Efficacy of budesonide/formoterol inhalation powder in treating viral pneumonia in children

Abstract

BACKGROUND

Respiratory viruses are increasingly detected in children with community-acquired pneumonia. Further strategies to limit antibiotic use in children with viral pneumonia are warranted.

AIM

To explore clinical efficacy of budesonide/formoterol inhalation powder for viral pneumonia in children and its impact on cellular immunity and inflammatory factor production.

METHODS

A total of 60 children with viral pneumonia were recruited: 30 receiving budesonide/formoterol inhalation powder and 30 conventional symptomatic treatment. Outcome measures included peripheral blood levels of inflammatory cytokines, CD4⁺, CD8⁺, Th1, Th2, Th17 and Treg, clinical efficacy, and incidence of adverse reactions.

RESULTS

Compared with the control group, the observation group showed a significant reduction in interleukin-6 and high-sensitivity C-reactive protein levels after treatment. Compared with the control group, the observation group showed a significant increase in CD4⁺/CD8⁺ and Th1/Th2 levels, and a decrease in Th17/Treg levels after treatment. The total effective rates in the observation group and the control group were 93.75% and 85.00%, respectively, which was a significant difference (P = 0.003).

CONCLUSION

Budesonide/formoterol inhalation powder significantly improved therapeutic efficacy for viral pneumonia in children. The mechanism of action may be related to downregulation of the inflammatory response and improved cellular immune function.

Key Words: Budesonide/Formoterol inhalation powder, Viral pneumonia, Immunity, CD4+/CD8+, Th1/Th2, Th17/Treg

Core tip: Treatment with budesonide/formoterol inhalation powder can significantly improve the efficacy of treatment of viral pneumonia in children. The mechanism of action may be related to downregulation of the inflammatory response and improvement of cellular immune function.

INTRODUCTION

Viral pneumonia is an acute lower respiratory tract infectious disease that commonly occurs in children, with major symptoms including cough, wheezing and fever[1,2]. Most affected children have a favorable prognosis, but in some cases, the condition can progress rapidly, leading to multiple organ dysfunction and poorer prognosis[3]. In the past, the clinical approach for treating pediatric viral pneumonia involved antiviral therapy and symptomatic treatment[4]. The etiology of pediatric viral pneumonia is mainly attributed to various viral infections, with respiratory syncytial virus being the primary cause[5]. However, due to the frequent occurrence of adverse reactions and the development of drug resistance associated with antiviral therapy, the clinical efficacy has been unsatisfactory[6]. Therefore, how to improve the clinical effectiveness of treatment of pediatric viral pneumonia has become a hot topic among medical professionals.

The pathogenesis of pediatric viral pneumonia is complex, involving multiple pathological processes, among which the outbreak of inflammatory reactions is a central element in the pathological response of children with viral pneumonia[7]. It is also one of the mechanisms leading to multiple organ dysfunction. There has been extensive research on proinflammatory factors such as interleukin (IL)-6 and C-reactive protein (CRP)[8]. Research has shown that imbalanced regulation of cellular immune function is an important influencing factor in inflammatory reactions, and the most significant manifestation of this imbalance is in the disproportion of CD4⁺ T lymphocyte subgroups[9]. Budesonide/formoterol inhalation powder is a long-acting β2-adrenergic agonist (LABA)/inhaled corticosteroid (ICS) combination formulation[10]. It possesses potent anti-inflammatory effects and exhibits good inhibitory properties against the release of inflammatory mediators and the chemotaxis of inflammatory cells[11]. Additionally, it can reduce epithelial cell damage and inhibit their proliferation[12]. Based on these properties, this study aimed to analyze the impact of using budesonide/formoterol inhalation powder in the treatment of pediatric viral pneumonia on inflammation and lung function.

MATERIALS AND METHODS

Patients

According to a completely randomized design for comparing means when sample sizes are equal and the minimum sample size requirement for quantitative studies, we randomly selected 30 pediatric inpatients diagnosed with viral pneumonia in our hospital from March 2021 to March 2022 as the observation group. Additionally, we chose 30 healthy children from the outpatient department as the control group. This study obtained approval from the Medical Ethics Committee, and all parents of the affected children were informed and provided written informed consent. The patients were divided into an observation group and a control group based on different treatment methods, with each group containing 60 cases. There were no significant differences in age, course of disease, and gender between the two groups (P > 0.05), indicating comparability (Table 1).

Table 1 Comparison of general information between the two groups of pediatric viral pneumonia patients treated with different methods.

