Diagonal 696, Barcelona, 08034, SpainTel +34 934020110Fax +34 934039082Email darba@ub.eduObjective: To determine the economic impact of the fraction of exhaled nitric oxide (FeNO) in asthma diagnosis and management in primary care in Sweden.Methods: An economic model has been developed to determine the economic impact of the fraction of exhaled nitric oxide (FeNO) in asthma diagnosis and management in primary care in Sweden. The model includes the use and cost of commonly used tests, the associated outcomes and diagnostic accuracy. We compared FeNO with spirometry and reversibility testing, methacholine challenge test, allergy testing, and blood eosinophil count. One-way sensitivity analyses were performed to confirm the robustness of results.Results: Adding FeNO measurement in asthma diagnosis resulted in cost savings of SEK 672 per patient by the fourth year. The use of FeNO testing in asthma management proved to be a dominant strategy when compared with each other test except methacholine challenge test. Sensitivity analyses confirmed the robustness of the results.Conclusion: Introducing FeNO testing in clinical practice for the diagnosis and management of asthma in primary care in Sweden is less costly than standard methods while providing similar health benefits.Keywords: asthma, management, diagnosis, FeNO, exhaled nitric oxide, health economy

Placental nitric oxide (NO) is critical for maintaining perfusion in the maternal-fetal-placental circulation during normal pregnancy. NO and its many metabolites are also increased in pregnancies complicated by maternal inflammation such as preeclampsia, fetal growth restriction, gestational diabetes, and bacterial infection. However, it is unclear how increased levels of NO or its metabolites affect placental function or how the placenta deals with excessive levels of NO or its metabolites. Since there is uncertainty over the direction of change in plasma levels of NO metabolites in preeclampsia, we measured the levels of these metabolites at the placental tissue level. We found that NO metabolites are increased in placentas from patients with preeclampsia compared to healthy controls. We also discovered by ozone-based chemiluminescence and electron paramagnetic resonance that nitrite is efficiently converted into iron nitrosyl complexes (FeNOs) within the human placenta and also observed the existence of endogenous FeNOs within placentas from sheep and rats. We show these nitrite-derived FeNOs are relatively short-lived, predominantly protein-bound, heme-FeNOs. The efficient formation of FeNOs from nitrite in the human placenta hints toward the importance of both nitrite and FeNOs in placental physiology or pathology. As iron nitrosylation is an important posttranslational modification that affects the activity of multiple iron-containing proteins such as those in the electron transport chain, or those involved in epigenetic regulation, we conclude that FeNOs merit increased study in pregnancy complications.

Background Allergic diseases are considered to be some of the fastest growing chronic conditions in Africa. Of concern is the paucity of knowledge about the local environment and its role in allergic disease development. In response to this, we explored whether Imbrasia belina, a popular indigenous edible insect commonly known as mopane worm, is a potential allergen of clinical and public health significance in Zimbabwe. This study was intended to assess the plausibility and feasibility of this hypothesis with a view to evaluate the insect’s health impact in a larger study. Methods The study participants included male and female villagers aged 10 years and above in Gwanda district, Zimbabwe. Eligible participants who completed the household questionnaire were referred to the local clinic for skin prick tests and to measure lung function and allergic airway inflammation. Allergen sensitisation patterns were evaluated using 10 different inhalant allergen extracts including an in-house preparation of mopane worm. Lung function was measured with a Koko Legend spirometer, and fractional exhaled nitric oxide levels (FeNO) (NIOX VERO) were measured in participants with at least one abnormal spirometric parameter. Data was analysed using Stata version 13 software. Results Of the 46 eligible participants that completed the household questionnaire, 17 went to the clinic giving a response rate of 37%. The majority who completed the questionnaire were adults (91%) and the children (9%) were all female. The prevalence of sensitisation to Imbrasia belina was 50%, and the prevalence ranged from 22 to 72% for the other allergens including cockroach, mosquito and house dust mites. The data collection tools were safe and well tolerated by participants with no adverse events reported. Self-reported respiratory symptoms, abnormal lung function and elevated FeNO were recorded amongst participants sensitised to mopane worm. Conclusion Pre-defined feasibility criteria were met with the exception of a lower than expected response rate for clinic data collection in this pilot study. For the main study, modifying the sampling strategy and applying more consistent community engagement will improve the response rates.

Background A commonly held public belief is that cow’s milk products increase mucus production and respiratory symptoms. Dietary milk elimination is often attempted despite lack of evidence. Our objective was to investigate whether a single exposure to cow’s milk is associated with respiratory symptoms and changes in pulmonary functions in asthmatic and non-asthmatic children. Methods We conducted a prospective double blind, placebo-controlled trial on non-asthmatic and asthmatic children aged 6–18 years evaluated at a pediatric pulmonology unit. The children were randomly challenged with cow’s milk or soy milk substitute. Symptoms, spirometry, fractional-exhaled nitric-oxide (FeNO), and pulse oximetry findings were obtained at baseline and at 30, 60, 90, and 120 min following challenge. A two-way ANCOVA (with repeated measures when required) was used to compare the performances of all groups and subgroups over time. The outcome measures of each participant were compared to his/her own variables over time and in relation to his/her baseline values. In case of missing data points, missingness analysis was performed using Little’s missing completely at random (MCAR) test. Results Fifty non-asthmatic children (26 assigned to the cow’s milk group and 24 to the soy substitute group), and 46 asthmatic children (22 in the cow’s milk group and 24 in the soy substitute group) were enrolled. Age, gender, and body mass index Z-score were comparable between the two groups. No changes in symptoms, spirometry, FeNO, or oxygen saturation measurements were observed following challenge in any of the participants in both groups, at any time point compared to baseline. Conclusions A single exposure to cow’s milk is not associated with symptoms, bronchial inflammation, or bronchial constriction in both non-asthmatic and asthmatic children. Our findings do not support the strict elimination of dairy products from a child’s diet for the prevention of respiratory symptoms. Trial registration This study was approved by the Tel Aviv Sourasky Medical Center Institutional Review Board and the Israeli Ministry of Health review board (Helsinki Committee, NIH #NCT02745899). Registered April 2016 https://clinicaltrials.gov/ct2/show/NCT02745899?cond=milk+asthma&rank=1.

