Detailed characterization and impact of small airway dysfunction in school-age asthma.

BACKGROUND: Small airway dysfunction (SAD) is increasingly recognized as an important feature of pediatric asthma yet typically relies on spirometry-derived FEF25-75 to detect its presence. Multiple breath washout (MBW) and oscillometry potentially offer improved sensitivity for SAD detection, but their utility in comparison to FEF25-75, and correlations with clinical outcomes remains unclear for school-age asthma. We investigated SAD occurrence using these techniques, between-test correlation and links to clinical outcomes in 57 asthmatic children aged 8-18 years. METHODS: MBW and spirometry abnormality were defined as z-scores above/below ± 1.96, generating MBW reference equations from contemporaneous controls (n = 69). Abnormal oscillometry was defined as > 97.5th percentile, also from contemporaneous controls (n = 146). Individuals with abnormal FEF25-75, MBW, or oscillometry were considered to have SAD. RESULTS: Using these limits of normal, SAD was present on oscillometry in 63% (resistance at 5-20 Hz; R5-R20; >97.5th percentile), on MBW in 54% (Scond; z-scores> +1.96) and in spirometry FEF25-75 in 44% of participants (z-scores< -1.96). SAD, defined by oscillometry and/or MBW abnormality, occurred in 77%. Among those with abnormal R5-R20, Scond was abnormal in 71%. Correlations indicated both R5-R20 and Scond were linked to asthma medication burden, baseline FEV1 and reversibility. Additionally, Scond correlated with FENO and magnitude of bronchial hyper-responsiveness. SAD, detected by oscillometry and/or MBW, occurred in almost 80% of school-aged asthmatic children, surpassing FEF25-75 detection rates. CONCLUSIONS: Discordant oscillometry and MBW abnormality suggests they reflect different aspects of SAD, serving as complementary tools. Key asthma clinical features, like reversibility, had stronger correlation with MBW-derived Scond than oscillometry-derived R5-R20.

Severe bronchial hyperresponsiveness along with house dust mite allergy indicates persistence of asthma in young children.

BACKGROUND: Significant risk factors for persistence of asthma later in life are family history of allergies, early allergic sensitization and bronchial hyperresponsiveness (BHR). The evolution of BHR in young children without allergic sensitization and with house dust mite allergy (HDM) was investigated. METHODS: In this retrospective analysis, electronic charts of 4850 young children with asthma and wheezy bronchitis between 2005 and 2018 were reviewed in order to study all patients ≤6 years with BHR assessed by methacholine provocation tests (MCT) at least once (n = 1175). Patients with more than two follow-up measurements were divided in group 1 (no allergic sensitization; n = 110) and group 2 (HDM allergy; n = 88). Additionally, skin prick test, exhaled nitrite oxide (eNO), and asthma treatment were analyzed. RESULTS: Forty-seven patients of group 1 aged median 4.3 years and 48 patients of group 2 aged median 4.7 years showed initially severe BHR <0.1 mg. At follow-up, patients with HDM were more likely to show persistence of severe BHR than non-sensitized patients (severe BHR group 1: n = 5 (10.6%) vs. group 2: n = 21 (43.8%), p < .001). In addition, 89.4% of group 1 had mild to moderate or no BHR, compared to only 56.2% of group 2. There was a significant difference in eN0 (median group 1: 9 ppb vs. group 2: 26 ppb, p < .001), at last follow-up. Age, sex, and asthma therapy had no effect on BHR. CONCLUSION: In young children without sensitization BHR normalizes, whereas HDM allergy indicates a persistence of asthma beyond infancy.

[THE RELATIONSHIP AMONG BRONCHIAL HYPERSENSITIVITY, BRONCHIAL HYPER REACTIVITY, AND BRONCHIAL HYPERRESPONSIVENESS IN ASTOGRAPH].