Group	Gender		Age	Duration of illness
	Male	Female
Control group (n = 30)	15	15	4.83 ± 1.42	5.77 ± 1.33
Observation group (n = 30)	17	13	4.90 ± 1.54	5.80 ± 1.19
t	0.510		-0.175	-0.102
P value	0.612		0.862	0.919

Inclusion criteria and exclusion criteria

Inclusion criteria for the observation group were: (1) Children aged 1 month to 14 years; (2) complied with the diagnostic criteria for pneumonia in the 9^th edition of "Pediatrics" textbook: presented with clinical features of fever, cough, dyspnea, respiratory distress, and coarse moist rales in the lungs, and radiological examination showed pulmonary changes consistent with pneumonia; (3) pathogen testing indicated viral infection; and (4) signed informed consent. Inclusion criteria for the control group were outpatient healthy children aged 1 month to 14 years undergoing physical examination and signed informed consent form for the experimental study. Exclusion criteria for the observation group were: (1) Children younger than 1 month or older than 14 years; (2) coexisting bacterial pneumonia or other infectious pneumonia, such as Mycoplasma or Chlamydia infection; (3) children with viral pneumonia who had autoimmune diseases or malignant tumors; and (4) children with viral pneumonia who had autoimmune diseases or malignant tumors.

Treatment methods

Both groups received symptomatic treatment, such as cough suppression, bronchodilation, and maintaining airway patency. At the same time, ribavirin (Henan Furen Huaiqingtang Pharmaceutical Co. Ltd., approved by the China Food and Drug Administration, with registration No. H20044698) 15 mg/kg/d was administered intravenously by infusion in 250 mL 5% glucose injection. The observation group received additional treatment with budesonide/formoterol (AstraZeneca AB, with registration no. H20140459, at a dose of 160 μg budesonide and 4.5 μg formoterol per inhalation, with 60 inhalations per device) inhalation powder, administered with one inhalation, twice daily, for a continuous duration of 7 d.

Outcome measures

Measurement of inflammatory-cytokine-related indicators: Both groups collected 3 mL of fasting venous blood from the elbow before and after treatment in the early morning. The blood samples were centrifuged at 3000 r/min for 10 min, left to stand for 15 min, and the supernatant was retained and stored at 20°C in a refrigerator for later use. ELISA was used to measure serum IL-6 levels, and the immunoturbidimetric method was used to measure serum high-sensitivity CRP (hs-CRP). The reagent kits were purchased from Shenzhen Weike Biotechnology Co. Ltd.

Measurement of cellular immune-related indicators: All patients had 2 mL fasting venous blood collected from the elbow before and after treatment. Peripheral blood levels of CD4⁺, CD8⁺, Th1, Th2, Th17 and Treg were measured using a flow cytometer (manufactured by Beckman, USA). The CD4⁺/CD8⁺, Th1/Th2, and Th17/Treg ratios were calculated.

Clinical efficacy was evaluated in both groups after treatment. (1) Cure: All symptoms and signs disappeared, and no abnormalities were observed on chest X-ray examination; (2) Significant improvement: Most symptoms disappeared, body temperature was normal, and chest X-ray examination and laboratory tests were nearly normal; (3) Effective: The symptoms significantly improved, signs reduced, and there was improvement in chest X-ray compared to before treatment; and (4) Ineffective: Symptoms and signs have not improved significantly or have worsened partially, and there was no improvement in chest X-ray and laboratory tests. Overall effective = number of cured cases + number of significantly improved cases + number of effectively improved cases.

Incidence of adverse reactions: All patients underwent weekly follow-up for complete blood count, liver and kidney function, and coagulation function, and adverse reactions were recorded.

Statistical analysis

The data were analyzed using SPSS 19.0 statistical software. The measurement data were analyzed using the t test and expressed as mean ± SD. The numerical data were analyzed using the t test and expressed as percentages (%). The significance level was set at α = 0.05.

RESULTS

Comparison of pulmonary-function-related indicators

Before treatment, there were no significant differences in pulmonary function indicators between the two groups (P > 0.05) (Table 2). After treatment, the improvement in pulmonary function for all parameters in the observation group was significantly better than that in the control group (P < 0.05).

Table 2 Comparison of pulmonary-function-related indicators between the two groups of pediatric viral pneumonia patients treated with different methods.

