Impulse oscillometry in the diagnosis of cough variant asthma in children.

BACKGROUND: Cough variant asthma (CVA) is one of the most common causes of chronic cough in children worldwide. The diagnosis of CVA in children remains challenging. This study aimed to assess the diagnostic utility of impulse oscillometry (IOS) pulmonary function in children with CVA. METHODS: This study included children aged 4 to 12 years diagnosed with CVA who underwent IOS pulmonary function and bronchodilation (BD) tests. A control group of healthy children was matched. Pre- and post-BD IOS parameters were recorded and presented as mean ± standard deviation or median. Receiver operating characteristic (ROC) curves were plotted, and the area under the curve (AUC) was calculated to evaluate the discriminatory potential of the IOS parameters for diagnosing CVA. RESULTS: A total of 180 patients with CVA and 65 control subjects were included. The baseline IOS parameters in the CVA group, except X5%pred, were significantly greater compared to the control group. After inhalation of salbutamol sulfate, all IOS parameters improved significantly in the CVA group. However, Z5%pred, R5%pred, and R20%pred remained greater in the CVA group compared to the control group. The improvement rates of IOS parameters in the CVA group significantly surpassed those in the control group. The ROC curve results for pre-BD IOS parameters and the improvement rate during the BD test showed that the combinations of pre-Z5%pred+△Z5% and pre-R5%pred+△R5% achieved the highest AUC value of 0.920 and 0.898, respectively. The AUC values of these combined parameters surpassed those of individual ones. CONCLUSIONS: This study highlights that children with CVA exhibit greater IOS parameters compared to healthy children. The changes in IOS parameters during the BD test provided valuable diagnostic information for CVA, and the combination of various parameters can help pediatricians accurately identify CVA in children.

The Effects of Budesonide Inhalation Treatment on the Expression Levels of Serum IL-6, TGF-ß1, and IgE and Pulmonary Function in Patients with Cough Variant Asthma and an Evaluation of Treatment Efficacy.

Objective: To retrospectively study the effects of budesonide inhalation combined with conventional symptomatic treatment on serum inflammatory factor expression levels and pulmonary function in patients with cough variant asthma (CVA) and to evaluate treatment efficacy. Methods: This retrospective cohort study included 200 patients diagnosed with CVA at the Second Hospital of Jiaxing between January 2022 and June 2023 and given conventional symptomatic treatment plus budesonide inhalation were included in this study. Patients were divided into a no remission group, a partial remission group and a complete remission group based on treatment effect. The expression levels of serum inflammatory factors, cough symptom scores, and small airway function indicators in the three groups of patients at different time points were compared. Results: In the three groups of CVA patients, after receiving budesonide inhalation combined with conventional symptomatic treatment, the expression levels of serum IL-5, IL-6, IL-8, TNF-α, TGF-ß1, and IgE and number of eosinophils significantly decreased (P <0.05). There were statistically significant differences in the IL-6 and TGF-ß1 levels among the three groups of CVA patients at T1, T2 and T3. There were statistically significant differences in IgE levels, number of eosinophils, cough symptom scores, and small airway function indicators between T2 and T3 (P<0.05). The receiver operating characteristic (ROC) curve prediction analysis revealed significant differences in the expression of IL-6 and TGF-ß1 at T1, T2, and T3. Conclusion: Budesonide inhalation combined with conventional symptomatic treatment can significantly reduce the levels of serum inflammatory factors in patients with CVA to reduce inflammation and the allergic response, thereby reducing the cough symptom score, improving pulmonary function, and improving therapeutic efficacy. In addition, IL-6 and TGF-ß1 can be used as early predictors of budesonide inhalation efficacy.

[Effect and mechanism of Maxing Shigan Decoction on reducing inflammatory response in rats with cough variant asthma via TLR4/MyD88/NF-κB and p38 MAPK signaling pathways].

