Wheezing is one of the most common respiratory symptoms among preschool children, with an estimated 30–40% experiencing at least one episode before the age of six [1]. These episodes, frequently triggered by viral infections, encompass different phenotypes, including episodic viral wheeze and multi-trigger wheeze [2]. While many children outgrow symptoms, some progress to develop asthma [3]. The heterogeneity of preschool wheeze complicates both diagnosis and treatment, particularly in the absence of definitive biomarkers and difficulty performing reliable lung function tests in young children [4, 5].

Short-acting beta-agonists (SABAs) such as salbutamol are widely accepted as first-line treatment for acute wheezing. However, debate continues regarding the role of corticosteroids in this population. Studies have shown variable outcomes, with some demonstrating reduced hospitalisation and improved clinical scores, particularly in children with atopic features or recurrent wheezing [6, 7], while others report no significant benefit or potential adverse effects, including cortisol suppression [8, 9]. Current guidelines remain inconsistent, with the Global Initiative for Asthma (GINA) recommending daily low-dose inhaled corticosteroids, followed by as-needed (PRN) use for preschool children with frequent viral-induced wheeze and interval asthma symptoms [10]. At the same time, the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) suggests their use in children less than 5 years old for 8-12 weeks as maintenance, given that they have asthma phenotypes [11]. Recent evidence from Lee et al. (2024) suggests that oral corticosteroids may reduce symptom severity and length of hospital stay [12], yet significant practice variation persists between institutions.

Despite widespread use, the optimal role of combining salbutamol and corticosteroids for preschool wheeze remains unclear. Previous studies report varied outcomes based on phenotype, dosing, route of delivery, and timing of administration. To address this gap, a systematic review was conducted to synthesise current evidence comparing the effectiveness of salbutamol alone versus salbutamol combined with corticosteroids in managing acute wheezing episodes among preschool children without a formal asthma diagnosis. This review aims to inform clinical decision-making and provide guidance on the appropriate use of corticosteroids in this challenging population. The review focuses on findings reported in peer-reviewed journal articles, rather than on data from clinical trial registries or unpublished RCT databases.

This systematic review summarised 15 studies comprising approximately 265,000 preschool children with acute wheezing to determine whether the use of salbutamol alone or in combination with corticosteroids is effective. The results showed broad heterogeneity in treatment outcomes; some studies demonstrated a clear benefit of combination therapy, while others showed no effect or even harmful effects. These divergent results underscore the complexity of managing preschool wheeze and highlight the urgent need for phenotype-specific treatment approaches rather than universal protocols.

Among the included studies, there was significant variation in the effect of combining corticosteroids with salbutamol. Various studies have reported short-term benefits in symptoms and hospitalisation rates, but others have not found significant benefits or only slight benefits compared with salbutamol monotherapy. This inconsistency is probably due to variations in disease severity, the timing of corticosteroid initiation, and the underlying wheeze phenotype. The evidence indicates that corticosteroid addition therapy is most effective for moderate-to-severe or recurrent wheezing, but salbutamol is adequate in mild cases caused by a virus. The results presented by Razi et al. [7] indicated that nebulised budesonide with salbutamol had a significant effect on reducing hospitalisation rates and PIS within two hours. Similarly, Ciftci et al. [20] found that intravenous or oral systemic corticosteroids reduced CAS and predicted reduced admissions in children with recurrent wheeze. Levine et al. [22] also demonstrated that inhaled corticosteroid-based management decreased emergency visits and hospitalisations compared with bronchodilator-only management. The effectiveness of corticosteroids in preschool wheeze is also supported by a recent individual participant data meta-analysis by Lee et al. [12], which found that oral corticosteroids reduced the severity score at 4 hours post-treatment, with the effect most pronounced among preschoolers with asthma risk factors.

Symptom-free days and lung function have also been found to increase with regular inhaled corticosteroids, as reported by Papi et al. [26-27] with beclomethasone dipropionate and Mallol et al. [23] with fluticasone propionate, without affecting cortisol levels or growth. These results align with previous literature indicating that early corticosteroids are effective in the management of multi-trigger wheeze to prevent exacerbations and improve long-term control [29-30]. In contrast, Clavenna et al. [21] found no significant efficacy of corticosteroids versus placebo in mild- or virus-associated wheeze, indicating that corticosteroids are not necessarily effective.