Group	FVC (L)		FEVl (L)		FEVl/FVC (%)		PEF (L/min)
	Before	After	Before	After	Before	After	Before	After
Control group (n = 30)	2.09 ± 0.31	2.39 ± 0.39a	1.66 ± 0.22	2.14 ± 0.37a	54.53 ± 7.14	76.11 ± 7.49a	254.28 ± 22.22	319.11 ± 21.63a
Observation group (n = 30)	2.04 ± 0.41	3.10 ± 0.42a	1.69 ± 0.31	3.08 ± 0.35a	54.18 ± 6.55	83.59 ± 5.17a	253.73 ± 23.75	352.50 ± 14.89a
t	0.428	-6.801	-0.466	-10.084	0.198	-4.509	0.547	0.040
P value	0.663	< 0.001	0.643	< 0.001	0.844	< 0.001	0.927	< 0.001

^aP < 0.05 vs before treatment. FVC: Forced vital capacity; FEV1: Forced expiratory volume in 1 s; PEF: Peak expiratory flow.

Comparison of inflammatory-cytokine-related indicators

There were no significant differences in IL-6 and hs-CRP levels between the two groups before treatment (P > 0.05) (Table 3). Compared with the control group, the observation group showed a significant reduction in IL-6 and hs-CRP levels after treatment (P < 0.05). Compared with the baseline levels within each group, both groups showed a significant decrease in IL-6 and hs-CRP levels after treatment.

Table 3 Comparison of inflammatory-cytokine-related indicators between the two groups of pediatric viral pneumonia patients treated with different methods.

Group	IL-6 (U/L)		hs-CRP (mg/L)
	Before	After	Before	After
Control group (n = 30)	35.97 ± 4.27	26.37 ± 3.46a	40.53 ± 5.24	25.23 ± 3.09a
Observation group (n = 30)	35.54 ± 4.50	17.21 ± 2.25a	39.28 ± 3.37	18.15 ± 3.37a
χ2/t	0.375	12.145	1.062	8.478
P value	0.709	< 0.001	0.293	< 0.001

^aP < 0.05 vs before treatment. IL-6: Interleukin-6; hs-CRP: High-sensitivity C-reactive protein.

Comparison of cellular immune-related indicators

Before treatment, there were no significant differences in CD4⁺/CD8⁺, Th1/Th2, and Th17/Treg levels between the two groups (P > 0.05) (Table 4). Compared with the control group, the observation group showed a significant increase in CD4⁺/CD8+ and Th1/Th2 levels, and a decrease in Th17/Treg levels after treatment (P < 0.05). Compared with the baseline levels within each group, both groups showed a significant increase in CD4⁺/CD8⁺ and Th1/Th2 levels, and a decrease in Th17/Treg levels after treatment.

Table 4 Comparison of CD4⁺/CD8⁺, Th1/Th2, and Th17/Treg between the two groups of pediatric viral pneumonia patients treated with different methods.

Group	CD4+/CD8+		Th1/Th2		Th17/Treg
	Before	After	Before	After	Before	After
Control group (n = 30)	0.92 ± 0.05	1.05 ± 0.11a	5.59 ± 0.45a	7.56 ± 0.39a	0.82 ± 0.07a	0.72 ± 0.13a
Observation group (n = 30)	0.91 ± 0.04	1.28 ± 0.15a	5.50 ± 0.45a	6.51 ± 0.30a	0.84 ± 0.05a	0.63 ± 0.07a
χ2/t	1.113	-6.522	0.819	11.601	-1.345	3.354
P value	0.270	< 0.001	0.416	< 0.001	0.184	0.002

^aP < 0.05 vs before treatment.

Comparison of clinical efficacy

The total effective rates in the observation group and the control group were 93.75% and 85.00%, respectively, with a statistically significant difference (P = 0.003) (Table 5).

Table 5 Comparison of clinical efficacy between the two groups of pediatric viral pneumonia patients treated with different methods.

Group	Cure	Significant improvement	Effective	Ineffective	Total effective
Control group (n = 30)	13	9	6	2	28
Observation group (n = 30)	9	10	6	5	25

Incidence of adverse reactions

In the observation group, two patients experienced mild liver function impairment, and in the control group, one experienced mild liver function impairment. After receiving hepatoprotective medication for 1 wk, liver function returned to normal in both cases. Both groups had one patient with mild prolongation of prothrombin time, which was not treated and returned to normal after 1 wk.

DISCUSSION

Viral pneumonia is one of the acute respiratory tract infections in children. The common viral pathogens in clinical cases include nearly 20 types, with respiratory syncytial virus being the predominant pathogen[13]. Pediatric viral pneumonia is characterized by acute inflammatory exudative changes in the lungs following respiratory viral infections[14]. It presents with diverse clinical manifestations, and symptoms and signs lack specificity[15].