This study aims to investigate the effect and mechanism of Maxingshigan Decoction on inflammation in the rat model of cough variant asthma(CVA). The SPF-grade SD rats of 6-8 weeks were randomized into normal, model, Montelukast sodium, and low-, medium-, and high-dose Maxing Shigan Decoction groups, with 8 rats in each group. The CVA rat model was induced by ovalbumin(OVA) and aluminum hydroxide sensitization and ovalbumin stimulation. The normal group and model group were administrated with equal volume of normal saline by gavage, and other groups with corresponding drugs by gavage. After the experiment, the number of white blood cells in blood and the levels of interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α) in the serum were measured. The lung tissue was stained with hematoxylin-eosin(HE). Western blot was employed to determine the protein levels of nuclear factor-κB(NF-κB), Toll-like receptor 4(TLR4), myeloid differentiation protein(MyD88), and mitogen-activated protein kinase(MAPK) in the lung tissue. Real-time PCR was carried out to measure the mRNA levels of TLR4 and MyD88 in the lung tissue. Compared with the normal group, the model group showed increased white blood cells, elevated IL-6 and TNF-α levels(P<0.01), lowered IL-10 level(P<0.01), up-regulated protein levels of TLR4, MyD88, p-p65/NF-κB p65, and p-p38 MAPK/p38 MAPK(P<0.01) and mRNA levels of TLR4 and MyD88(P<0.01) in the lung tissue. HE staining showed obvious infiltration of inflammatory cells around the airway and cell disarrangement in the model group. Compared with the model group, Montelukast sodium and high-dose Maxing Shigan Decoction reduced the white blood cells, lowered the IL-6 and TNF-α levels(P<0.01), and elevated the IL-10 level(P<0.01). Moreover, they down-regulated the protein levels of TLR4, MyD88, p-p65/NF-κB p65, p-p38 MAPK/p38 MAPK in the lung tissue(P<0.01) and the mRNA levels of TLR4 and MyD88 in the lung tissue(P<0.01). HE staining showed that Montelukast sodium and high-dose Maxing Shigan Decoction reduced inflammatory cell infiltration and cell disarrangement. The number of white blood cells, the levels of IL-10 and TNF-α in the serum, the protein levels of TLR4, MyD88, p-p65/NF-κB p65, and p-p38 MAPK/p38 MAPK, and the mRNA levels of TLR4 and MyD88 in the lung tissue showed no significant differences between the Montelukast sodium group and high-dose Maxing Shigan Decoction group. Maxing Shigan Decoction can inhibit airway inflammation in CVA rats by inhibiting the activation of TLR4/MyD88/NF-κB and p38 MAPK signaling pathways.

Effect of the modified painless blistering moxibustion with wheat-grain sized moxa cone on cough variant asthma of pathogenic wind attacking the lung: a randomized controlled trial. / æ”¹è‰¯æ— ç—›éº¦ç²’åŒ–è„“ç¸æ²»ç–—é£Žé‚ªçŠ¯è‚ºåž‹å’³å—½å˜å¼‚æ€§å“®å–˜ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the clinical effect of the modified painless blistering moxibustion with wheat-grain sized moxa cone on cough variant asthma (CVA) differentiated as pathogenic wind attacking the lung and explore the influences on eosinophil count (EOS) in the peripheral blood and the content of interleukin-4 (IL-4) and tumor necrosis factor-α (TNF-α) in the serum of patients. METHODS: Ninety-two patients with CVA of pathogenic wind attacking the lung were randomly divided into an observation group and a control group, 46 cases in each group. In the observation group, the modified painless blistering moxibustion with wheat-grain sized moxa cone was applied to the unilateral Feishu (BL 13), Gaohuang (BL 43) and Zusanli (ST 36) in each session of treatment, once every 3 days. In the control group, budesonide and formoterol powder inhaler was delivered, 4.5 µg per inhalation, once every half an hour after breakfast and dinner; one more time of inhalation needed if the symptoms were not well controlled, but less than 6 times of inhalation per day. The duration of treatment was 8 weeks in both groups. Separately, before and after treatment, and during the 1-month follow-up after treatment completion, the score of the symptoms of traditional Chinese medicine (TCM) was observed in the two groups; using the lung function detector, the indexes of pulmonary function (forced expiratory volume in one second [FEV1], FEV1/forced vital capacity [FVC] and peak expiratory flow [PEF]) were determined, and the count of EOS in the peripheral blood and the content of IL-4 and TNF-α in the serum were determined before and after treatment; and the clinical effect was compared between the two groups. RESULTS: After treatment and in follow-up, the TCM symptom scores were decreased compared with those before treatment in the two groups (P<0.05), and the score in the observation group was lower than that of the control group in follow-up (P<0.05). After treatment, FEV1, FEV1/FVC and PEF were increased when compared with those before treatment in the two groups (P<0.05), and the count of EOS in the peripheral blood and the content of IL-4 and TNF-α in the serum were reduced (P<0.05); there was no statistical difference in these indexes between the two groups (P>0.05). After treatment, the total effective rate of the observation group was 95.7% (44/46), which was not different statistically in comparison with the control group (93.5% [43/46], P>0.05). In the follow-up, the total effective rate of the observation group was 95.7% (44/46), which was higher than that of the control group (78.3% [36/46], P<0.05). CONCLUSIONS: The modified painless blistering moxibustion with wheat-grain sized moxa cone may ameliorate the symptoms of CVA of pathogenic wind attacking the lung and improve the pulmonary functions, which is probably related to the regulation of the count of EOS in the peripheral blood and the content of IL-4 and TNF-α in the serum, thereby, reducing the inflammatory response.