Identifying which children respond to corticosteroids remains a major clinical challenge. Bannier et al. [6] identified exhaled volatile organic compounds that could distinguish between steroid-responsive and non-responsive patients with good sensitivity and specificity. This non-invasive modality with validation could inform clinicians to restrict corticosteroid therapy only to individuals who are likely to respond without exposing them to causes of unwarranted exposures. Conversely, the conventional signs of inflammation have demonstrated poor predictive capabilities. Van de Kant et al. [4] reported that, despite differences in FeNO levels among wheeze phenotypes, these did not predict corticosteroid response, indicating that preschool wheeze is characterized by different inflammatory mechanisms other than asthma. The European Respiratory Society (ERS) position statement endorsed the same findings, concluding that phenotype-specific biomarkers, such as blood eosinophils and aeroallergen sensitization, can identify ICS-responsive subgroups, highlight the limitations of FeNO in preschoolers, and call for a biomarker-guided approach [2]. Another recent comprehensive review of phenotype/ endotype heterogeneity also explained why treatment response varies dramatically across these groups of children and found that only ~25% of preschoolers fit the classical atopic/eosinophilic phenotype [31]. A review of 3 clinical trials examining preschool wheeze phenotypes found that higher eosinophilic counts were associated with higher exacerbation and hospitalisation rates, and that when inhaled corticosteroids were initiated daily, this was associated with decreased exacerbations thereafter [32].

Another review had conflicting findings on the use of FeNO in preschool wheeze. It may be useful in classifying types of preschool wheezing and evaluating the risk of later asthma or impaired lung development. However, data on the added benefit of FeNO over clinical factors are inconsistent, although high FeNO levels in schoolchildren have been shown to predict asthma development and slower growth in lung function over time [33]. Further research to demonstrate the utility of exhaled breath analysis in phenotype-based, larger populations would enhance precision-based therapy and clinical decision-making. Treatment heterogeneity is also explained by genetics. This is supported by a 2024 review [34] that examined studies on the genetics of preschool wheeze. One of these studies examined CDHR3 [35], which identifies the Rhinovirus C receptor, IL33, and the 17q locus, which includes the GSDMB and ORMDL3 genes. The 17q locus is the strongest wheeze and childhood-onset asthma locus and has been shown to interact with many environmental factors, including smoking and infections. Another study looked into the ANXA1 gene [36], which was recently associated with early-onset, persistent wheeze.

The use of corticosteroids to combat the inflammation is also relevant in preschool wheeze. A multi-omics study in 2025 [37] showed that the inflammation-dominant phenotype in preschool wheeze, compared with the epithelial remodeling-dominant phenotype that progresses to asthma, supports endotype-based treatment in this group. On the other hand, not all preschool wheeze is an allergic wheeze phenotype; a study examining the immunological aspects of preschool wheeze found that the majority are non-atopic (88% vs 11%), and this group accounts for two-thirds of health care utilisation [38]. This emphasised the undertreatment of non-atopic preschool wheeze with proper management, such as corticosteroids. Even for the episodic viral wheeze phenotype, intermittent or continuous inhaled corticosteroid use reduced the risk of viral-induced wheezing in preschool children [39].

Clinical outcomes also depend on the delivery methods and formulation. The study by Mecklin et al. [24-25] demonstrated that MDIs with spacers are equally effective as nebulisers and have greater practicality, portability, lower cost, and reduced risk of infection. Csonka et al. [17] reported that over 50% of emergency departments continue to use nebulisers with an insufficient match between evidence and practice. Another 2020 non-inferiority trial introduced a novel device: a portable MESH nebulizer for delivering ICS and salbutamol. It has similar clinical efficacy to MDI with a spacer but a lower acceptance rate and usability [40]. Therefore, educational interventions and standardised treatment regimes are required to enhance evidence-based utilisation of MDIs with spacers. Similarly, for corticosteroid formulations, Gileles-Hillel et al. [8] reported that betamethasone was equally effective as dexamethasone with lower cumulative steroid exposure, whereas prednisolone was associated with increased vomiting. By optimising corticosteroid selection, it is possible to improve compliance and minimise adverse effects, thereby enhancing patient comfort and clinical outcomes.

