122 children with variant cough were admitted in our hospital between March 2020 and May 2023. The subjects were divided into observation therapy (XZM + FPS, n = 60) and control therapy (FPS, n = 60) according to block randomization. In observation therapy, there were 28 males and 32 females, aged 2–11 years, with an average age of 6.14 ± 1.35 years, the duration of the disease is 1–20 months, the average (14.5 ± 3.8) month. There were 22 cases of intermittent attacks, 30 cases of mild persistent attacks, 5 cases of moderate persistent attacks, and 3 cases of severe persistent attacks; There were 29 males and 33 females in control therapy, aged 2–12 years, with an average age of 6.23 ± 1.48 years, the duration of the disease is 2–21 months, the average (15.1 ± 3.7) month. There were 20 cases of intermittent attacks, 31 cases of mild persistent attacks, 6 cases of moderate persistent attacks, and 5 cases of severe persistent attacks. There was no noticeable discrepancy between two groups (P > 0.05).

This study was approved by the Ethics Committee of Shijiazhuang Maternity and Child Health Hospital with the official approval number: 20201112. All study procedures complied with the Declaration of Helsinki (2013 version) and the Guidelines for the Use of Controlled Traditional Chinese Medicines in Children (2019 Edition, National Medical Products Administration). Guardians provided written informed consent.

Potential addiction risk was assessed at months 1, 2, and 3 post-treatment, with no dependence symptoms observed in either group. To monitor potential growth impact from fluticasone, height and weight were measured monthly. No significant intergroup difference in growth velocity was found (0.32 ± 0.11 cm/month vs. 0.30 ± 0.10 cm/month, P = 0.389), indicating no adverse effect on development.

Inclusion criteria: (1) All children met the diagnostic criteria of cough variant asthma (16); (2) The child was less than 12 years old; (3) Persistent cough for more than 4 weeks, mostly in the morning and at night; (4) Cough was mainly dry cough, without wheezing; (5) Exclude chronic cough caused by other reasons; (6) Positive bronchial provocation test; (7) Antibiotic treatment was ineffective, while anti-asthma medication was effective; (8) The parents gave informed consent for the treatment. Exclusion criteria: (1) Patients with infectious disease occurring before or within months of treatment; (2) During the investigational treatment of other drugs; (3) Children with severe insufficiency of the kidney or other important organs; (4) Children with other infectious diseases occurring 1 month before treatment.

Control therapy was treated with FPS (H20170361, GlaxoSmithKline Australia Pty Ltd.) 100 μg/time, twice a day. Observation therapy was given XZM + FPS (Z20050288, Gansu Pu’an Pharmaceutical Co., Ltd.) 10 mL/time, three a day. The treatment period was 3 months in both groups.

After treatment, the ORR of observation therapy was better than control therapy (Table 1, P < 0.05).

Before treatment, there were on prominent discrepancy in IL-4, TNF-α, SAA as well as CRP levels between control therapy and observation therapy (P > 0.05). After processing, the level of IL-4 was upgraded, the TNF-α, SAA as well as CRP levels were lessened. Also, the IL-4 was higher, while TNF-α, SAA as well as CRP levels were lowered in observation therapy than control therapy (Figure 1, P < 0.05).

Before treatment, there was no notable diversity in peripheral eosinophil between two groups (P > 0.05). Via treatment cycles, the peripheral eosinophil count of observation were evidently lessened than control (Figure 2, P < 0.05).

Via treatment cycles, the FEV1 and FEV1/FVC in observation therapy were higher than control therapy (Figure 3, P < 0.05).

The post-processing scores of daytime and nighttime cough were reduced than pre-processing in two groups (P < 0.05). Besides, the scores in observation were lower than control (P < 0.05) (Figure 4, P < 0.05).

Before therapy, CD³⁺, CD⁴⁺, CD⁴⁺/CD⁸⁺ of the two groups were similar (P > 0.05). Through treatment cycles, the CD³⁺, CD⁴⁺, CD⁴⁺/CD⁸⁺ in observation therapy were markedly upgraded than control (Figure 5, P < 0.05).

The incidence of adverse reactions in the observation and control therapy were no noteworthy diversity in untoward reaction Table 2.

Childhood variant cough is a common childhood disease, which is closely related to environmental, immune, genetic and other factors (21–24). In addition, children with variant cough have more obvious nighttime symptoms, and clinical symptoms are easily aggravated by environmental factors such as cold air and smoke (25). Clinical studies have found that chronic cough in children with this disease persists for a long time and has a long course of illness, seriously affecting the child’s physical health (24, 26–28). Presently, western medicine mainly uses leukotriene receptor antagonists, bronchodilators and glucocorticoid for treatment, among which fluticasone propionate suspension (FPS) is a glucocorticoid drug that has a strong affinity for glucocorticoid receptors and plays a strong local anti-inflammatory role (29). And it can exert anti-inflammatory effects by restraining phospholipase A, affecting the synthesis of inflammatory mediators. Concurrently, nebulization inhalation can minimize the toxicity of the drug (20). A meta-analysis found that the combined treatment of montelukast sodium for variant cough in children is more effective than using budesonide, fluticasone propionate, salmeterol fluticasone or ketotifen alone (30). Although the combination or single use of glucocorticoids has a quick effect, long-term extensive use can cause high recurrence rate and systemic hormonal side effects (31). Hence, it is crucial to find treatment methods with less side roles and superior efficacy for children with variant cough.