Clinical efficacy of montelukast sodium combination therapy for cough variant asthma in children: A meta-analysis.

This meta-analysis aims to assess the clinical effectiveness of combination therapy with montelukast sodium for the treatment of cough variant asthma (CVA) in children, intending to provide clinical evidence and data to guide the selection of clinical therapy. A literature review was conducted using numerous databases, including China National Knowledge Infrastructure (CNKI), Wanfang database, Embase, PubMed, and Web of Science, from inception to December 2023. Trials meeting the criteria for the combined treatment of montelukast sodium for CVA in children were included. Stata 16.0 software was utilized for meta-analysis. The combined treatment group received montelukast sodium in addition to the control group, while the control group received budesonide, fluticasone propionate, salmeterol-fluticasone, or ketotifen alone. This investigation included 18 papers. All subjects were from the Chinese population. Compared to the control group, the combined treatment group demonstrated a higher effective rate (relative ratio [RR] = 1.23, 95% confidence interval [CI]: 1.18-1.29, p < .001), but no difference in the incidence of adverse reactions (RR = 0.65, 95% CI: 0.42-1.02, p = .060) after treatment. Moreover, the peak expiratory flow (PEF) (SMD = 1.69, 95% CI: 1.09-2.30, p < .001), forced vital capacity (FVC) (SMD = 1.67, 95% CI: 0.94-2.39, p < .001), forced expiratory volume in 1 s (FEV1) (SMD = 1.74, 95% CI: 1.09-2.40, p < .001), and FEV1/FVC (SMD = 1.84, 95% CI: 0.41-3.28, p = .012) were significantly higher in the combined treatment group than in the control group after treatment. Compared with the control group, the levels of tumor necrosis factor-α (SMD = -2.38, 95% CI: -3.22 to -1.55, p < .001), IL-4 (SMD = -2.65, 95% CI: -3.26 to -2.04, p < .001), and IgE (SMD = -2.98, 95% CI: -3.24 to -2.72, p < .001) were significantly lower in the combined treatment group after treatment. The combined use of montelukast sodium in the treatment of pediatric CVA in China is associated with a significant clinical effect, making it a reasonable therapeutic approach.

Prevalence and causes of chronic cough in Japan.

BACKGROUND: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted. METHODS: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered. RESULTS: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor. CONCLUSIONS: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough.

Microbiota Alterations in Lung, Ileum, and Colon of Guinea Pigs with Cough Variant Asthma.

Alterations in the microbiota composition, or ecological dysbiosis, have been implicated in the development of various diseases, including allergic diseases and asthma. Examining the relationship between microbiota alterations in the host and cough variant asthma (CVA) may facilitate the discovery of novel therapeutic strategies. To elucidate the diversity and difference of microbiota across three ecological niches, we performed 16S rDNA amplicon sequencing on lung, ileum, and colon samples. We assessed the levels of interleukin-12 (IL-12) and interleukin-13 (IL-13) in guinea pig bronchoalveolar lavage fluid using the enzyme-linked immunosorbent assay (ELISA). We applied Spearman's analytical method to evaluate the correlation between microbiota and cytokines. The results demonstrated that the relative abundance, α-diversity, and ß-diversity of the microbial composition of the lung, ileum, and colon varied considerably. The ELISA results indicated a substantial increase in the level of IL-13 and a decreasing trend in the level of IL-12 in the CVA guinea pigs. The Spearman analysis identified a correlation between Mycoplasma, Faecalibaculum, and Ruminococcus and the inflammatory factors in the CVA guinea pigs. Our guinea pig model showed that core microorganisms, such as Mycoplasma in the lung, Faecalibaculum in the ileum, and Ruminococcus in the colon, may play a crucial role in the pathogenesis of CVA. The most conspicuous changes in the ecological niche were observed in the guinea pig ileum, followed by the lung, while relatively minor changes were observed in the colon. Notably, the microbial structure of the ileum niche approximated that of the colon niche. Therefore, the results of this study suggest that CVA development is closely related to the dysregulation of ileal, lung, and colon microbiota and the ensuing inflammatory changes in the lung.

Spirometry in the diagnosis of cough variant asthma in children.