BACKGROUND: Bronchial hyperresponsiveness testing is useful for diagnosing and predicting the risk of bronchial asthma attacks. The Astograph is a tidal breathing method often used in as bronchial provocation testing in Japan. The minimum methachorine dose (Dmin) indicates bronchial sensitivity and is used mainly as an index of bronchial hyperresponsiveness. However, Dmin does not measured hyperresponsiveness, it cannot be compared directly with PC20 in standard methods using FEV1. METHODS: We investigated the relationship among sensitivity, reactivity, and hyperresponsiveness with the Astograph. We recruited 142 patients with confirmed or suspected bronchial asthma from outpatient clinic at St. Marianna University School of Medicine, Yokohama City Seibu Hospital. We calculated Dmin, SGrs/Grscont, PD35Grs, and PD15Grs compared them as bronchial hyperresponsiveness indices. RESULTS: Subjects had suspected asthma (n=103), or required assessment of asthma remission (n=39). There were significant relationships between logDmin and logPD35Grs (r=0.838, p<0.001), and between parameters and SGrs/Grscont (log PD35Grs r=-0.504, p<0.001, strong, logDmin: r=-0.191, p=0.023, weaker). Among subjects positive for hypersensitivity, (Dmin<10), 38 (36.5%) showed negative hyperresponsiveness (PD35Grs>25). PD15Grs was a strongly and significantly correlated with Dmin and PD35Grs. The ROC curve to detect PD35Grs<25, showed that the cutoff of PD15Grs was 10.7 (AUC 0.983, sensitivity 0.984, specificity 0.905). CONCLUSION: In Astograph, evaluation of bronchial hyperresponsiveness, we focused on relationship differences between sensitivity and reactivity, and hyperresponsiveness. We revealed the usefulness of the PD15Grs evaluation method.

The Practical Role of FEF25-75 in Young Patients with Allergic Rhinitis.

Allergic rhinitis (AR) is a relevant risk factor asthma as it may frequently precede asthma onset. There is evidence that lung function may be early impaired in AR patients. In this regard, the forced expiratory flow at 25%-75% of vital capacity (FEF25-75) could be a reliable marker of bronchial impairment in AR. Therefore, the present study investigated the practical role of FEF25-75 in young people with AR. The parameters included history, body mass index (BMI), lung function, bronchial hyperresponsiveness (BHR), and fractional exhaled nitric oxide (FeNO). This cross-sectional study included 759 patients (74 females and 685 males, mean age of 29.2 years) suffering from AR. The study demonstrated a significant association between low FEF25-75 values and BMI (OR 0.80), FEV1 (OR 1.29), FEV1/FVC (OR 1.71), and BHR (OR 0.11). Stratifying the patients on the basis of the presence (or absence) of BHR, sensitization to house dust mites (OR 1.81), AR duration (OR 1.08), FEF25-75 (OR 0.94), and FeNO (OR 1.08) were associated with BHR. Stratifying patients based on high FeNO values (>50 ppb), BHR was associated with high FeNO (OR 39). In conclusion, the present study showed that FEF25-75 was associated with low FEV1 and FEV1/FVC and BHR in AR patients. Therefore, spirometry should be considered in the long-term workup of patients with allergic rhinitis as impaired FEF25-75 might suggest an initial progression toward asthma.

Mannitol Challenge to Assess Therapy Response in Asthmatic Children: An Interventional Cohort Study.

Bronchial provocation tests, such as the mannitol challenge, can be performed to identify and quantify the severity of bronchial hyperresponsiveness in asthmatic patients. Studies of the mannitol challenge as a monitoring tool in asthmatic children are limited. Our primary aim was to compare the bronchial hyperresponsiveness to mannitol in treatment-naive asthmatic children between baseline and three months after receiving the indicated asthma prophylaxis. Twenty-three asthmatic patients aged 4-16 years were analyzed in this prospective cohort study. All subjects underwent the mannitol challenge at baseline and after three months of treatment with budesonide ± formoterol. The difference in the provocative dose of mannitol to induce a 15% drop in FEV1 (PD15) between baseline and follow-up, as well as its association with the presence of exercise-induced or nocturnal asthma symptoms, were evaluated. The PD15 value increased significantly post-treatment (228.5 mg [4.50-458.15]; p = 0.04). Independently of the evaluation time point, the PD15 values were significantly lower in the presence of nocturnal asthma symptoms (490 mg [122-635] vs. 635 mg [635-635]; p = 0.03), whereas there was no association between the PD15 value and the presence of exercise-induced asthma (p = 0.73). These results suggest that bronchial hyperresponsiveness to mannitol may be a potential monitoring tool in the pediatric asthmatic population, reflecting therapy response in children receiving prophylactic treatment.

Occupational Exposure and Health Impact Assessment of Diisocyanates in Finland.

