Circadian rhythm and variability of large and small airway spirometric variables in healthy individuals.

Objective: To assess the diurnal rhythm and variability of lung function in healthy individuals, encompassing both large and small airways. Methods: A prospective study enrolled 35 healthy adults without a history of smoking. Initial spirometry and a bronchodilation test were performed using the Jaeger spirometer, followed by a seven-day continuous home monitoring using the GOSPT2000. We evaluated repeatability using the intraclass correlation coefficient and agreement through linear regression and Bland-Altman analyses. Circadian rhythm and variability in spirometric measurements were analyzed using the coefficient of variation (CV) and daily variation rate. Results: The GOSPT2000 demonstrated strong repeatability and high agreement with the Jaeger spirometer. Notable findings included a decrease in nocturnal forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV3 by 44, 59, and 53 mL, respectively. In contrast, peak expiratory flow at noon showed an increase of 0.143L/min. Small-airway variables, including forced expiratory flow at 50% and 75% of the FVC and maximum midexpiratory flow, showed no significant diurnal variation. The nocturnal CV for large-airway variables was ≤ 4%, while for small-airway variables, it was ≤ 11.89%. Conclusion: This study has established a spectrum of variability for both large and small airways in healthy populations. The variability of small-airway variables is higher than that of large-airway variables. The investigation into the diurnal rhythms and variability characteristics of both large and small airway variables in the healthy population can serve as a foundation for diagnosing asthma or assessing the efficacy of asthma treatments.

Retrospective analysis of laboratory results in 18 cases of severe asthma treated with omalizumab.

OBJECTIVE: The aim of this study was to explore the laboratory results in severe as asthma patients with omalizumab therapy and provide evidence for estimating omalizumab efficacy. METHODS: Retrospective study of 18 patients with severe asthma received omalizumab therapy in Shanghai General Hospital from 2020 to 2022 was performed. The basic data of patients were collected. The absolute number and the percentage of basophil and eosinophil in peripheral blood, total IgE level in serum, and as pulmonary function were detected at the beginning of treatment and 4 months after treatment. Differences between two groups were analyzed using Paired T test. RESULTS: The most common allergens collected from patients with moderate to severe asthma were dust mite (positive ratio 55.56%), mixed mold (16.67%), cat and dog dander, and Aspergillus fumigatus (11.11%). There was no significant difference in eosinophil and basophil counts in peripheral blood between the two groups. However, serum total IgE levels increased from (437.55±279.35) KU/L to (1071.42±721.28) KU/L (P=0.004), and FEV1/FVC ratio increased from (65.53±14.15)% to (73.91±13.63)% (P=0.005) after 4 months of treatment. CONCLUSIONS: The existing laboratory indicators for evaluation of omalizumab efficacy are still very limited, and new biomarkers need to be further developed. Elevated serum IgE levels at four weeks of treatment and FEV1/FVC may be potential indicators for omalizumab monitoring.

Evaluating the effects of vitamin D Level on airway obstruction in two asthma endotypes in humans and in two mouse models with different intake of vitamin D during early-life.

Introduction: Asthma is primarily divided into two categories: type 2 (T2-high) and non-type 2 (T2-low). A relationship between asthma severity and vitamin D deficiency has been identified, but its impact on each asthma endotype remains unknown. Methods: We clinically examined the influence of vitamin D on patients with T2-high (n = 60) or T2-low asthma (n = 36) compared with controls (n = 40). Serum 25(OH)D levels, inflammatory cytokines and spirometry were measured. Mouse models were then used to further analyze the effects of vitamin D on both asthmatic endotypes. BALB/c mice were fed with vitamin D-deficient (LVD), -sufficient (NVD), or -supplemented diets (HVD) throughout lactation and offspring followed the same diet after weaning. Offspring were sensitized/challenged with ovalbumin (OVA) to establish "T2-high" asthma or OVA combined with ozone exposure (OVA + ozone) to induce "T2-low" asthma. Spirometry and serum, bronchoalveolar lavage fluid (BALF), and lung tissues were analyzed. Results: Serum 25(OH)D levels were decreased in asthmatic patients compared with controls. Patients with vitamin D deficiency (Lo) had varying degrees of elevation of the pro-inflammatory cytokines IL-5, IL-6, and IL-17A, decreased expression of the anti-inflammatory cytokine IL-10, and altered forced expiratory volume in the first second as a percentage of predicted value (FEV1%pred) in both asthmatic endotypes. Vitamin D status had a stronger correlation with FEV1%pred in T2-low asthma than T2-high asthma, and 25(OH)D level was only positively linked to maximal mid-expiratory flow as a percentage of predicted value (MMEF%pred) in the T2-low group. Inflammation, hyperresponsiveness, and airway resistance (RL) was increased in both asthma models compared with controls while vitamin D deficiency further increased airway inflammation and airway obstruction. These findings were particularly prominent in T2-low asthma. Discussion: The potential function and mechanisms of vitamin D and both asthma endotypes should be studied individually, and further analysis of the potential signaling pathways involved with vitamin D on T2-low asthma is warranted.