OBJECTIVE: This study aimed to assess the diagnostic utility of spirometry, particularly focusing on small airway parameters, in children with cough variant asthma (CVA). METHODS: This study included children aged 5-12 years with a diagnosis of CVA. Pre- and postbronchodilation spirometry parameters, including FEV1 %pred, FVC%pred, FEV1 /FVC%pred, PEF%pred, FEF25 %pred, FEF50 %pred, FEF75 %pred, MMEF%pred, were recorded. Receiver operating characteristic curves were plotted, and the area under the curve (AUC) was calculated to assess the discriminatory potential of these spirometry parameters for CVA. A prediction model based on logistic regression (LR) was performed. RESULTS: A total of 200 patients with CVA and 73 control subjects were included. Baseline spirometry parameters in the CVA group, except for FVC%pred, were significantly lower compared to the control group. After inhalation of salbutamol sulfate, all parameters showed significant improvement in the CVA group. However, these parameters, except for FEV1 %pred and FVC%pred, remained lower in the CVA group compared to the control group. The improvement rate of each parameter in the CVA group, except for ∆ FVC%, was significantly higher than that in the control group. △ MMEF% achieved the highest AUC of 0.797 with a threshold value of 16.09%, followed by △ FEF75 % (0.792), △ FEV1 % (0.756), and △ FEF50 % (0.747) with threshold values of 19.01%, 4.48%, and 19.4%, respectively. The clinical prediction model included four variables (age, △ FEF25 %, △ FEF75 %, and △ MMEF%) and demonstrated excellent performance distinguishing patients with and without CVA (AUC = 0.850). In the CVA group, the △ FEV1 % showed a positive correlation with small airway parameters. CONCLUSIONS: This study highlights that children with CVA exhibit lower pulmonary function parameters compared to healthy children. Changes in small airway parameters during bronchodilator tests can be valuable in diagnosing CVA, and the LR prediction model incorporating age and several pulmonary parameters can assist physicians in accurately identifying CVA in clinical practice.

Alveolar nitric oxide concentration plays an important role in identifying cough variant asthma and assessing asthma control in children.

OBJECTIVE: To study the value of alveolar nitric oxide concentration (CaNO) in the identification and disease control of cough variant asthma. METHODS: A retrospective study was conducted on cough variant asthma (CVA-Group), nonasthmatic cough (NAC-Group) and healthy control children (C-Group) aged 5-12 years. The exhaled nitric oxide and spirometry test results of the three groups were collected and compared. RESULTS: A total of 410 children were included in this study, including 190 in the CVA-Group, 183 in the NAC-Group, and 37 in the C-Group. The CaNO values of the CVA-Group [11.40 ppb (8.48-14.25)] were significantly higher than those of the NAC-Group and C-Group (all p values <.05). The MMEF %pred values of the CVA-Group [63.65 (56.28-73.58)] were significantly lower than those of the NAC-Group and C-Group (all p values <.05). FeNO50, JawNO and other spirometry indices (FVC %pred, FEV1%pred, FEV1/FVC %pred) showed no significant difference among the three groups. ROC curve analysis showed that the optimal cutoff point value of CaNO was 9.45 ppb, corresponding to 0.816 sensitivity and 0.736 specificity. Spearman correlation analysis showed a significant negative correlation between the CaNO measurement and CVA control score. CONCLUSIONS: CaNO can not only help identify CVA early in children aged 5-12 years with chronic cough but is also significantly negatively correlated with the CVA control score.

Regulation of Immune Balance by Traditional Chinese Medicine in Treatment of Cough Variant Asthma： A Review / 中国实验方剂学杂志

Cough variant asthma （CVA） is a chronic respiratory disease with cough as its main symptom. The occurrence of CVA is closely related to non-specific airway inflammation， and its pathogenesis involves environmental， genetic， immune， and other factors. In recent years， the advantages of traditional Chinese medicine （TCM） in the treatment of CVA have attracted the attention of experts and scholars in China and abroad， especially its prominent role in regulating immune balance， relieving cough symptoms in CVA patients， and reducing recurrence. T Helper cells 1 （Th1）， T helper cells 2 （Th2）， T helper cells 17 （Th17）， and regulatory T cells （Treg） are derived from CD4+ T cells. Immune imbalance of Th1/Th2 and Th17/Treg is a new hotspot in the pathogenesis of CVA and a potential key target in the treatment of CVA by TCM. Th cell subsets are in dynamic balance under physiological conditions， maintaining respiratory immune homeostasis in which pro-inflammatory cytokines and anti-inflammatory cytokines are balanced. Immature helper T cells （Th0） can be differentiated into Th1， Th2， Th17， Treg， and other cell subsets due to cytokine types in the microenvironment in the stage of CVA maturation. The proliferation of Th2 cells leads to eosinophilic airway inflammation. Excessive differentiation of Th17 cells induces neutrophil airway inflammation. Th1/Th2 and Th17/Treg cells are mutually restricted in number and function， and the immune imbalance of Th1/Th2 and Th17/Treg is easy to aggravate the generation of inflammatory response. Restoring immune balance is particularly important for the airway anti-inflammatory therapy of CVA. In this paper， the imbalance of Th1/Th2 and Th17/Treg and the pathogenesis of CVA were systematically expounded. Meanwhile， the latest research on the regulation of immune imbalance by TCM compound， single TCM， and its effective ingredients in the treatment of CVA was reviewed. It provides ideas and references for revealing the scientific connotation of TCM regulating immune balance therapy of CVA， as well as the development of clinical treatment and basic research of CVA.