Diisocyanates are a group of chemicals widely used in different industrial applications. The critical health effects related to diisocyanate exposure are isocyanate sensitisation, occupational asthma and bronchial hyperresponsiveness (BHR). Industrial air measurements and human biomonitoring (HBM) samples were gathered in specific occupational sectors to examine MDI, TDI, HDI and IPDI and the respective metabolites from Finnish screening studies. HBM data can give a more accurate picture of diisocyanate exposure, especially if workers have been exposed dermally or used respiratory protection. The HBM data were used for conducting a health impact assessment (HIA) in specific Finnish occupational sectors. For this purpose, exposure reconstruction was performed on the basis of HBM measurements of TDI and MDI exposures using a PBPK model, and a correlation equation was made for HDI exposure. Subsequently, the exposure estimates were compared to a previously published dose-response curve for excess BHR risk. The results showed that the mean and median diisocyanate exposure levels and HBM concentrations were low for all diisocyanates. In HIA, the excess risk of BHR from MDI exposure over a working life period was highest in the construction and motor and vehicle industries and repair sectors, resulting in estimated excess risks of BHR of 2.0% and 2.6%, and 113 and 244 extra BHR cases in Finland, respectively. Occupational exposure to diisocyanates must be monitored because a clear threshold for DI sensitisation cannot be established.

Bronchodilator Response in FEF25-75 for the Diagnosis of Asthma in Children.

BACKGROUND: Spirometry tests with a bronchodilator response (BDR) in FEV1, a methacholine concentration that produces a 20% drop in FEV1 (PC20) ≤ 2 mg/mL, and a positive exercise test have high specificity for the diagnosis of asthma in children. However, the value of forced expiratory flow during the middle half of the FVC maneuver (FEF25-75) in spirometry has been questioned. The objective of this study was to relate the BDR in FEF25-75 of spirometry tests with normal FEV1 and FEV1/FVC to airway hyper-responsiveness (AHR) to methacholine or exercise in children age 5-15 y with clinical suspicion of asthma. METHODS: This was a cross-sectional study of spirometry tests performed between January 2017-December 2019 in children age 5-15 y with diagnostic suspicion of asthma who had a methacholine and/or exercise testing within a period not exceeding 60 d between exams. RESULTS: The mean (± SD) age of the children was 9.04 ± 2.67 y, with a range of 5-15 y, and 56.17% were male. Of the 324 spirometry tests with normal FEV1 and FEV1/FVC, 66 (20.4%) tests showed BDR in FEF25-75. A total of 46.9% and 33.3% of the children with and without BDR in FEF25-75, respectively, had a PC20 value ≤ 2 mg/mL and/or a positive exercise testing (P = .039). CONCLUSIONS: Children with suspected asthma and normal spirometry, other than BDR in FEF25-75, had greater AHR than those without BDR in FEF25-75. BDR in FEF25-75 was not always accompanied by AHR to confirm the diagnosis of asthma, so this study suggests that assessment of FEF25-75 alone is not always reliable for ruling in or ruling out AHR in the setting of otherwise normal spirometry results in children with suspected asthma.

Bronchodilator reversibility testing in long-term cough and dyspnea after Covid-19 viral infection: a trigger for asthma?

Objective: This study aims to investigate the presence of underlying chronic airway disease in individuals with chronic cough and dyspnea lasting longer than eight weeks and who had previously Coronavirus disease 2019 (COVID-19) and had no known lung disease.Methods: A total of 151 patients admitted to the respiratory diseases outpatient room with the complaint of cough and/or dyspnea that persisted for at least eight weeks following COVID-19 infection were accrued to the study. Demographic characteristics, smoking history, the severity of lung involvement on chest computed tomography in the acute phase of Covid-19 infection, and bronchodilator reversibility test results were recorded. Smoking history and forced expiratory volume in the first second (FEV1) were compared.Results: FEV1 increase ≥ 200 ml was observed in 40 (26.5%) patients. In 24 (15.9%) patients, an increase in FEV1 was found to be 200 ml and above, and the percentage of FEV1 was 12% or more. While 14 (9.3%) patients were diagnosed with asthma, 13 (8.6%) patients were diagnosed with nonreversible airflow obstruction (NRAO), and 1 (0.7%) patient was diagnosed with chronic obstructive pulmonary disease (COPD).Conclusions: COVID-19 infection may play a vital role in initiating asthma pathogenesis. It should be kept in mind that viral infection-related asthma may be the underlying cause of prolonged cough and dyspnea after COVID-19 infection.