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

Background Fractional exhaled nitric oxide (FeNO) is a convenient to use biomarker of airway inflammation. However, the mutual relationship between FeNO, peripheral blood eosinophil, total immunoglobulin E (IgE) and inflammatory cytokines showed some controversy. Objective This study was carried out to determine the accuracy of peripheral blood eosinophil and total IgE to detect eosinophilic airway inflammation as determined by two FeNO cutoff points. The correlation between FeNO, peripheral blood eosinophil, total IgE and certain inflammatory cytokines was also examined. Methods Seventy-six patients with partly controlled asthma performed the following tests on the same day: FeNO, pulmonary function tests (PFTs), peripheral blood eosinophils, total IgE, and inflammatory cytokine assay. The correlation between these markers was investigated and the diagnostic accuracy of peripheral blood eosinophils and total IgE to identify eosinophilic asthma phenotype was calculated using receiver operating characteristics area under the curve (ROC AUC). Results FeNO was positively correlated with percentage of blood eosinophils (r=0.276, p=0.017) and total blood IgE (r=0.3647; p=0.0013). No relationship between FeNO and serum inflammatory cytokines was detected. AUC of blood eosinophils and total IgE were 57% and 64% at FeNO ≥25 ppb and were 67% and 64% at FeNO >50, respectively. The higher predictive ability was detected at FeNO >50 ppb where the best cutoff point for blood eosinophil % was ≥4.0% (sensitivity 66.7%, specificity 60.0%) and the best cutoff point for total IgE was ≥350 (sensitivity 66.7%, specificity 63.6%). Conclusion In patients with partly controlled asthma, peripheral blood eosinophil and total IgE showed equal useful accuracy in predicting eosinophilic airways. However, higher predictive values were reported at FeNO level >50 ppb. FeNO was positively correlated with peripheral blood eosinophil, total IgE but not with any of the studied cytokines.

Background: Exhaled nitric oxide (FeNO) measurements and eucapnic voluntary hyperventilation (EVH) tests have been used as diagnostic tools for asthma. Data on the impact of hyperventilation on the level of FeNO are limited. Aim: We aimed to evaluate whether EVH tests affect the level of FeNO in children aged 10–16 years. Methods: A total of 234 children aged 10–16 years had a 6‐min EVH test performed. In total, FeNO values for 153 of 234 children were measured before the test and within 15 min after the test. According to a baseline FeNO level of 20 ppb, children were divided into two groups: those with low values (FeNO < 20 ppb) and those with high values (FeNO ≥ 20 ppb). Results: The median age of the children was 13.4 years (interquartile range 12.3–15.3 years); 58% were boys and 42% were girls. Of these children, 51% were sensitized to aeroallergens. In 101 of 153 children (66%), the FeNO values decreased after the EVH test. In children with low and high baseline levels, the median level of FeNO decreased after the EVH test: 10.5 ppb before versus 9.5 ppb after (p < .011), and 31.0 ppb before versus 28.0 ppb after (p < .011), respectively. The decrease in FeNO after EVH test was not associated with induced bronchoconstriction expressed as a change in FEV1 (Rs = .19). Conclusions: The EVH test decreases FeNO levels. Therefore, FeNO should be measured before an EVH test is performed.

Background Exhaled nitric oxide (NO), especially fractional concentration of exhaled NO (FENO) has been used to predict the responsiveness to inhaled corticosteroid (ICS) in children with asthma. However, the use of exhaled NO for predicting asthma control in children is still controversial. Methods This was a perspective observational study. Asthmatic children who were naïve to inhaled corticosteroid (ICS) were included in the present study. The measurements of FENO and CANO (concentration of NO in the gas phase of the alveolar), spirometry, blood eosinophil counts (BEC), and total IgE levels were done for each asthmatic child. All study subjects started proper asthma treatment after the enrollment. Results Ninety three asthmatic children (9±3 years) with moderate (63.4%) to severe (36.6%) asthma were included and finished the 3-month study. The levels of FENO and CANO at inclusion were 37±11 ppb and 5.8±1.4 ppb, respectively; the mean of BEC was 617±258 cells/μL; the level of total IgE was 1563±576 UI/mL; 89% of subjects were positive for at least one respiratory allergen. The percentage of severe asthma was reduced significantly after 3 months (P5ppb had a risk of uncontrolled asthma at 3 months (OR: 1.7, CI 95% [(0.8) - (3.3)], P35 ppb at inclusion had a positive predictive value for asthma control at 3 months (OR: 3.5, CI 95% [2.2-5.9], P