Sex differences of small airway function and fractional exhaled nitric oxide in patients with mild asthma.

BACKGROUND: Sex differences of small airway function (SAF) and fractional exhaled nitric oxide (FeNO) in patients with mild asthma remain unclear. OBJECTIVE: To evaluate sex differences of SAF and FeNO in patients with mild asthma confirmed by positive methacholine challenge test (MCT) result. METHODS: This cross-sectional, double-centered, observational study enrolled 1609 adult patients with forced expiratory volume in 1 second greater than or equal to 80% and suspected asthma symptoms. Data of spirometry, FeNO, impulse oscillometry measurements, and peripheral blood test result were compared between males and females. The receiver-operating characteristic curves of SAF parameters and FeNO in predicting positive MCT result were also calculated. RESULTS: In patients with mild asthma matched by age, males had better SAF but higher FeNO levels than females (60 [29.27%] vs 187 [46.75%] for small airway dysfunction, 78.6% vs 72.0% for forced expiratory flow [FEF]50%, 67.5% vs 60.1% for FEF75%, 73.7% vs 67.4% for FEF25%-75%, and 42.0 ppb vs 29.0 ppb for FeNO, respectively, all P ≤ .001). The FeNO levels in male current smokers were considerably lower than those of nonsmokers. SAF and FeNO values declined more rapidly with age among female than male patients with asthma. The optimal cutoff values of FEF25%-75%, FEF50%, and FeNO for predicting a positive MCT result were 81.5%, 86.4%, and 41.0 ppb in males vs 73.7%, 76.9%, and 35.0 ppb in females. CONCLUSION: In patients with mild asthma, the female patients have worse SAF, lower FeNO levels, and a more prominent decline trend of those parameters with age than males. Sex-specific cutoff values should be considered when SAF parameters (FEF25%-75%, FEF50%), alone or combined with FeNO, are used to predict positive MCT result in asthma diagnosis.

Prediction of bronchodilation test in adults with chronic cough suspected of cough variant asthma.

Background: Many patients with cough variant asthma (CVA) are underdiagnosed and undertreated due to the atypical symptoms, low diagnostic sensitivity of bronchodilator response (BDR), and limited application of bronchial challenge test. Objective: To investigate whether airway reversibility in BDR can predict CVA diagnosis in patients with chronic cough and negative BDR. Methods: This open-label, prospective cohort study included patients with chronic cough, nearly normal chest CT scan, and negative BDR results. Inhaled corticosteroids and long-acting ß2 agonists were given for 4 weeks. The confirmed diagnosis of CVA was defined as improved symptoms and an increase of forced expiratory volume in 1 s (FEV1) by >12% and >200 mL after 4 weeks of treatment. Results: Of 155 patients recruited, 140 completed the study. Patients in the CVA positive diagnosis group had greater absolute (Δ) and percent (Δ%) improvements in FEV1 and forced expiratory flows (FEFs), and higher fractional exhaled nitric oxide (FENO) than in the CVA negative diagnosis group. The area under the receiver operating characteristic curves (AUCs) of ΔFEV1%, FEF25-75%pred (percentage of predicted forced expiratory flow at 25% to 75%) and FENO for CVA positive diagnosis was 0.825, 0.714, and 0.637, with cutoff values of 5.90%, 61.99% and 41.50 ppb, respectively. A joint model of ΔFEV1% combined with FEF25-75%pred or FENO increased the AUC to 0.848 and 0.847, respectively. Conclusion: ΔFEV1% in BDR can predict a CVA diagnosis and response to anti-asthma treatment in patients with chronic cough and negative BDR. Clinical trial registration: [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR2000029065].

Age-related circadian rhythm and variability of large- and small-airway function in healthy non-smoking adults: Data from 7-day diurnal and nocturnal home monitoring using an electronic portable spirometer.