Traditional Chinese medicine believes that variant cough belongs to the category of “cough asthma” and “cough,” which is caused by the accumulation of internal heat in children, the combination of phlegm and heat, the invasion of external pathogens, and the stimulation of latent phlegm, leading to the loss of lung circulation. Cold qi and phlegm are the main pathological mechanisms (32). In recent years, it has been shown that traditional Chinese medicine can achieve good treatment efficacy in children with variant cough (22). Xuanfei Zhisou mixture (XZM) has the effects of dispelling wind, promoting lung circulation, stopping cough and resolving phlegm. Hu et al. demonstrated that XZM was able to diminish the symptoms of cough after wind cold lung accumulation infection and combined therapy exhibited better effect, which was consistent with the results of our experimental study (15). Our findings clarified that XZM plus FPS possessed better clinical efficacy and diminished daytime and nighttime cough scores, which were superior to FPS alone. This might be due to the fact that Aster tataricus in XZM can relieve cough and moisten the lungs. Stemona can reduce phlegm and heat, relax bronchial smooth muscle, and relieve spasms. Platycodon grandiflorum can promote lung function, relieve asthma, and relieve cough and phlegm. Pericarpium Citri Reticulatae can regulate qi and phlegm, relieve bronchial smooth muscle. Houttuynia cordata can have anti-inflammatory and anti-infective effects. Poppy shells can act on the cough center and have a cough suppressing effect. Licorice can dispel phlegm and inhibit smooth muscle. The combination of various medicines could prominently relieve the clinical symptoms of childhood. Additionally, our results elucidated that observation therapy was able to upgrade FEV1 and FEV1/FVC, hinting XZM plus FPS exerted a momentous role in raising childhood pulmonary function. The peripheral eosinophil count in observation therapy were lessened than control therapy, hinting that XZM combined with FPS was able to depress eosinophil count. What’s more, CD³⁺, CD⁴⁺, CD⁴⁺/CD⁸⁺ were enhanced in observation therapy, which implied that XZM plus FPS could amplify the childhood’s immune function and improve the childhood’s quality of life.

Chronic airway inflammation is closely related to the occur of variant cough (33–36). IL-4 is an important anti-inflammatory cytokine in the inflammatory response. The high expression of IL-4 can inhibit inflammatory response, thereby reducing pulmonary inflammation in children (37). TNF-α enhances the expression of IL-like inflammatory factors through Akt and JNK signaling, promoting the occurrence of airway inflammatory disease and causing damage to airway epithelial cells, ultimately leading to airway obstruction in children (38). SAA and CRP are both acute phase response proteins that rapidly increase in response to pathogen invasion during inflammation in the body. This acute phase reaction is often accompanied by airway inflammation, leading to increased airway hyperresponsiveness. The sharp increase of SAA and CRP may lead to worsening cough in children and exacerbate the inflammatory response of respiratory mucosa (39–41). It was found that the IL-4 was higher, while TNF-α, SAA as well as CRP levels were lowered in observation therapy than control therapy. The reason for this is that XZM and FPS can inhibit the formation of various inflammatory cells in the lungs, alleviate airway inflammation, and the effective ingredient pseudoephedrine in Ephedra can alleviate bronchospasm and reduce inflammation; The phenylpropanofuran derivatives in Jingjie have good anti-inflammatory and anti-infective effects; Fluticasone propionate reduces respiratory mucosal inflammation response; The combination of the above active ingredients jointly exerts the effect of inhibiting the release of inflammatory factors and reducing airway inflammation response. Interestingly, there was no diversity in adverse reactions between the two groups.

While the therapeutic efficacy of XZM-FPS combination has been confirmed, addressing concerns about drug safety–especially potential pharmacokinetic interactions and the safety of controlled components in XZM–is critical for clinical application. Two lines of evidence support the safety of this combination: ➀ Pharmacokinetic safety: A previous study (17) on 50 children with variant cough showed that combined use of XZM (10 mL tid) and FPS (100 μg bid) did not alter the serum concentration of FPS (Cmax: 125.3 ± 21.5 ng/mL in the combined group vs. 128.7 ± 19.8 ng/mL in the FPS-alone group; P = 0.623). This confirms no significant interaction in drug absorption or metabolism. ➁ Component safety of XZM: The Papaver somniferum husk in XZM contains low levels of morphine (0.05 mg per 10 mL) (19), which is far below the threshold for respiratory depression or addiction in children (≥0.5 mg/kg/day) (18). Our 3-months monitoring also showed no signs of dependence. These findings address concerns about drug interactions and controlled component safety, supporting the clinical applicability of the combination.

Nevertheless, this study existed some limitations. The sample size of this study was relatively small. On the one hand, small sample size can lead to insufficient statistical ability, resulting in false negative results. On the other hand, the sample size is too small and contains limited information, which may lead to insufficient reliability and representativeness of the research results, making it difficult to accurately reflect the true situation of the results. In addition, this experiment was a retrospective study and there might be some bias in the results. As a result, it is crucial to design a multicenter, large sample research experiment. Furthermore, all samples in this study were Chinese children, and no non-Chinese populations were included. Due to potential differences in genetic backgrounds (such as polymorphisms of inflammation-related genes), living habits, and metabolic capacity of traditional Chinese medicine among children of different ethnicities, and considering the unique cultural background of Chinese populations in accepting and using traditional Chinese medicine, the conclusions of this study may not be directly generalized to children of other ethnic or cultural backgrounds. The lack of population diversity further limits the external validity of the research results. Therefore, in future multi-center studies, it is urgent to include children from different countries and ethnic groups to verify the applicability of XZM combined with FPS therapy in a wider population. The next step is to increase the single dose group of XZM and study the upstream and downstream regulatory pathways to explore its mechanism of action. Drug interaction data were based on small-sample preclinical studies; large-scale pharmacokinetic trials are needed to confirm XZM-FPS safety in diverse pediatric populations (e.g., children with liver impairment). The single-center design may limit generalizability; multi-center studies with stricter ethical oversight (e.g., independent data monitoring committees) are recommended.