Objective To examine the feasibility of fractional exhaled nitrous oxide (FeNO) guided stepped care in patients with chronic persistent asthma. Methods 160 patients with asthma were enrolled and randomly divided into study and control groups, and were given standardized treatment according to GINA 2014. All patients were evaluated every 3 months and their medication was adjusted according to the results of evaluation. The control group was adjusted according to the recommended protocol from GINA, while the study group was adjusted on the basis of the control group and combined with the results of FeNO. The complete control rate, failure rate of stepwise treatment, ACQ score, lung function, and peripheral blood eosinophil count were compared between the two groups. Results In both study and control groups, the patient condition was effectively controlled. Strikingly, the failure rate of step therapy in study group was lower than that of control group (P0.05). Furthermore, the levels of FeNO positively correlated with ACQ scores and eosinophil counts or negatively with lung function. Conclusions The dynamic monitoring of FeNO could effectively guide the medication and reduce the rate of treatment failure, which could be used to inform standardized management of asthma.

BackgroundPeanut allergy affects 3% of Australian children and has a higher risk of anaphylaxis than most food allergies. Predicting who is likely to develop anaphylaxis is still an inexact science. The fraction of exhaled nitric oxide (FeNO) shows promise as a biomarker involved in peanut allergy, as nitric oxide plays a role in inhibiting mast cell degranulation which is relevant in anaphylaxis, where mast cell degranulation plays a mediator role. The aim of this study was to assess the change in FeNO in children during peanut challenge.MethodsThirty-six children aged from 5 to 17 years were recruited for open-labelled peanut challenge. Participants had skin prick test to peanut performed, and serum collected for Ara h2 specific IgE and peanut specific IgE. FeNO was measured by portable device (NIOX VERO) prior to and throughout the peanut challenge.ResultsWhen grouped according to reaction type at peanut challenge (anaphylaxis, clinical allergy not anaphylaxis and tolerant), there were significant differences in the mean change in FeNO measurement between the anaphylaxis group and the clinical allergy, not anaphylaxis group (p = 0.005), and between the anaphylaxis group and tolerant group (p ConclusionsFeNO decreased more significantly in those who subsequently developed anaphylaxis than in those with clinical allergy, not anaphylaxis or negative peanut challenge (tolerance). As a bedside test that can be used in children, it has potential for further research into mechanisms of anaphylaxis in food allergy and potentially assists in predicting an imminent anaphylactic reaction in some patients.Trial registrationClinicalTrials.gov: PEAnut Anaphylaxis Predictors (PEAAP) NCT02424136.

The nature of the inflammatory and fibrotic processes found in patients with post-COVID-19 syndrome makes it possible to speculate that in such patients fractional exhaled nitric oxide (FeNO) may be a useful biomarker. Consequently, we set out to verify the consistency of this hypothesis. We consecutively enrolled 68 post-COVID patients after being hospitalized for persistent clinical manifestations within 2 months from disease onset and 29 healthy volunteers as control group. None of post-COVID patients had bronchial asthma or were being treated with a corticosteroid. Only 19 out of 68 post-COVID-19 patients reported a FeNO value > 25 ppb. The mean FeNO value in post-COVID-19 patients was 18.55 ppb (95% CI: 15.50 to 21.58), while in healthy subjects it was 17.46 ppb (95% CI: 15.75 to 19.17). The mean difference was not statistically significant (P = 0.053). However, the mean FeNO value of post-COVID-19 patients was higher in men than in women (20.97 ppb; 95% CI: 16.61 to 25.33 vs 14.36 ppb; 95% CI: 11.11 to 17.61) with a difference between the two sexes that was statistically significant (P = 0.016). Mean FeNO was 14.89 ppb (95% CI: 10.90 to 18.89) in patients who had been treated with systemic corticosteroids because of their COVID-19, and 20.80 ppb (95% CI: 16.56 to 25.04) in those who had not taken them, with a difference that was statistically significant (P = 0.043). The data generated in this study suggest that measurement of FeNO is not useful as a biomarker in post-COVID-19 patient. However, this hypothesis needs solid validation with additional specifically designed studies.

This study aimed to evaluate the correlation between fractional exhaled nitric oxide (FeNO) and nasal nitric oxide (nNO) in allergic rhinitis (AR) and patients with or without bronchial asthma (BA). A total of 90 patients who were diagnosed with persistent AR (AR group, n = 30), BA (BA group, n = 30), or allergic rhinitis with bronchial asthma (AR-BA) (AR-BA group, n = 30), were enrolled in this study, along with 30 healthy adult volunteers (control group, n = 30). The participants were further divided into 2 groups based on the results of a skin-prick test (SPT): a highly atopic group (SPT = 3+ and above) and a moderately atopic group (SPT = 2+ and below). All participants underwent FeNO and nNO measurement, an absolute blood eosinophil count, total serum immunoglobulin measurement, and horizontal baseline lung capacity determination. The results showed that the FeNO levels in the 3 observation groups were significantly higher than those in the control group (P .05). The levels of nNO in the BA group were also significantly different from those in the control group (P