Efficacy of ß2-adrenergic receptor agonist combined with corticosteroid in the treatment of children with cough variant asthma.

BACKGROUND: Cough variant asthma (CVA) is one of the most common respiratory diseases in children, which has a serious impact on the quality of life and daily activities of children. For severe CVA, immunomodulatory drugs are needed. AIM: To evaluate the efficacy of salmeterol combined with budesonide in the treatment of pediatric CVA. METHODS: 130 children with CVA from January 2020 to December 2022 were prospectively selected and randomly divided into an observation group (salmeterol combined with budesonide) and a control group (budesonide combined with a placebo). Compare the clinical efficacy of two groups before and after intervention. The evaluation parameters include cough frequency score, nocturnal cough arousal, and lung function indicators. Serum inflammatory markers, immune function markers and airway anatomical indicators were also measured. RESULTS: After the intervention, the total effective rate of the observation group was significantly higher than that of the control group, and the cough frequency score and the night cough wake rate of the observation group were lower than that of the control group, with a statistically significant difference. In addition, the changes of lung function indicators, serum markers and immune function markers in the observation group were better than those in the control group. CONCLUSION: The clinical efficacy of salmeterol combined with Budesonide in the treatment of CVA is better than that of Budesonide alone.

An efficacy and safety evaluation of montelukast + fluticasone propionate vs. fluticasone propionate in the treatment of cough variant asthma in children: a meta-analysis.

PURPOSE: This study aimed to evaluate the efficacy and safety of montelukast (Mon) + fluticasone propionate (Flu) versus Flu in the treatment of cough variant asthma (CVA) in children. METHODS: Eligible documents were selected from various databases. Weighted mean difference (WMD) and 95% confidence interval (CI) were used to evaluate continuous variables, and categorical variables were evaluated using risk ratio (RR) and 95% CI. Heterogeneity analysis was performed using Cochran's Q test and I2 statistics, followed by sensitivity analysis and publication bias evaluation. RESULTS: Nine studies were included, and Flu + Mon was found to significantly improve the total effective rate and reduce cough recurrence compared to Flu. The cough remission and disappearance times in the Mon + Flu group were significantly lower than those in the Flu group. FEV1% recovery in the Mon + Flu group was significantly better than that in the Flu group. CONCLUSION: Mon + Flu is effective and safe for the treatment of CVA in children.

Patient response to the management during the acute presentation of cough variant Asthma: Retrospective cohort study.

The clinical improvement after assessing patients with cough variant asthma in outpatient clinics, and therapy success varied depending on the subjective improvement. Cough could be controlled within appropriate time and subsequent management can consist of inhaled corticosteroids. In this study we used the cough improvement, the only available clinical response, as a predictable factor to determine the effect of different modalities of treatment among patients with cough variant asthma. Retrospective observational analysis was performed in Saudi Arabia's King Saud University Medical City, on the presentation, diagnosis, course of therapy, and responsiveness to oral and inhaled steroids in patients with cough variant asthma. All patients who visited the clinic on multiple occasions with persistent, acute coughing without being pre-screened between September 2021 and September 2022 included based on medical records. Cough resembles cough variant asthma is the term used to describe a cough without a diagnosed etiology. To identify patients eligible for CVA treatment, iindividuals having GERD-associated cough, allergic rhinitis, bronchial asthma, smokers and atopic cough was excluded. For the examination of these findings, IBM SPSS version 28 (Armonk, NY, USA) was employed. As a result of using budesonide-formoterol inhaler, most patients (86.3 %) showed improvement in their cough symptoms (with 95 %CI: 78.3 to 94.9). There was a significant yet weak positive correlation between the frequency of cough symptoms before and after using budesonide-formoterol (r = 0.318, P value < 0.001). The understanding of treatment response and patient selection for budesonide-formoterol inhaler therapy, providing clinicians with valuable information to optimize patient care.

Ethanol Extract of Anacyclus pyrethrum Root Ameliorates Cough-Variant Asthma Through the TLR4/NF-κB Pathway and Wnt/ß-Catenin Pathway.