Distinct Endotypes of Pediatric Rhinitis Based on Cluster Analysis.

PURPOSE: Despite the wide spectrum of pediatric rhinitis, endotyping of rhinitis based on type 2 inflammation and bronchial hyper-responsiveness (BHR) is lacking. This study aimed to investigate endotypes of pediatric rhinitis using cluster analysis. METHODS: Cluster analysis was performed on data from 241 children with rhinitis by using 12 variables reflecting clinical characteristics of skin prick, laboratory, and pulmonary function tests. After extracting clusters, between-cluster differences in clinical features, such as nasal symptom scores and asthma comorbidity, were assessed to investigate the association between the endotypes and clinical features. RESULTS: Four clusters were extracted by hierarchical cluster analysis. Cluster 1 (n = 32 [13.3%]) was the non-allergic rhinitis dominant cluster with low type 2 inflammation and the lowest rate of BHR. Patients in cluster 1 had the mildest nasal symptoms and no asthma comorbidity. Cluster 2 (n = 114 [47.3%]) was the largest cluster and exhibited intermediate type 2 inflammation and low BHR. Cluster 3 (n = 65 [27.0%]) showed high type 2 inflammation and intermediate BHR. However, the severity of nasal symptoms and asthma comorbidity in this cluster were comparable with those in cluster 2. Cluster 4 (n = 30 [12.4%]) revealed high type 2 inflammation and BHR with potential functional airway impairment. Additionally, cluster 4 displayed the most severe nasal symptoms and frequent asthma comorbidity. CONCLUSIONS: Four distinct endotypes of pediatric rhinitis based on allergen sensitization, type 2 inflammation, and BHR correlate to symptoms and asthma comorbidity. These endotypes may aid clinicians in understanding the wide spectrum of pediatric rhinitis.

Dose-Response Effect of Saccharomyces cerevisiae UFMG A-905 on the Prevention of Asthma in an Animal Model.

Probiotics should be administered in adequate amounts to confer health benefits. Probiotic dose-response studies are still missing. Saccharomyces cerevisiae UFMG A-905 prevented asthma development; however, the ideal dose has not been investigated. We evaluated the optimal dose and administration regimen of S. cerevisiae UFMG A-905 in the prevention of asthma. Male Balb/c mice were sensitized intraperitoneally with ovalbumin (OVA) and challenged with OVA intranasally. Mice received, via gavage, daily or alternate-day S. cerevisiae UFMG A-905. In daily regimen, different concentrations (107, 108, or 109 CFU/mL) were given 10 days before OVA sensitization and during challenges. In alternate-day regimen, a concentration of 109 CFU/mL was administered three times per week for 5 weeks, starting 2 weeks prior to the first sensitization. After the last challenge, in vivo bronchial hyperresponsiveness and airway and lung inflammation were assessed. OVA-challenged mice, when compared to saline-challenged mice, presented a significant increase in bronchial hyperresponsiveness and airway and lung inflammation. Daily and alternate-day administration of 109 CFU/mL of S. cerevisiae UFMG A-905 significantly reduced bronchial hyperresponsiveness; lower concentrations of S. cerevisiae UFMG A-905 did not significantly reduce bronchial hyperresponsiveness. Daily regimen with the highest concentration significantly reduced total cell number, eosinophil count in the BAL, and the levels of IL-4, IL-5, and IL-13. Daily administration of S. cerevisiae UFMG A-905 at 107 and 108 CFU/mL and alternate-day regimen did not significantly decrease airway and lung inflammation. S. cerevisiae UFMG A-905 led to a significant attenuation of bronchial hyperresponsiveness and lung inflammation in a dose-dependent manner.

Bronchial hyperresponsiveness and asthma during oral immunotherapy for egg or peanut allergy in children.