SummaryBackground The major trigger of asthma exacerbations is infection with a respiratory virus, most commonly rhinovirus. Type 2 inflammation is known to be associated with an increased risk of exacerbations in general. Whether type 2 inflammation at baseline increases the risk of future virus-induced exacerbations is unknown. Objective To assess whether type 2 inflammation is associated with an increased risk of virus-induced exacerbations of asthma. Methods Stable asthmatics had spirometry, skin prick test, measurement of FeNO and sputum induced for differential cell counts. Patients were followed up for 18 months, during which they were assessed at the research unit when they had symptoms of an exacerbation. Nasal swabs collected at these assessments underwent viral detection by PCR. Results A total of 81 asthma patients were recruited, of which 22 (27%) experienced an exacerbation during the follow-up period. Of these, 15 (68%) had a respiratory virus detected at exacerbation. Sputum eosinophils >1% at baseline increased the risk of having a subsequent virus-induced exacerbation (HR 7.6 95% CI: 1.6-35.2, P=.010) as did having FeNO >25 ppb (HR 3.4 95% CI: 1.1-10.4, P=.033). Conclusion and Clinical Relevance Established type 2 inflammation during stable disease is a risk factor for virus-induced exacerbations in a real-life setting. Measures of type 2 inflammation, such as sputum eosinophils and FeNO, could be included in the risk assessment of patients with asthma in future studies.

Background The links between microbial environmental exposures and asthma are well documented, but no study has combined deep-sequencing results from pulmonary and indoor microbiomes of asthmatic patients with spirometry, clinical and endotype parameters. Objective The goal of this study was to investigate the links between indoor microbial exposures and pulmonary microbial communities and to document the role of microbial exposures on inflammatory and clinical outcomes of patients with severe asthma (SA). Methods Fifty-five SA patients from the national COBRA cohort were enrolled for analyzing their indoor microbial flora through the use of electrostatic dust collectors (EDCs). Among these patients, 22 were able to produce sputa during stable or pulmonary exacerbation periods and had complete pairs of EDC and sputum samples, both collected and analysed. We used amplicon targeted metagenomics to compare microbial communities from EDC and sputum samples of patients according to type 2 (T2)-asthma endotypes. Results Compared to patients with T2-low SA, patients with T2-high SA exhibited an increase in bacterial alpha-diversity and a decrease in fungal alpha-diversity of their indoor microbial floras, the latter being significantly correlated with FeNO levels. The beta-diversity of the EDC mycobiome significantly clustered according to T2 endotypes. Moreover, the proportion of fungal taxa in common between sputum and EDC samples was significantly higher when patients exhibited acute exacerbation. Conclusion These results illustrated, for the first time, a potential association between the indoor mycobiome and clinical features of SA patients, which should renew interest in deciphering the interactions between indoor environment, fungi, and host in asthma., Graphical abstract, Capsule summary. This study is the first to date that investigates both the endogenous and the exogenous mycobiomes and microbiomes of asthmatic patients and reveals associations between indoor microbial communities, exacerbation, and T2 of severe asthma.

Exhaled nitric oxide (FeNO) is an established respiratory biomarker with clinical applications in the diagnosis and management of asthma. Because FeNO depends strongly on the flow (exhalation) rate, early protocols specified that measurements should be taken when subjects exhaled at a fixed rate of 50 ml/s. Subsequently, multiple flow (or “extended”) protocols were introduced which measure FeNO across a range of fixed flow rates, allowing estimation of parameters including CawNO and CANO which partition the physiological sources of NO into proximal airway wall tissue and distal alveolar regions (respectively). A recently developed dynamic model of FeNO uses flow‐concentration data from the entire exhalation maneuver rather than plateau means, permitting estimation of CawNO and CANO from a wide variety of protocols. In this paper, we use a simulation study to compare CawNO and CANO estimation from a variety of fixed flow protocols, including: single maneuvers (30, 50,100, or 300 ml/s) and three established multiple maneuver protocols. We quantify the improved precision with multiple maneuvers and the importance of low flow maneuvers in estimating CawNO. We conclude by applying the dynamic model to FeNO data from 100 participants of the Southern California Children's Health Study, establishing the feasibility of using the dynamic method to reanalyze archived online FeNO data and extract new information on CawNO and CANO in situations where these estimates would have been impossible to obtain using traditional steady‐state two compartment model estimation methods., A recently developed Bayesian dynamic two‐compartment model of FeNO uses flow‐concentration data from the entire exhalation, which permits estimation of CawNO and CANO from a wide variety of protocols. We compare estimation under single and multiple fixed expiratory flow protocols to demonstrate the gains in precision of multiple flow protocols and the feasibility of estimation with multiple 50 ml/s maneuvers informing, respectively, future study designs and the re‐analysis of archived online FeNO data.

Background Idiopathic pulmonary arterial hypertension (IPAH) is a fatal illness. Despite many improvements in the treatment of these patients, there is no unique prognostic variable available to track these patients. The aim of this study was to evaluate the association between fractional exhaled nitric oxide (FeNO) levels, as a noninvasive biomarker, with disease severity and treatment outcome. Methods Thirty-six patients (29 women and 7 men, mean age 38.4 ± 11.3 years) with IPAH referred to the outpatient’s clinic of Masih Daneshvari Hospital, Tehran, Iran, were enrolled into this pilot observational study. Echocardiography, six-minute walking test (6MWT), FeNO, brain natriuretic peptide (BNP) levels and the functional class of patients was assessed before patients started treatment. Assessments were repeated after three months. 30 healthy non-IPAH subjects were recruited as control subjects. Results There was no significant difference in FeNO levels at baseline between patients with IPAH and subjects in the control group. There was also no significant increase in FeNO levels during the three months of treatment and levels did not correlate with other disease measures. In contrast, other markers of disease severity were correlated with treatment effect over the three months. Conclusion FeNO levels are a poor non-invasive measure of IPAH severity and of treatment response in patients in this pilot study.