Cough-variant asthma (CVA) has been recognized as the initial stage or pre-asthmatic state of classic asthma, which characterized by cough as the primary clinical presentation. Inhaled glucocorticoids, oral leukotriene receptor antagonists and antihistamines are the clinical treatments, but their efficacy is not satisfactory. Some traditional Chinese medicine (TCM) has been reported to have certain advantages in the treatment of CVA, but the underlying molecular mechanisms are still unclear. Recent research has indicated that Anacyclus pyerhrurm (L) DC. is commonly used in the treatment of human diseases. The aim of our study was to evaluate the anti-inflammatory and anti-oxidative mechanism of the ethanol extract of Anacyclus pyrethrum (L) DC. root (EEAP) in a model of CVA. In our study, we indicated that EEAP ameliorated CVA by reducing cough frequency and inflammatory effect and oxidative stress in an in vivo rat model of CVA. In addition, EEAP ameliorated LPS-induced cell apoptosis and regulated inflammatory effect and oxidative stress in vitro. Mechanistically, EEAP exerted anti-inflammatory effects through regulating the TLR4/NF-κB pathway and Wnt/ß-catenin pathway, and overexpressing TLR4 or activating the Wnt/ß-catenin pathway by SKL2001 reversed EEAP-exerted effects in LPS-exposed BEAS-2B and 16-HBE cells. In conclusion, EEAP attenuated cell apoptosis, inflammation and oxidative stress through restraining the TLR4/NF-κB pathway and Wnt/ß-catenin pathway in CVA, which shown that EEAP might be a promising therapeutic agent for CVA and may provide a theoretical basis for clinical treatment with CVA patients.

Xiaoqinglong decoction suppresses childhood cough variant asthma and inhibited the body inflammatory response by regulating IL-6/STAT3 signalling pathway.

Xiaoqinglong decoction (XQLD) is widely used clinically in the treatment of childhood cough variant asthma (CVA). However, its potential mechanism is still unknown. In the present study, the authors investigate the biological network and signalling pathway of XQLD in treatment of childhood CVA using network pharmacology-based analysis and experimental validation. By using the Bioinformatics Analysis Tool Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) database, the authors confirmed the correlation between XQLD and asthma, and the authors screened 1338 potential target genes of Mahuang and Guizhi, the most active herbs in XQLD. By overlapping "Childhood asthma-related genes" of DisGeNET database, the authors identified 58 intersecting genes of Childhood asthma and 1338 target genes of Mahuang and Guizhi. The intersecting genes were used to construct the protein-to-protein interaction and performed Gene Ontology (GO) functional and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Gene Ontology enrichment analysis demonstrated 359 Biological Process terms, 16 Cellular Component terms, and 26 Molecular Function terms. Meantime, 75 terms of Kyoto Encyclopedia of Genes and Genomes signalling pathway were involved in enrichment analysis. These candidates showed a significant correlation with inflammatory response and positive regulation of tyrosine phosphorylation of STAT protein. In addition, XQLD treatment significantly upregulated serum interferon-γ expression, and downregulated serum interlukin-6 expression of CVA mice. XQLD treatment significantly inhibited phosphorylation of STAT3 in bronchial-lung tissues. Our data suggest that XQLD effectively alleviated bronchial-lung tissue damage in CVA mice and inhibited the body inflammatory response by regulating interlukin-6/STAT3 signalling pathway.

Validity of fractional exhaled nitric oxide and small airway lung function measured by IOS in the diagnosis of cough variant asthma in preschool children with chronic cough.

BACKGROUND: To investigate the role of combined impulse oscillometry (IOS) and fractional exhaled nitric oxide (FeNO) in the diagnosis of cough variant asthma (CVA) in preschool children. METHODS: A total of 197 preschool-aged children with chronic cough were selected from the paediatric outpatient clinic. Allergy histories were collected for all children along with IOS and FeNO. Paediatric respiratory specialists divided the children into a CVA group (n = 90) and a noncough variant asthma (nCVA) group (n = 107) according to the diagnostic criteria for CVA After diagnostic treatment, the correlation between the FeNO and IOS values and the diagnosis in the two groups was analysed, and the area under the curve (AUC) of each index was calculated. RESULTS: (1) X5 was significantly different between the CVA group and the nCVA group (- 4.22 vs. - 3.64, p < 0.001), as was the FeNO value (29.07 vs. 16.64, p < 0.001). (2) Receiver operating characteristic (ROC) analysis showed that the AUCs of FeNO alone and X5 alone were 0.779 and 0.657, respectively, while the AUC of FeNO (cut-off value of 18 ppb) plus X5 (cut-off value of -4.15 cmH2O/(l/s)) reached 0.809. CONCLUSIONS: Children with CVA may have small airway dysfunction at an early stage. For preschool children with chronic cough, the combination of FeNO and X5 can better identify those with CVA. TRIAL REGISTRATION NUMBER: This trial was registered with and approved by the Chinese Clinical Trial Registry, with registration number ChiCTRcRRC-17011738, and was reviewed and approved by the Ethics Committee of Southwest Hospital.