Background: The aim of the study was to investigate the possible influencing factors of the large- and small-airway function variation in healthy non-smoking adults. Methods: Healthy non-medical non-smoking adults were enrolled in this prospective cohort study. Each participant took the portable spirometer test relying only on video teaching. Then conventional spirometry and bronchodilation test were conducted using a Jaeger spirometer, followed by 7-day diurnal and nocturnal home monitoring using a portable spirometer. Results: A drop in both large- and small-airway function began at about 25 years of age, and a rapidly decline at about 50 years. The CV of FEV1 (r = 0.47, P = 0.0082) and small-airway function variables correlated with age (r ≥ 0.37, P < 0.05 for both MEFs and MEFs/FVC), especially for evening small-airway function variables. The CV of large (4.666 ± 1.946, P = 0.002 for FEV1; 4.565 ± 2.478, P = 0.017 for FEV3) and small airways (10.38 ± 3.196, P = 0.031 for MEF50 and 11.21 ± 4.178, P = 0.023 for MMEF) was higher in the 45- to 60-year subgroup than in the 30- to 45-year and 18- to 30-year subgroups. Interpretation: Age was the main influencing factor of both central and peripheral airway function variability, especially for the small-airway function in the evening. The LLN of small-airway variables varies depending on the age and circadian rhythm. People older than 45 years should pay more attention to monitoring small-airway function in the evening, which will be helpful for early clinical detection of those at high risk for asthma. Trial registration number: ChiCTR2100050355.

Small-Airway Function Variables in Spirometry, Fractional Exhaled Nitric Oxide, and Circulating Eosinophils Predicted Airway Hyperresponsiveness in Patients with Mild Asthma.

PURPOSE: Patients with variable symptoms suggestive of asthma but with normal forced expiratory volume in 1 second (FEV1) often fail to be diagnosed without a bronchial provocation test, but the test is expensive, time-consuming, risky, and not readily available in all clinical settings. PATIENTS AND METHODS: A cross-sectional study was performed in 692 patients with FEV1≥80% predicted; normal neutrophils and chest high-resolution computed tomography; and recurrent dyspnea, cough, wheeze, and chest tightness. RESULTS: Compared with subjects negative for AHR (n=522), subjects positive for AHR (n=170) showed increased FENO values, peripheral eosinophils (EOS), and R5-R20; decreased FEV1, FEV1/Forced vital capacity (FVC), and forced expiratory flow (FEFs) (P≤.001 for all). Small-airway dysfunction was identified in 104 AHR+ patients (61.17%), and 132 AHR- patients (25.29%) (P<0.001). The areas under the curve (AUCs) of variables used singly for an AHR diagnosis were lower than 0.77. Using joint models of FEF50%, FEF75%, or FEF25%-75% with FENO increased the AUCs to 0.845, 0.824, and 0.844, respectively, significantly higher than univariate AUCs (P <0.001 for all). Patients who reported chest tightness (n=75) had lower FEFs than patients who did not (P<0.001 for all). In subjects with chest tightness, the combination of FEF50% or FEF25%-75% with EOS also increased the AUCs substantially, to 0.815 and 0.816, respectively (P <0.001 for all versus the univariate AUCs). CONCLUSION: FENO combined with FEF50% and FEF25%-75% predict AHR in patients with normal FEV1. FEF25%-75%, FEF50%, or FEF25%-75% together with EOS also can potentially suggest asthma in patients with chest tightness.

Spirometric Changes in Bronchodilation Tests as Predictors of Asthma Diagnosis and Treatment Response in Patients with FEV1 ≥ 80% Predicted.

BACKGROUND: Many patients with mild asthma are undiagnosed and untreated due to the low diagnostic sensitivity of bronchodilation test (BDT). OBJECTIVE: To investigate whether airway reversibility in BDT and fractional exhaled nitric oxide (Feno) can predict the response to antiasthma therapy (RAT) in patients with suspected asthma. METHODS: This open-label, prospective cohort study included patients with chronic recurrent asthma symptoms, normal FEV1, and negative BDT results. Inhaled corticosteroids and long-acting ß agonists were given for 4 weeks. A positive RAT was defined as improved symptoms and an increase of more than 200 mL in FEV1 after inhaled corticosteroid/long-acting ß agonist treatment. Lung tissues from another 19 patients who underwent pneumectomy for lung nodules were also analyzed. RESULTS: Of 110 patients recruited, 102 completed the study. Patients in the positive RAT group had a higher Feno and greater absolute (Δ) and percent (Δ%) improvements in forced vital capacity, FEV1, and forced expiratory flows (FEFs) in BDT than in the negative RAT group. The area under the curves of Feno, ΔFEV1%, ΔFEF25-75% (percent improvement in FEF at 25%-75% of forced vital capacity), and ΔFEF75% (percent improvement in FEF at 75% of forced vital capacity) for positive RAT were 0.703, 0.824, 0.736, and 0.710, with cutoff values of 33 parts per billion and 3.50%, 15.26%, and 26.04%, respectively. A joint model of Feno and ΔFEV1% increased the area under the curve to 0.880. Inflammatory cytokines were higher in the lung tissues of patients with predicted positive RAT than in those with predicted negative RAT. CONCLUSIONS: ΔFEV1% in BDT together with Feno predicted a positive RAT and an asthma diagnosis in patients with a normal FEV1 and negative BDT. Evidence of pathological changes increases the credibility of the predictive model.