Background There are limited data assessing the predictive value of fraction of exhaled nitric oxide (FENO) in infants/toddlers with recurrent wheezing for asthma at school age. Objectives In a cohort of infants/toddlers with recurrent wheezing determine the predictive values of sedated single-breath FENO (SB-FENO) and awake tidal-breathing mixed-expired FENO (tidal-FENO) for active asthma, severe exacerbations, and lung function at age 6 years. Methods In 44 infants/toddlers, SB-FENO was measured under sedation at 50 mL/sec in conjunction with forced expiratory flow and volume measurements, and tidal-FENO was measured during awake tidal breathing. Clinical outcomes and lung function were assessed at age 6 years in 36 subjects. Results Enrollment SB-FENO was significantly higher among subjects with active asthma at age 6 years than among subjects without asthma (36.4 vs. 16.9 ppb, p < 0.0001), and the odds of asthma was 7.6 times greater (OR 7.6; 95% CI 1.8–31.6) for every 10 ppb increase in enrollment SB-FENO. A ROC analysis demonstrated that an enrollment SB-FENO > 31.5 ppb predicted active asthma at age 6 years with an area under the curve (AUC) of 0.92 (95% CI: 0.82–1). SB-FENO was also higher among subjects who experienced severe asthma exacerbations during the year preceding age of 6 years. SB-FENO at enrollment and lung function measures at age 6 years were modestly correlated (FEV1: r = −0.4; FEF25-75: r = −0.41; FEV1/FVC ratio: r=−0.46), and SB-FENO was significantly higher among subjects with bronchodilator responsiveness (BDR) at age 6 years. Tidal-FENO was not predictive of active asthma, exacerbations, or lung function at age 6 years. Conclusion In wheezy infants/toddlers, SB-FENO was predictive of school-age asthma and associated with lung function measures at age 6 years.

Nitric oxide (NO) is a potential bioactive gas produced continuously and constantly in the airways of healthy subjects. In allergic airway inflammation, the level of exhaled NO is usually increased and mediated by inducible nitric oxide synthase (iNOS) enzyme presenting in the epithelium and different inflammatory cells. The measurement of NO concentration in the airway is possible with portable devices which use an electroluminescence technique. In subjects with upper airway with allergic inflammation such as in allergic rhinitis, the measurement of nasal NO (nNO) may help to diagnose and manage the disease. In the lower airway, increased fractional exhaled NO (FENO) reflects directly the inflammatory process that occurs in the airways that are typically seen in asthma. It has been shown that there is a strong correlation between FENO levels and increased activity of airway inflammation mediated by immuno-allergic cells and mediators. Thus, FENO has higher specificity and sensitivity than other methods in diagnosing the severity of inflammation in asthmatic patients. Moreover, the correlation between increased FENO levels and a high risk of bronchial hyperresponsiveness has also been demonstrated. FENO is also a relevant biomarker to evaluate asthma status due to the change of its values occurring earlier than clinical manifestations and spirometry parameters. In addition, the measurement of FENO with portable devices helps to support the diagnosis of asthma, to follow-up the control of asthma and to personalize asthmatic patients for target treatment with biologic therapy. Therefore, measuring FENO with portable devices in the diagnosis and treatment of allergic airway inflammation, especially in asthma, is one of the most essential applications of NO biomarkers in exhaled breath.

Asthma and chronic obstructive pulmonary disease (COPD) can present as unique conditions or as a combination known as asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS). These condition(s) can be categorized as obstructive conditions, causing inflammation of small airways leading to decrease airflow, mucus production, and bronchoconstriction. Asthma and COPD affect every age, gender, ethnicity, and socioeconomic status, thus increasing mortality and morbidity burden in our society. Fractional exhaled nitric oxide (FeNO) is an endogenous gaseous molecule which can be measured in the human breath test because of airway inflammation. It has been studied extensively as a marker of inflammation and has been incorporated into an algorithm for asthma management. The purpose of this study was to investigate whether FeNO testing can lead to a change in the diagnosis. A retrospective chart review of 95 patients with asthma, COPD, and ACOS was performed, and FeNO levels were recorded. Out of 95 patients, 36%, 24%, and 22% of the patients had an initial diagnosis of asthma, COPD, and ACOS, respectively. After the FeNO testing, the number of patients with the final diagnosis of asthma and ACOS increased, and COPD decreased. Our results support the utility of FeNO as a viable marker in diagnosing and managing complex cases of asthma, COPD, and ACOS.

Background The expiration-to-inspiration sound power ratio in a midfrequency range (E/I MF), a parameter of lung sound analysis (LSA), has been reported to be useful as an index of airway inflammation in patients with bronchial asthma. However, the E/I MF reflects airway narrowing caused by airway inflammation, and there is thus concern that it may not be an index of airway eosinophilic inflammation itself. Methods A total of 131 patients with bronchial asthma were classified into four groups according to the presence or absence of airway narrowing and airway inflammation to examine whether the E/I MF could serve as an index of airway inflammation. Results The E/I MF was significantly higher in patients with a normal forced expiratory volume in one second (FEV1) and high fractional exhaled nitric oxide (FeNO), those with a low FEV1 and normal FeNO, and those with a low FEV1 and high FeNO than in those with a normal FEV1 and normal FeNO (p < 0.05–0.01). In particular, the E/I MF was high even in the patients who had no airway narrowing but had airway inflammation (p < 0.01). The results of multivariate analysis of factors involved in FeNO in patients with a normal FEV1 revealed that the E/I MF was an independent factor (p = 0.0281). Conclusion The E/I MF is a useful index of airway inflammation in the treatment of asthma, regardless of the presence or absence of airway narrowing.