Background: Bronchial hyperresponsiveness (BHR) and asthma are frequently present in children with food allergy. We assessed BHR in children receiving oral immunotherapy (OIT) for persistent egg or peanut allergy and examined whether OIT affects asthma control. Methods: Methacholine challenge testing was performed in 89 children with persistent egg or peanut allergy diagnosed by double-blind, placebo-controlled food challenge and 80 control children without food allergy. Of the 89 food-allergic children, 50 started OIT for egg allergy and 39 for peanut allergy. Sensitization to aeroallergens was evaluated by skin prick testing. Forty of the 89 children with regular controller treatment for asthma underwent methacholine challenge testing and 34 measurement of exhaled nitric oxide (FeNO) at baseline and after 6-12 months of OIT. Results: Methacholine challenge testing revealed significant BHR in 29/50 children (58%) with egg allergy, 15/39 children (38%) with peanut allergy, and 6/80 controls (7.5%). The mean cumulative dose of methacholine causing a 20% fall in FEV1 differed significantly between the egg and peanut-allergic versus the control children (1009 µg, 1104 µg, and 2068 µg, respectively, p < 0.001). Egg or peanut OIT did not affect lung function, the degree of BHR or FeNO levels in children with asthma and had no adverse effect on asthma control. Lung function or BHR did not associate with the OIT outcome. Conclusion: BHR was significantly more frequent in children with persistent egg or peanut allergy than in children without food allergy. Oral immunotherapy did not increase BHR and was safe for children on regular asthma medication.

Therapeutic Efficacy of Weissella cibaria CMU and CMS1 on Allergic Inflammation Exacerbated by Diesel Exhaust Particulate Matter in a Murine Asthma Model.

Background and Objectives: Diesel exhaust particulate matter (DEPM) is an air pollutant that is associated with asthma. In this study, the therapeutic efficacy of Weissella cibaria strains CMU (Chonnam Medical University) and CMS (Chonnam Medical School) 1, together with the drug Synatura, an anti-tussive expectorant, was investigated in a murine asthma model exacerbated by DEPM. Materials and Methods: BALB/c mice were sensitized with ovalbumin (OVA) before intranasal challenge with OVA and DEPM. W. cibaria CMU, CMS1, and Synatura were administered orally for 21 days. Results: Neither Synatura nor W. cibaria strains affected spleen, liver, or lung weights. W. cibaria strains CMU and CMS1 significantly reduced the levels of interleukin (IL)-4, OVA-specific immunoglobulin E (IgE), and total lung collagen in bronchoalveolar lavage fluid (BALF), similar to those with Synatura, regardless of the oral dose concentration (p < 0.05). In addition, the W. cibaria CMU strain significantly alleviated IL-1ß, IL-6, IL-12, monocyte chemotactic protein-1, and tumor necrosis factor-α in BALF, whereas the CMS1 strain significantly alleviated IL-10 and IL-12 in BALF (p < 0.05); however, Synatura did not show any statistical efficacy against them (p > 0.05). All concentrations of W. cibaria CMU and low concentrations of W. cibaria CMS1 significantly reduced lung bronchiolar changes and inflammatory cell infiltration. Conclusions: In conclusion, W. cibaria CMU in asthmatic mice showed better efficacy than W. cibaria CMS1 in improving asthma exacerbated by DEPM exposure, as well as better results than pharmaceuticals.

Role of TRPA1/TRPV1 in acute ozone exposure induced murine model of airway inflammation and bronchial hyperresponsiveness.

Background: Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) mediate the development of lung injury and inflammation. This study investigated the role and mechanism of the TRPA1/TRPV1 pathway in airway inflammation and bronchial hyperresponsiveness (BHR) induced by acute ozone exposure. Methods: C57BL/6 mice (8-10 weeks) were intraperitoneally injected with phosphate buffered saline (PBS), A967079 (TRPA1 inhibitor) or AMG9810 (TRPV1 inhibitor) 1 h before or after ozone exposure (2.5 ppm, 3 h). BHR, cell counts in bronchoalveolar lavage (BAL) fluid, oxidative stress biomarkers, inflammatory cytokines, TRPA1 and TPRV1 protein levels, mitochondrial dynamics- and mitophagy-related protein levels, and activities of mitochondrial respiratory chain (MRC) in lung were measured. Results: The preventive treatment effect was similar to the therapeutic treatment effect. Both A967079 and AMG9810 intervention suppressed BHR, inflammatory cytokines, total BAL fluid cells, malondialdehyde (MDA) levels and inflammatory cytokines mRNA including Substance P (SP), Keratinocyte-Derived Chemokine (KC), interleukin-18 (IL-18) and chemokine (C-X-C motif) ligand 8 (CXCL8) expression, and enhanced reduced glutathione (GSH)/oxidized glutathione (GSSG) levels compared with ozone-exposed mice. A967079 and AMG9810 intervention inhibited dynamin-related protein (DRP1), mitochondrial fission factor (MFF), Parkinson protein 2 E3 ubiquitin protein ligase (PARK2) and Sequestosome 1 (SQSTM1)/p62 expression, increased Optic atrophy 1 (OPA1), mitofusin 2 (MFN2) and PTEN-induced putative kinase 1 (PINK1) expression, and up-regulated the activities of MRC complex III and V in lung tissue. Conclusions: The results show that both TRPA1 and TRPV1 pathways are involved in acute ozone exposure-induced airway inflammation and BHR and influence oxidative stress, mitochondrial quality control and MRC activity, which could be a potential target for clinical therapy of respiratory diseases.