Efficacy and Safety of Yukmijihwang-Tang in the Treatment of Cough-Variant Asthma: Study Protocol for a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.

BACKGROUND: Cough-variant asthma (CVA), a precursor of typical asthma, is the main cause of chronic cough. We hypothesize that yukmijihwang-tang (YJT), which has been used for chronic cough in traditional medicine and has been reported to have an anti-inflammatory effect, could be an adjuvant to asthma treatment. METHODS: We plan a randomized, double-blind, placebo-controlled, multicenter, phase 2 trial to investigate the efficacy and safety of YJT in CVA patients. A total of 60 patients with CVA will be recruited and randomly assigned to either a high-dose YJT group, standard-dose YJT group, or control group (placebo) in a 1:1:1 allocation ratio after a 2-week run-in period. For the run-in period, only inhaled corticosteroids (ICSs) will be used, and the investigational drug will be administered once a day with concomitant ICS for 6 weeks. Data will be collected at baseline, week 3, and week 6, and the primary outcome measure will be the mean cough symptom score (CSS) change before and after medication. The secondary outcome measures will include the Leicester cough questionnaire-Korean version (LCQ-K) score, eosinophil count and eosinophil cationic protein level, pulmonary function test, and the number of uses of rescue medication, and so on. CONCLUSION: This study aimed to evaluate the efficacy and safety of YJT in concomitant treatment with ICS in patients with CVA and to determine the optimal dosage of YJT. The results are expected to provide evidence for the use of YJT as an adjuvant treatment for CVA.Cough-Variant-Asthma (CVA), eine Frühform von typischem Asthma, ist die Hauptursache von chronischem Husten. Unserer Vermutung nach könnte Yukmijihwang-Tang (YJT), das in der traditionellen Medizin zur Behandlung von chronischem Husten eingesetzt wird und das Berichten zufolge einen entzündungshemmenden Effekt hat, unterstützend in der Asthma-Therapie wirken.en: Wir planen eine randomisierte, doppelblinde, placebokontrollierte, multizentrische Phase-2-Studie, um die Wirksamkeit und Sicherheit von YJT bei Patienten mit CVA zu untersuchen. Insgesamt werden 60 CVA-Patienten für die Studie rekrutiert und nach einer zweiwöchigen Run-in-Phase randomisiert im Verhältnis 1:1:1 einer Gruppe mit hochdosiertem YJT, einer Gruppe, die YJT in der Standarddosierung erhält oder einer Kontrollgruppe (Placebo) zugewiesen. Während der Run-in-Phase werden nur inhalative Corticosteroide (ICS) verwendet, und das Prüfpräparat wird über 6 Wochen einmal täglich gleichzeitig mit den ICS angewendet. Die Datenerhebung erfolgt bei Studienbeginn, in Woche 3 sowie in Woche 6, und das primäre Zielkriterium ist die Änderung des mittleren Hustenscores (cough symptom score, CSS) vor und nach der Anwendung der Medikamente. Zu den sekundären Zielkriterien gehören der Score des Leicester Hustenfragebogens - koreanische Version (LCQ-K), die Eosinophilenzahl und der Spiegel an eosinophilem kationischen Protein, Lungenfunktionstests sowie die Anzahl der Anwendungen von Bedarfsmedikation usw.Ziel dieser Studie ist es, die Wirksamkeit und Sicherheit von YJT bei gleichzeitiger Behandlung mit ICS bei Patienten mit CVA zu bewerten und die optimale YJT-Dosis zu ermitteln. Es wird erwartet, dass die Ergebnisse Belege für die Anwendung von YJT als adjuvante Therapie bei CVA liefern werden.WHO International Clinical Trials Registry Platform, Clinical Research Information Service (CRIS), KCT0006994, registriert am 10. Februar 2022, https://cris.nih.go.kr/cris/search/detailSearch.do/21743.

A comparative study on the value of lower airway exhaled nitric oxide combined with small airway parameters for diagnosing cough-variant asthma.