Purpose Chronic cough in allergic rhinitis (AR) patients is common with multiple etiologies including cough variant asthma (CVA), non-asthmatic eosinophilic bronchitis (NAEB), gastroesophageal reflux-related cough (GERC), and upper airway cough syndrome (UACS). Practical indicators that distinguish these categories are lacking. We aimed to explore the diagnostic value of the fraction of exhaled nitric oxide (FeNO) and forced expiratory flow at 25% and 75% of pulmonary volume (FEF25–75) in specifically identifying CVA and NAEB in these patients. Methods Consecutive AR patients with chronic cough were screened and underwent induced sputum, FeNO, nasal nitric oxide, spirometry, and methacholine bronchial provocation testing. All patients also completed gastroesophageal reflux disease questionnaires. Results Among 1,680 AR patients, 324 (19.3%) were identified with chronic cough, of whom 316 (97.5%) underwent etiology analyses. Overall, 87 (27.5%) patients had chronic cough caused by NAEB, 78 (24.7%) by CVA, 16 (5.1%) by GERC, and 81 (25.6%) by UACS. Patients with either NAEB or CVA (n = 165, in total) were further assigned to a common group designated as CVA/NAEB, because they both responded to corticosteroid therapy. Receiver operating characteristic curves of FeNO revealed obvious differences among CVA, NAEB, and CVA/NAEB (area under the curve = 0.855, 0.699, and 0.923, respectively). The cutoff values of FeNO at 43.5 and 32.5 ppb were shown to best differentiate CVA and CVA/NAEB, respectively. FEF25–75 was significantly lower in patients with CVA than in those with other causes. A FEF25–75 value of 74.6% showed good sensitivity and specificity for identifying patients with CVA. Conclusions NAEB, CVA, and UACS are common causes of chronic cough in patients with AR. FeNO can first be used to discriminate patients with CVA/NAEB, then FEF25–75 (or combined with FeNO) can further discriminate patients with CVA from those with CVA/NAEB.

Background Heredity and environmental parameters jointly affect allergy development. Here, we used a Swedish prospective cohort to study the influence of heredity and factors usually associated with allergic disease and the development of allergic manifestations in combination with immunoglobulin E (IgE) sensitization at four different time points until 10 years of age. Methods Parents‐to‐be were characterized concerning allergy and their children (n = 281) were divided based on allergic heredity and followed from birth and clinically examined for IgE‐associated allergic symptoms until 10 years of age. The relation between allergy and early‐life parameters was analyzed by logistic regression. Group‐wise comparisons were made by nonparametrical tests. Results Early life eczema and/or asthma in combination with IgE sensitization, was a strong indicator of allergy at a later time point. Further, the early occurrence of multiple allergic symptoms among IgE‐sensitized children predisposed for a more complex allergic phenotype at later ages, independently of allergic heredity. At 10 years of age, allergic children had higher fractional exhaled nitrogen oxide (FeNO) levels, regardless of asthma, and FeNO levels were also influenced by heredity. Birth season was strongly associated with allergy development, but only in children with two allergic parents. Conclusion Allergic eczema/asthma in early life, being born during the autumn/winter, having multiple allergic symptoms and two allergic parents were all strong predictors for having allergic diseases at 5 and 10 years of age. However, the allergic march seems to be independent of heredity, as IgE‐mediated allergies follow the same trajectories in children with and without allergic heredity.

The consequences of air pollution pose one of the most serious threats to human health, and especially impact children from large agglomerations. The measurement of nitric oxide concentration in exhaled air (FeNO) is a valuable biomarker in detecting and monitoring airway inflammation. However, only a few studies have assessed the relationship between FeNO and the level of air pollution. The study aims to estimate the concentration of FeNO in the population of children aged 8–9 attending the third grade of public primary schools in Krakow, as well as to determine the relationship between FeNO concentration and dust and gaseous air pollutants. The research included 4580 children aged 8–9 years who had two FeNO measurements in the winter–autumn and spring–summer periods. The degree of air pollution was obtained from the Regional Inspectorate of Environmental Protection in Krakow. The concentration of pollutants was obtained from three measurement stations located in different parts of the city. The FeNO results were related to air pollution parameters. The study showed weak but significant relationships between FeNO and air pollution parameters. The most significant positive correlations were found for CO8h (r = 0.1491, p &lt, 0.001), C6H6 (r = 0.1420, p &lt, 0.001), PM10 (r = 0.1054, p &lt, 0.001) and PM2.5 (r = 0.1112, p &lt, 0.001). We suggest that particulate and gaseous air pollutants impact FeNO concentration in children aged 8–9 years. More research is needed to assess the impact of air pollution on FeNO concentration in children. The results of such studies could help to explain the increase in the number of allergic and respiratory diseases seen in children in recent decades.