The pathogenesis of viral pneumonia is complex, and a small percentage of patients have a poor prognosis[16]. Most researchers believe that the pathogenesis of viral pneumonia is related to viral invasion, immune function dysregulation, and a cascade of inflammatory mediators and cytokine reactions[17]. There are reports indicating that the severity of viral pneumonia is related to the viral load invading the body[18]. The higher the viral load, the more severe the immune imbalance in the body, resulting in more severe disease progression[19]. The severity of viral pneumonia is not linearly correlated with the viral load; pathogenesis is mainly associated with the virus invading the body, triggering antigen-presenting-cell immune responses, and subsequently leading to abnormalities in humoral immune responses and dysregulation of cellular immune functions[20]. Some studies have shown that the body can mount immunoregulatory responses through three pathways: innate immunity, cellular immunity, and humoral immunity[21].

T lymphocytes are the main immune cells in the body, accounting for about 60% of the total number of lymphocytes in peripheral blood. Processing and presentation of viral antigens enable lymphocytes to recognize specific receptors, undergo cloning, differentiation and proliferation, thereby generating a specific immune response. During the process of exogenous antigen presentation, a series of degradation, transportation, and binding reactions activate T lymphocytes[22]. CD3⁺, CD4⁺ and natural killer (NK) cells are the main immune subsets in the body. Researchers have found that children with severe viral infections may exhibit abnormal cellular immune function, characterized by decreased levels of CD3⁺, CD4⁺ and NK cells, increased CD8⁺ levels, and imbalanced CD3⁺/CD4⁺ ratio[23]. Decreased levels of CD3⁺, CD4⁺ and NK cells are only observed in a small number of critically ill children with severe viral infections, suggesting that most children with viral infections exhibit only mild decreases in CD3⁺ and CD4⁺ levels[24].

With the continuous advancement of research on cellular immune function, it has been discovered that CD4⁺ T lymphocytes consist of various subgroups, such as Th1, Th2, Th17 and Treg. Activated Th cells are classified into two subgroups, Th1 and Th2, based on the different cytokines they secrete. Th1 primarily secretes anti-inflammatory cytokines such as -interferon and IL-2, while Th2 mainly secretes proinflammatory cytokines such as IL-4, which can induce the proliferation and differentiation of B lymphocytes[25]. If the immunoregulation of the body becomes imbalanced, it manifests as a decrease in Th1 cells and an increase in Th2 cells, resulting in a shift from Th1 to Th2 dominance. This phenomenon intensifies the inflammatory response and leads to significant inflammatory damage. Th17 can promote the secretion of IL-17, intensifying the inflammatory response in the body. Treg cells secrete anti-inflammatory cytokines such as transforming growth factor- and IL-10. The balance of Th17/Treg ratio plays a crucial role in the functioning of the immune system. In critically ill patients, there can be an early increase in Th17 Levels, leading to an overproduction of proinflammatory cytokines and mediators[26]. This excessive secretion of cytokines and inflammatory mediators exacerbates oxidative stress damage in the body. If the condition worsens further, an increase in Th cells can lead to immunosuppression[27]. Therefore, children with viral pneumonia may exhibit an imbalance in CD4⁺/CD8⁺ ratio, a shift from Th1 to Th2, and elevated Th17/Treg levels. This study showed that after treatment, both groups exhibited an increase in CD4⁺/CD8⁺ and Th1/Th2 levels, and a decrease in Th17/Treg levels. Improvement in the observation group was superior to that in the control group, with significant differences observed. These results indicate that budesonide/formoterol powder inhalation can regulate the cellular immune balance of children with viral pneumonia and thereby exert a therapeutic effect.

The inflammatory outbreak in the body is a central part of the pathological and physiological response to viral pneumonia. The elevation of inflammatory mediators and cytokines not only affects the functional differentiation of lymphocytes, but also promotes the differentiation and migration of neutrophils and enhances the phagocytic activity of macrophages. IL-6 is an important proinflammatory cytokine, and its elevated levels are consistent with the degree of inflammatory response in the body. It is also a significant indicator of the inflammatory response. CRP is a nonspecific proinflammatory cytokine mainly secreted by liver cells and is an important inflammatory marker associated with viral pneumonia. There are reports literature that serum IL-6 and CRP levels are significantly elevated in patients with viral pneumonia, and the degree of elevation of both is related to the prognosis to a certain extent[28,29]. This study showed that serum IL-6 and hs-CRP levels decreased in both groups after treatment, and the observation group had a significantly greater reduction than the control group. This indicates that budesonide/formoterol inhalation powder can downregulate the inflammatory response and thus reduce tissue damage.

CONCLUSION

Treatment with budesonide/formoterol inhalation powder can significantly improve the clinical efficacy of viral pneumonia in children. The mechanism of action may be related to the downregulation of the inflammatory response and improvement of cellular immune function by budesonide/formoterol inhalation powder. The limitations of this study include a small sample size, and the conclusions need to be confirmed by expanding the sample size in future studies.