Prevalence and Determinants of Wheezing and Bronchodilatation in Children With Cystic Fibrosis: A Retrospective Cohort Study.

Background: Many patients with cystic fibrosis (CF) wheeze, and are dubbed as having CF-asthma. Understanding the determinants of such wheezing may avoid unnecessary treatments and open newer treatment avenues. Objectives: Main: To evaluate the prevalence and characteristics of wheezing and a positive bronchodilatory response (BDR) in children with CF. Secondary: To identify the predictive markers and the impact of current wheezing a positive BDR. Methods: A retrospective single-center study in children with CF. We determined the characteristics of physician-reported wheeze in patients <6 years, and a BDR in patients aged 6-17 years. Anthropometric, lung function, laboratory, genetic and microbiological data were recorded in all groups. Variables were compared using the Chi2 and Student t-tests, and ANOVA. Results: 125 preschool and 69 school-aged children and adolescents with CF were included in the study. 71.2% of patients <6 years of age had had at least one episode of wheezing: 26.3% of patients were Transient Early Wheezers, 12.6% Late Onset Wheezers and 37.9% were Persistent Wheezers. The prevalence of a positive BDR was 73.5, 48.5, and 52.9% in the 6-8 years, 10-12 years, and 15-17 years age groups, respectively. Allergic factors were not predictive of wheezing in preschoolers. In the 6-8 years age group, the sum of wheal diameters of allergic skin prick tests (SPT, house dust mite + cat + dog dander) was greater in those with a BDR vs. no BDR (4 [2.0-8.8] vs. 1 [0-7.0] mm, p = 0.01). The presence of Pseudomonas aeruginosa in the bronchial secretions before 3 years of age was not significantly associated with either the presence of wheezing at the age of 6 years or a BDR in school-aged children and adolescents. The proportion of homozygous p.F508del patients was significantly lower in the group of patients who had wheezed by 6 years of age (60% vs. 72.7%, p = 0.009), but higher in the 6-8 years old group with a BDR vs. no BDR (64% vs. 36%, p = 0.04). Current wheezers at 6 years had a lower mean FEV1 vs. the non-current wheezers (91.5 ± 4.4% vs. 100.9 ± 2.4%; p = 0.047). Similarly, forced vital capacity (FVC) was significantly lower in the 6-8 years old group with BDR vs. no BDR (85 ± 19 vs. 101 ± 21%, p = 0.015). Conclusion: Wheezing and BDR are very frequent findings in children with CF. Current wheeze at the age of 6 years was associated with worse lung function. Labeling wheezing in CF as "CF-Asthma" is misleading since the determinants are different, and may lead to inappropriate prescriptions of inhaled steroids.

Wheeze is an unreliable endpoint for bronchial methacholine challenges in preschool children.

BACKGROUND: Onset of wheeze is the endpoint often used in the determination of a positive bronchial challenge test (BCT) in young children who cannot perform spirometry. We sought to assess several clinical endpoints at the time of a positive BCT in young children with recurrent wheeze compared to findings in school-aged children with asthma. METHODS: Positive BCT was defined in: (1) preschool children (n = 22) as either persistent cough, wheeze, fall in oxygen saturation (SpO2 ) of ≥5%, or ≥50% increase in respiratory rate (RR) from baseline; and (2) school-aged children (n = 22) as the concentration of methacholine (MCh) required to elicit a 20% decline in FEV1 (PC20 ). RESULTS: All preschool children (mean age 3.4 years) had a positive BCT (median provocative MCh concentration 1.25 mg/ml [IQR, 0.62, 1.25]). Twenty (91%) school-aged children (mean age 11.3 years) had a positive BCT (median PC20 1.25 mg/ml [IQR, 0.55, 2.5]). At the time of the positive BCT, the mean fall in SpO2 (6.9% vs. 3.8%; p = .001) and the mean % increase in RR (61% vs. 22%; p < .001) were greater among preschool-aged than among school-aged children. A minority of children developed wheeze at time of positive BCT (23% preschool- vs. 15% school-aged children; p = .5). CONCLUSIONS: The use of wheeze as an endpoint for BCT in preschool children is unreliable, as it rarely occurs. The use of clinical endpoints, such as ≥25% increase in RR or fall in SpO2 of ≥3%, captured all of our positive BCT in preschool children, while minimizing undue respiratory distress.