BACKGROUND: The diagnosis of cough-variant asthma (CVA) is based on bronchial provocation test, which is challenging to be conducted. Most CVA patients have type 2 airway inflammation and small airway dysfunction. FeNO200, reflecting small airway inflammation, may be used to diagnose CVA. OBJECTIVE: This study aimed to explore and compare the value of lower airway exhaled nitric oxide (FeNO50, FeNO200, and CaNO) combined with small airway parameters for diagnosing CVA. METHODS: Chronic cough patients who attended the clinic from September 2021 to August 2022 were enrolled and divided into CVA group (n = 71) and non-CVA (NCVA) group (n = 212). The diagnostic values of FeNO50, FeNO200, concentration of alveolar nitric oxide (CaNO), maximal mid-expiratory flow (MMEF), forced expiratory flow at 75% of forced vital capacity (FEF75%) and forced expiratory flow at 50% of forced vital capacity (FEF50%) for CVA were evaluated. RESULTS: FeNO50 [39(39) ppb versus 17(12) parts per billion (ppb), p < 0.01], FeNO200 [17(14) ppb versus 8(5) ppb, p < 0.01] and CaNO [5.0(6.1) ppb versus 3.5(3.6) ppb, p < 0.01] in CVA group were significantly higher than those in NCVA group. The optimal cut-off values of FeNO50, FeNO200, and CaNO for diagnosis of CVA were 27.00 ppb [area under the curve (AUC) 0.88, sensitivity 78.87%, specificity 79.25%], 11.00 ppb (AUC 0.92, sensitivity 88.73%, specificity 81.60%) and 3.60 ppb (AUC 0.66, sensitivity 73.24%, specificity 52.36%), respectively. For diagnosing CVA, the value of FeNO200 was better than FeNO50 (p = 0.04). The optimal cut-off values of MMEF, FEF75%, and FEF50% for the diagnosis of CVA were 63.80% (AUC 0.75, sensitivity 53.52%, specificity 86.32%), 77.9% (AUC 0.74, sensitivity 57.75%, specificity 83.49%) and 73.50% (AUC 0.75, sensitivity 60.56%, specificity 80.19%), respectively. The AUCs of FeNO50 combined with MMEF, FEF75%, and FEF50% for the diagnosis of CVA were all 0.89. The AUCs of FeNO200 combined with MMEF, FEF75%, and FEF50% for the diagnosis of CVA were all 0.93. CONCLUSION: FeNO200 > 11 ppb contributed strongly for differentiating CVA from chronic cough, especially in patients with small airway dysfunction.

Efficacy and safety of montelukast adjuvant therapy in adults with cough variant asthma: A systematic review and meta-analysis.

BACKGROUND: Montelukast is a highly selective and specific cysteinyl leukotriene receptor antagonist used in the treatment of asthma. Whether montelukast as adjuvant therapy can significantly and safely treat adults with cough variant asthma (CVA) remains inconclusive. AIMS: This meta-analysis systematically evaluated the efficacy and safety of montelukast as an adjuvant treatment for adults with CVA. MATERIALS AND METHODS: Randomized controlled trials (RCTs) on montelukast combined with inhaled corticosteroids (ICS) and long-acting ß2 agonists (LABAs) to treat CVA in adults, from inception to March 6, 2023, were retrieved from the CNKI, Wanfang, VIP, CBM, PubMed, Embase, Cochrane Library, and Web of Science databases and Clinical Trials website. Review Manager (version 5.4) and Stata (version 15.0) were used to conduct the meta-analysis. RESULTS: A total of 15 RCTs were ultimately included in the meta-analysis. It was established that montelukast as adjuvant therapy raised the total effective rate (RR = 1.20, 95% confidence interval [CI] [1.13, 1.27], P < 0.01) and improved the FEV1% (SMD = 0.91, 95% CI [0.40, 1.41], P < 0.01), PEF% (SMD = 0.63, 95% CI [0.38, 0.88], P < 0.01), FEV1 (SMD = 1.15, 95% CI [0.53, 1.77], P < 0.01), PEF (SMD = 0.64, 95% CI [0.42, 0.86], P < 0.01), and FEV1/FVC% (SMD = 0.76, 95% CI [0.51, 1.01], P < 0.01) and reduced the recurrence rate (RR = 0.28, 95% CI [0.15, 0.53], P < 0.01). The incidence of adverse reactions was higher in the montelukast auxiliary group compared to the control group but with no statistical difference (RR = 1.32, 95% CI [0.89, 1.96], P = 0.17). CONCLUSION: Existing evidence indicated that the use of montelukast as an adjuvant therapy had therapeutic efficacy superior to ICS + LABA alone for the treatment of adult patients with CVA. However, further research is needed, especially a combination of high-quality long-term prospective studies and carefully designed RCTs.