IL-17 Aggravates Pseudomonas aeruginosa Airway Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

Pseudomonas aeruginosa airway infection increases risks of exacerbations and mortality in chronic obstructive pulmonary disease (COPD). We aimed to elucidate the role of IL-17 in the pathogenesis. We examined the expression and influences of IL-23/IL-17A in patients with stable COPD (n = 33) or acute COPD exacerbations with P. aeruginosa infection (n = 34). A mouse model of COPD (C57BL/6) was used to investigate the role of IL-17A in host inflammatory responses against P. aeruginosa infection through the application of IL-17A-neutralizing antibody or recombinant IL-17A. We found that P. aeruginosa infection increased IL-23/17A signaling in lungs of both COPD patients and COPD mouse models. When COPD mouse models were treated with neutralizing antibody targeting IL-17A, P. aeruginosa induced a significantly less polymorphonuclear leukocyte infiltration and less bacterial burden in their lungs compared to those of untreated counterparts. The lung function was also improved by neutralizing antibody. Furthermore, IL-17A-signaling blockade significantly reduced the expression of pro-inflammatory cytokine IL-1ß, IL-18, TNF-α, CXCL1, CXCL15 and MMP-9, and increased the expression of anti-inflammatory cytokine IL-10 and IL-1Ra. The application of mouse recombinant IL-17A exacerbated P. aeruginosa-mediated inflammatory responses and pulmonary dysfunction in COPD mouse models. A cytokine protein array revealed that the expression of retinol binding protein 4 (RBP4) was down-regulated by IL-17A, and exogenous RBP4-recombinant protein resulted in a decrease in the severity of P. aeruginosa-induced airway dysfunction. Concurrent application of IL-17A-neutralizing antibody and ciprofloxacin attenuated airway inflammation and ventilation after inoculation of P. aeruginosa in COPD mouse models. Our results revealed that IL-17 plays a detrimental role in the pathogenesis of P. aeruginosa airway infection during acute exacerbations of COPD. Targeting IL-17A is a potential therapeutic strategy in controlling the outcomes of P. aeruginosa infection in COPD patients.

The Value of Fractional Exhaled Nitric Oxide and Forced Mid-Expiratory Flow as Predictive Markers of Bronchial Hyperresponsiveness in Adults with Chronic Cough.

BACKGROUND: Bronchial provocation tests are standard for diagnosing the etiology of chronic cough, but they are time consuming and can induce severe bronchospasm. A safer and faster clinical examination to predict bronchial hyperresponsiveness (BHR) is needed. OBJECTIVE: The objective of this study was to investigate whether small-airway function tests can predict BHR in adult patients with chronic cough. METHODS: A retrospective, cross-sectional study of diagnoses made using spirometry and bronchial provocation test results was performed in 290 patients with chronic nonproductive cough. BHR-predictive values were analyzed via the area under receiver operating characteristic curves (AUCs). Optimal cutoff values were determined by maximizing the sum of sensitivity and specificity. RESULTS: Patients with chronic cough with BHR showed lower forced expiratory flow between 25% and 75% (FEF25%-75%), higher fractional exhaled nitric oxide (FENO), and a higher percentage of eosinophils in blood than patients without BHR (P < .0001 for all). The AUCs of FENO and FEF25%-75% for a BHR diagnosis were 0.788 (95% CI, 0.725-0.851) and 0.702 (95% CI, 0.641-0.763), respectively. Optimal cutoff values were 43 ppb for FENO and 78.5% for FEF25%-75%, with negative predictive values of 85.38% and 81.34%, respectively. The combined use of FENO and FEF25%-75% increased the AUC to 0.843 (95% CI, 0.794-0.892), significantly higher than either FENO (P = .012) or FEF25%-75% (P < .0001) alone. CONCLUSIONS: Small-airway dysfunction is present in patients with chronic cough and BHR. FEF25%-75% has value as a negative predictive parameter for BHR, especially when combined with FENO. FENO > 43 ppb and FEF25%-75% < 78.5% strongly predicted a positive bronchial provocation test.