Inflammatory Phenotypes of Cough Variant Asthma as Response Predictors to Anti-Asthmatic Therapy.

BACKGROUND: Eosinophilic inflammatory phenotype was thought to be the most common phenotype of cough variant asthma (CVA), nevertheless other phenotypes were also reported. PURPOSE: The study aimed to analyze the inflammatory phenotypes of CVA in relation to treatment response to the stepwise anti-asthmatic treatment. PATIENTS AND METHODS: The study included 45 patients with chronic cough (CC) and suspicion of CVA (normal chest X-ray, presence of bronchial hyperresponsiveness and no history of wheezing or dyspnea) in whom induced sputum was successfully collected. Based on the cellular composition of the sputum, patients were divided into major inflammatory phenotypes: eosinophilic, neutrophilic, paucigranulocytic or mixed granulocytic. A stepwise treatment, including inhaled corticosteroids with long-acting ß2-agonist, montelukast and short-term therapy with prednisone was initiated. Good treatment response was defined as the reduction in cough severity at least 20 mm from the baseline in visual analogue scale and improvement in cough-related quality of life assessed by the Leicester cough questionnaire at least 1.3 points after any of three steps. RESULTS: Finally, 40/45 (88.9%) patients improved after therapy. Eosinophilic asthma was found in 13/40 (32.5%) patients, neutrophilic in 6/40 (15.0%) and paucigranulocytic pattern in 21/40 (52.5%) patients. No one demonstrated a mixed granulocytic phenotype. The response to the treatment was similar in all groups. However, the reduction in cough severity was inversely related to the percentage of sputum neutrophils (r = -0.44, P = 0.003). We showed that the percentage of neutrophils in sputum >46% may be considered as a predictor of poor response to anti-asthmatic therapy. CONCLUSION: The diversity of inflammatory phenotypes with paucigranulocytic preponderance was found in subjects with CVA. The response to anti-asthmatic treatment in patients with CVA was not related to the inflammatory phenotype. High neutrophil count in sputum may predict poor response to anti-asthmatic therapy in patients with CC and bronchial hyperresponsiveness.

Which patients with asthma are most likely to benefit from allergen immunotherapy?

If allergen immunotherapy (AIT) is to be considered as a treatment option for allergic asthma, it must undergo the same developmental steps as other antiasthmatic drugs. The bronchial allergen challenge model has demonstrated excellent negative predictive value for the development of new therapies for asthma. Subcutaneous immunotherapy appears to have a clinical and significant effect on the early asthmatic response to mite, cat, and birch and grass pollens in children and adults. Use of AIT in children with asthma is widely practiced but not supported by as strong a level of evidence as in adults. House dust mite sublingual immunotherapy tablets demonstrate efficacy in asthma exacerbations and other outcomes when used as add-on therapy in adult patients. Using a biologic to improve the patient's lung functions and asthma control before initiating AIT can transform unsuitable candidates for AIT into appropriate candidates. Because AIT is a form of personalized medicine, phenotyping the most suitable patient is necessary. Field studies of adults and children have suggested that polysensitized patients with rhinitis and Global Initiative for Asthma class 2 to class 4 asthma appear the most likely to be good responders. We hypothesized that AIT responders are those who demonstrate a high eosinophilic response to natural or experimental exposure.

Usefulness of extended nitric oxide analysis in children with allergic rhinitis.