Introduction: The study aimed to compare the effect of obesity with and without metabolic syndrome on asthma severity, quality of life, sleep quality, sleep disordered breathing and inflammatory markers as compared to non-obese asthma patients. Material and methods: 60 asthma patients recruited for the study were divided equally into non-obese (NOA), obese without metabolic syndrome (OANMS) and obese with metabolic syndrome (OAMS) groups. Study cohorts were assessed for severity of asthma, quality of life and quality of sleep using questionnaires and inflammatory markers (FENO, hs-CRP, IL-5, IL-6 and leptin). Institutional ethical committee approved the study. Results: The results suggests OAMS patients may be a subtype of asthmatics having significantly severe asthma (p < 0.05), poor quality of life (p < 0.05), high risk of OSA (p < 0.05), decreased lung volumes (FRC) (p < 0.05), higher levels of inflammatory markers (leptin and IL-6) (p < 0.05), and high incidence of sleep disordered breathing (p < 0.05) in comparison to NOA and OANMS patients. Conclusions: The present study has shown that obese asthmatics especially with metabolic syndrome represent a subtype of asthmatic population. Hence, the treatment of metabolic syndrome may be necessary in addition to asthma to achieve optimal control.

Background Electronic cigarette (EC) use is an emerging behaviour that has been shown to help smokers to reduce cigarette consumption. The aim of this study was to illustrate long-term changes in exhaled breath measurements and respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to ECs. Materials and methods Prospective evaluation of cigarette consumption, fractional nitric oxide concentration in exhaled breath (FeNO), exhaled carbon monoxide (eCO) and symptom scores was performed in a 1-year randomized, controlled trial of ‘healthy’ smokers receiving 2·4% nicotine, 1·8% nicotine or no nicotine ECs. FeNO and eCO data are presented on the basis of participants’ pooled continuous smoking phenotype classification (failures, reducers and quitters). Results A significant effect of quitting classification was found on FeNo and eCO at all time points (P < 0·0001). Among quitters, FeNO (medians and interquartile range) rose from 5·5 (4·5–6·9) ppb to 17·7 (13·3–18·9) ppb by week 52. Baseline eCO (medians and interquartile range) decreased from 17 (12–20) ppm to 3 (1–4) ppm by week 52. No significant changes in FeNO and eCO levels were observed in failures and reducers. Improvements in FeNO and eCO levels were correlated with attenuations in symptom scores. Conclusions Smokers invited to switch to electronic cigarettes who completely abstained from smoking showed steady progressive improvements in their exhaled breath measurements and symptom scores. FeNo and eCO normalization is highly supportive of improved respiratory health outcomes and adds to the notion that quitting from tobacco smoking can reverse harm in the lung.

The prevalence of asthma is higher in Sweden and Finland than in neighbouring eastern countries including Estonia. Corresponding difference in bronchial eosinophilic inflammation could be studied by FENO measurements. We aimed to compare FENO in adult general populations of Sweden, Finland, and Estonia, to test the plausibility of the west-east disparity hypothesis of allergic diseases. We conducted clinical interviews (N = 2658) with participants randomly selected from the general populations in Sweden (Stockholm and Örebro), Finland (Helsinki), and Estonia (Narva and Saaremaa), and performed FENO (n = 1498) and skin prick tests (SPT) in 1997–2003. The median (interquartile range) of FENO (ppb) was 15.5 (9.3) in Sweden, 15.4 (13.6) in Finland and 12.5 (9.6) in Estonia. We found the lowest median FENO values in the Estonian centres Saaremaa 13.1 (9.5) and Narva 11.8 (8.6). In the pooled population, asthma was associated with FENO ≥25 ppb, odds ratio (OR) 3.91 (95% confidence intervals: 2.29–6.32) after adjusting for SPT result, smoking, gender and study centre. A positive SPT test increased the likelihood of asthma OR 3.19 (2.02–5.11). Compared to Saaremaa, the likelihood of having asthma was higher in Helsinki OR 2.40 (1.04–6.02), Narva OR 2.45 (1.05–6.19), Örebro OR 3.38 (1.59–8.09), and Stockholm OR 5.54 (2.18–14.79). There was a higher prevalence of asthma and allergic airway inflammation in adult general populations of Sweden and Finland compared to those of Estonia. Atopy and elevated FENO level were independently associated with an increased risk of asthma. In conclusion, the findings support the earlier west-east disparity hypothesis of allergic diseases.

Background: Few studies have investigated the 24-hour respiratory health effects of personal black carbon (BC) and ultrafine particles (UFP) exposure in schoolchildren. The objective of this study was to investigate these associations with the lung function in children 10-years old with and without persistent respiratory symptoms. Methods: We conducted a cross-sectional study in 305 children (147 and 158 with and without persistent respiratory symptoms, respectively) from three European birth-cohorts: PARIS (France) and INMA Sabadell and Valencia (Spain). Personal 24-hour measurements of exposure concentrations to BC and UFP were performed by portable devices, before lung function testing. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and the fraction of exhaled nitric oxide (FeNO) were determined. Results: There was no association of UFP with lung function parameters or FeNO whereas the increase in 24-hour BC exposure concentrations was related to a statistically significant decrease in lung function parameters only among children with persistent respiratory symptoms [-96.8 mL (95% Confidence Interval CI: -184.4 to -9.1 mL) in FVC, and -107.2 mL (95% CI: -177.5 to -36.9 mL) in FEV1 for an inter-quartile range of 1160 ng/m3 exposure increase]. A significant positive association between BC and FeNO was observed only in children with persistent respiratory symptoms with current wheezing and/or medication to improve breathing [FeNO increases with +6.9 ppb (95% CI: 0.7 to 13.1 ppb) with an inter-quartile range BC exposure increase]. Conclusion: Children suffering from persistent respiratory symptoms appear to be more vulnerable to BC exposure. The study in Sabadell was funded by grants from Instituto de Salud Carlos III Red INMA (G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds), CIBERESP, Generalitat de Catalunya-CIRIT 19995GR 00241, Generalitat de Catalunya-AGAUR (2009 SGR 501, 2014 SGR 822), Fundació la Marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), EU Commission (261357, 308333 and 603794), the European Community's Seventh Framework Programme (FP7/2007/2013) under grant agreements 308333-HELIX Project and 308610-EXPOSOMICS Project. Dr Maribel Casas received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128). The study in Valencia was funded by grants from European Union (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: Instituto de Salud Carlos III (FIS-FEDER funds: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/02032, PI14/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249).