The current findings are consistent with international guidelines, which remain cautious about the use of corticosteroids in the treatment of preschool wheeze. According to the GINA guideline [10], corticosteroids should be used in the frequent or severe phenotypes of wheezing or high-risk asthma, whereas the BTS/SIGN [11] restricts their use to severe or hospital-level cases only. These findings align with earlier trials that have shown no significant benefit of oral corticosteroids in mild-to-moderate exacerbations [41-42]. Similarly, a recent review [12] demonstrated reduced wheezing severity and hospitalisation with corticosteroid use, supporting the positive outcomes observed in several studies included in this review. Nevertheless, previous reviews [43-44] summarised that corticosteroids could only have a useful role in moderate-to-severe exacerbations, not in routine viral wheeze. This conservative perception is supported by the existing synthesis, which emphasises that treatment must be customised to the wheeze pattern, frequency, and the likelihood of asthma.

The heterogeneity of treatment response is also affected by age. It is still clinically challenging to differentiate between early asthma and transient viral-related wheeze. The GINA guidelines [10] recognise these diagnostic uncertainties and suggest using age-based factors to determine corticosteroid use. Even children under 2 years were found by Mallol et al. [23] to respond positively to inhaled corticosteroids, and no exclusion criterion should be based solely on age in the presence of risk factors. The available information comparing corticosteroid effectiveness across distinct age groups, however, is limited, limiting the ability to provide age-based guidance. Future research should categorise subjects into age subgroups to define differences in developmental responses to therapy. Lastly, hypertonic saline adjunct therapy has been proven to be beneficial. Ater et al. [19] and Taha et al. [28] have shown that the combination of hypertonic saline and salbutamol reduces hospitalisation and symptom alleviation, especially in children predisposed to asthma. These findings are also supported by a recent review on the effectiveness of hypertonic saline and salbutamol combination, which showed reduced hospital length of stay and severity scores in preschool wheeze [45]. The proposed mechanism of hydration of the airway surface, mucociliary clearance, and reduced oedema is biologically plausible, and the lack of side effects supports its clinical application.

In short, this review demonstrates that the management of preschool wheeze requires a personalised approach, grounded in evidence. Salbutamol is only effective in mild cases of the virus, and its effectiveness depends on certain phenotypes and corticosteroid severity. The management can be further optimised with emergent biomarkers, optimal inhalation techniques, and add-on treatments like hypertonic saline. It is essential to employ safer, more accurate, and more productive approaches to provide preschool wheeze care in future phenotype-stratified trials and to use clear criteria to develop guidelines.

This review highlights the need for a personalised and practical approach to managing preschool wheeze. Although preschool wheezers have heterogeneous pathologies, detecting these populations and treating them effectively is important to prevent asthma in later life. One significant pathology contributing to this is bacterial growth. An ERS congress in 2024 highlights that 50% of severe wheezers have positive BAL bacterial cultures when stable (Moraxella catarrhalis, H. influenzae predominant). Epithelial remodeling and H. influenzae infection are associated with a severe trajectory, and the report suggests that targeting dysbiosis with antibiotics/ bacterial lysates may prevent asthma progression [46].

Based on the available evidence, a phenotype-oriented approach appears most appropriate. In children with mild episodic viral wheeze, salbutamol remains the preferred first-line treatment, and routine corticosteroid use is not consistently supported. In contrast, in children with moderate-to-severe, recurrent, or likely multi-trigger wheeze, particularly those with atopic features or a family history of asthma, corticosteroids may provide additional benefit when used selectively.