OBJECTIVE: Evaluation of airway inflammation and dysfunction is important in management of allergic rhinitis (AR) since AR is a risk factor for developing asthma. Theoretical nonlinear modeling of exhaled nitric oxide (NO) has revealed extended flow-independent NO parameters that could explain where or how NO metabolism was altered. We aimed to evaluate the association between extended NO parameters and bronchial hyperresponsiveness (BHR) in children with AR. METHODS: Exhaled NO was measured in 74 children with AR on the same day they underwent the provocholine challenge test (PCT). Extended NO was measured in three different exhaled flow rates (30, 100, 200 mL/s) and calculated using the Högman-Meriläinen model. We compared the extended NO parameters including bronchial NO (JawNO), airway tissue NO (CawNO), alveolar tissue NO (CaNO), and diffusing capacity of NO (DawNO) between AR with and without BHR groups, and analyzed the correlation between extended NO parameters and the response-dose ratio (RDR) of the PCT. We additionally evaluated 49 respiratory healthy controls. RESULTS: Among the 74 children with AR, nine showed BHR. JawNO increased more in children with AR than the control group. In children with AR, JawNO was higher in the AR with BHR than without BHR group, and was correlated positively with log RDR (r = 0.373, p = .001). CONCLUSIONS: Extended NO analysis including JawNO can be a useful tool for assessing BHR in AR.

Allergic sensitisation did not affect bronchial hyper-responsiveness in children without respiratory tract symptoms.

AIM: The potential for immunotherapy to prevent asthma development has become a hot topic. This prompted us to revisit data from an early study that examined allergic sensitisation on bronchial hyperresponsiveness (BHR) in children with and without respiratory symptoms. Unlike previous studies, it used both indirect and direct test methods. METHODS: The study was conducted in Kuopio, Finland, in 1994 and 247 children (55.1% boys) with a mean age 10.5 ± 1.7 years were recruited using a school survey: 165 with lower respiratory symptoms and 82 healthy controls. Each child underwent a 6-min free-running test and a methacholine test with a cumulative dose of 4900 µg. All participants underwent skin-prick tests: 127were sensitised and 120 were non-sensitised. RESULTS: There were no significant differences in lung function between the sensitised and non-sensitised children. However, sensitisation was associated with BHR which was measured by both the methacholine test (2400 µg versus >4900 µg, p < 0.001) and the free-running test (-3.5% versus -2.6%, p = 0.042). No such differences were observed among the healthy controls. Sensitisation was a predictor of allergic diseases, and only multisensitisation to a minimum of four allergens increased the incidence of asthma. CONCLUSION: Allergic sensitisation did not affect BHR in children without respiratory symptoms.

The Usefulness of FEF25-75 in Predicting Airway Hyperresponsiveness to Mannitol.

BACKGROUND AND OBJECTIVE: Despite the usefulness of airway hyperresponsiveness (AHR) testing in diagnosing and monitoring asthma, it is challenging to perform in a real-world setting. Forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), a pulmonary measurement that can be obtained easily during routine spirometry, represents the status of medium-sized and small airways. However, the performance of FEF25-75 in predicting AHR has not been well elucidated. Therefore, we investigated whether FEF25-75 can predict AHR to mannitol. METHODS: We performed a retrospective cohort study of 428 patients who visited a single clinic due to cough, wheezing, or dyspnea. All patients underwent spirometry with a mannitol provocation test. We compared the area under the curve (AUC) of the percentage of the predicted values of FEF25-75 (FEF25-75 %pred) with that of forced expiratory volume in 1 second (FEV1%pred), FEV1/forced vital capacity (FVC), and FEF25-75/ FVC for predicting AHR. RESULTS: The rate of AHR to mannitol was 20.3%. In the overall study population, the AUC of FEF25-75 %pred for predicting AHR (0.772; 95% confidence interval [CI], 0.729-0.811) was significantly higher than that of FEV1%pred (0.666; 95% CI, 0.619-0.710; p < 0.001), FEV1/FVC (0.741; 95% CI, 0.697-0.782; p = 0.047), and FEF25-75/FVC (0.741, 95% CI = 0.696-0.782, p = 0.046). The sensitivity, specificity, positive predictive value, and negative predictive value of FEF25-75 %pred <81% for predicting AHR in the overall study population were 77.0% (95% CI = 66.8-85.4%), 63.9% (95% CI = 58.6-69.0), 35.3%, and 91.6%, respectively. When we restricted the study group to subjects with normal lung function, the results were similar. CONCLUSION: Our results indicate that FEF25-75 %pred can be used as a surrogate for predicting AHR in patients with respiratory symptoms.