Streszczenie Tlenek azotu, powstający przy udziale enzymów z grupy syntaz tlenku azotu, spełnia w organizmie człowieka szereg istotnych funkcji, ale produkowany w nadmiarze wykazuje działanie prozapalne. Pomiary stężenia tlenku azotu w powietrzu wydychanym znajdują zastosowanie w diagnostyce i monitorowaniu nasilenia stanu zapalnego dróg oddechowych o podłożu eozynofilowym, nie powinny być jednak wykorzystywane jako samodzielny parametr w diagnozowaniu astmy lub monitorowaniu jej leczenia. Ocena stężeń tlenku azotu w powietrzu wydychanym znajduje również zastosowanie w ustalaniu patogenezy objawów u pacjentów z nieżytem nosa. Jest także pomocna w wykrywaniu i monitorowaniu współistniejącego eozynofilowego stanu zapalnego w dolnych drogach oddechowych u tych chorych. Wartości tlenku azotu w powietrzu wydychanym mogą być nieprawidłowe (zarówno obniżone, jak i podwyższone) w innych chorobach przewlekłych takich jak: mukowiscydoza, pierwotna dyskineza rzęsek oraz nieswoiste zapalenia jelit. Na wartości pomiaru wpływają liczne czynniki, takie jak: atopia, polimorfizmy genów syntaz tlenku azotu i parametry przemiany lipidowej organizmu. Oprócz pomiarów tlenku azotu w powietrzu wydychanym przydatne są także pomiary nosowego tlenku azotu, które znalazły zastosowanie w ocenie występowania oraz nasilenia zapalenia eozynofilowego w górnych drogach oddechowych.

Asthma is the most common chronic respiratory disease in children characterized by airways inflammation, bronchial hyperresponsiveness, recurrent reversible airways obstruction, and respiratory symptoms. The diagnosis of the disease is based on clinical history, airways obstruction at spirometry, and bronchial reversibility. Asthma treatment is aimed to disease control, through the use of controller treatment and monitoring lung function. However, lung function and symptoms not always reflect the underlying airways inflammation and response to the therapy. Objective parameters of asthma inflammation could be important for the clinician in the management of patients with asthma. In the last years, some studies were focused on biomarkers to identify phenotype, inflammation, and pathobiological pathways to help the clinician in the diagnosis and in personalizing the management. Accordingly, clinically feasible tests are represented by the collection of exhaled breath condensate (EBC) and measurement of exhaled nitric oxide (FeNO). Other-methods such as the evaluation of volatile organic compound (VOCs), that reflect airways inflammation and treatment efficacy, are currently used for research purposes For some of these methods, The lack of standardization in pre-collection, collection, post-collection of samples, and interpretation of the results may a problem in clinical practice. Improved these limitations, several biomarkers will be useful to distinguish patients with a different disease condition to personalize the treatment.

Introduction Recently, several new biological therapies targeted IgE and IL‐5 in severe asthma have been developed and approved. In the last few years, there have been some reports on the therapeutic algorithms for severe asthmatic subjects screened by biomarkers. However, these algorithms have one problem. In atopic/eosinophilic overlapping asthmatic subjects, there is no effective answer to the question: “which is the optimal choice between Anti‐IgE and anti‐IL‐5?” Methods We propose a new three‐step algorithm for biological therapy in severe asthma. Results Step 1 is to divide subjects into four groups by measuring blood eosinophils and FeNO. Step 2 is to divide the subjects further into six groups by atopy test. In the case of elevated blood eosinophils, normal/elevated FeNO, and atopy, we perform a steroid trial in step 3 in order to decide whether to select anti‐IgE or anti‐IL‐5. The steroid trial is to assess the symptoms of asthma, lung function, blood eosinophils, and FeNO before and after 14 days treatment with 0.5 mg/kg oral prednisolone/day. We judge that cases in which blood eosinophils and FeNO decrease together are not “truely steroid resistance.” In such cases, considering the possibility that allergic type inflammation through adaptive immunity is dominant, anti‐IgE is selected when it is difficult to prevent exacerbations by improving environmental factors. Conversely, we consider that cases in which blood eosinophils and/or FeNO do not decrease, are “truely steroid resistance.” In this case, since there is a possibility that non‐allergic type inflammation due to innate immunity, etc. may remain, anti‐IL‐5, which is expected to be effective for steroid‐resistant eosinophilic inflammation, is selected. Conclusions Our three‐step algorithm including the steroid trial may be applicable to companion diagnostics testing for molecularly targeted therapies in severe asthma. Further validation is required to examine the effectiveness of this algorithm.