Salbutamol is the first-line intervention for all children with acute wheezing and should be administered via MDI with a spacer rather than a nebuliser, as it is equally effective and more convenient. Moderate-to-severe episodes that are unresponsive to initial bronchodilator treatment should receive corticosteroid therapy, particularly in children with recurrent wheeze and asthma risk factors, including atopy, a family history of asthma, or symptoms unrelated to viral infections. Rapid intervention in the emergency can shorten recovery and reduce hospital stay.

The route of corticosteroid administration should be determined by the clinical severity and recurrence pattern. Systemic therapy is recommended for severe acute attacks, while inhaled corticosteroids are used for recurrent episodes, with the lowest cumulative dose employed to minimize adverse effects. Notably, clinicians are advised to use the minimum effective cumulative steroid dose to reduce possible adverse effects. The existing evidence does not support the routine use of corticosteroids in all preschool wheezers, as non-selective prescribing can lead to unnecessary exposure to corticosteroids with no established benefits. Future advances in biomarker-guided therapy may enable clinicians to identify corticosteroid-responsive phenotypes more accurately and to implement safer, more targeted treatment strategies.

The primary strength of this review is its systematic and comprehensive synthesis of the current evidence on preschool wheeze in children who have not yet received an established asthma diagnosis, thereby filling an essential gap in the literature. The findings are informative, as they include studies conducted in various countries and healthcare settings, which are applicable across clinical settings. Also, this variety of RCTs and observational studies enables the review to include evidence of both controlled experimental studies and clinical practice.

A number of limitations, however, must be recognized. To begin with, the inclusion studies showed substantial heterogeneity in study design, patient populations, treatment regimens, corticosteroid type, dosing regimens, and outcome measures. This heterogeneity prevented direct comparability among the studies and precluded a quantitative meta-analysis. Second, not every study clearly differentiated between types of wheeze. In many studies, phenotype classification was either absent or defined by different criteria, preventing meaningful subgroup analysis across studies. This limitation restricts the ability to draw phenotype-specific conclusions regarding treatment responsiveness. Also, the non-asthmatic preschool wheeze remains clinically difficult to define, and the inconsistent findings may have been due to differences in diagnostic criteria across studies.

Moreover, many of the studies included were single-centre or institution-specific, which can introduce selection bias based on local clinical practices, patient populations, and healthcare resources. Consequently, the results might be inadequate in reflecting on wider paediatric populations in various healthcare systems. In addition, most studies were conducted in high- or middle-income countries with well-equipped healthcare systems. As such, the extent to which these findings can be generalised to low-resource settings where access to inhalation devices, corticosteroid preparations, or specialist paediatric care may be constrained must be approached with caution.

The other limitation concerns reporting safety outcomes. The effects of corticosteroid use on adverse effects were inconsistently reported across studies, potentially leading to an underestimation of harms. In addition, the study was limited to peer-reviewed articles published in English and omitted grey literature and clinical trial registries, which can introduce publication and language bias and may miss ongoing or unpublished studies that have not yet been reported in peer-reviewed journals. Lastly, many of the included studies had relatively short follow-up periods, so it was not possible to determine long-term treatment outcomes and safety profiles.

Future research should focus on properly designed, adequately powered randomized controlled trials using standard outcome measures and more precise phenotypic classification of wheeze. In addition, better reporting of adverse events and long-term follow-up will further inform clinical decision-making in the management of preschool wheeze. Future updates should also consider searching clinical trial registries to identify ongoing or unpublished studies, thereby reducing the risk of publication bias.

To conclude, while corticosteroids may provide clinical benefit when combined with salbutamol in selected preschool children with acute wheezing, particularly in moderate-to-severe cases or those with asthma risk factors, routine use in all wheezers is not supported and may expose children to unnecessary adverse effects. The considerable heterogeneity in treatment responses reflects the diverse pathophysiology underlying preschool wheeze and highlights the limitations of one-size-fits-all approaches. Future directions should focus on establishing dependable tools to detect responders at the point of care, such as biomarker-based phenotyping, and further improving the methods and formulations of corticosteroid delivery. Individualized clinical decisions should be made until this is available, based on disease severity, recurrence, and risk factors, to balance efficacy with safety in this susceptible age group.