Introduction
Skin prick testing (SPT) remains a cornerstone diagnostic method for immunoglobulin E (IgE)-mediated allergic diseases, such as allergic rhinitis and asthma. It provides clinically relevant information regarding allergen sensitization that guides environmental avoidance measures, pharmacotherapy, and allergen immunotherapy [1, 2]. The accuracy of SPT is therefore critical for personalized allergy management.
Several factors influence SPT results, including patient age, skin condition, and concurrent medication use. Among these, corticosteroids represent a major concern. Systemic corticosteroids are well known to suppress mast cell and basophil activity, thereby reducing immediate skin reactivity [3]. However, the effects of inhaled corticosteroids (ICS) on SPT remain controversial.
ICS are the mainstay of asthma and allergic airway disease management, widely prescribed due to their potent anti-inflammatory activity and relatively low systemic bioavailability [4, 5]. Yet, chronic ICS use can still result in measurable systemic exposure, potentially impacting both skin test responses and hypothalamic–pituitary–adrenal (HPA) axis function [6–8]. Previous studies have produced conflicting findings: some reported no effect of ICS on SPT reactivity [9, 10], while others suggested possible suppression depending on dose, duration, or cumulative corticosteroid exposure [11–13].
Additionally, ICS-associated adrenal suppression has been described even with standard therapeutic doses, particularly in children and long-term users, raising concerns about safety and the need for monitoring [14–16]. Salivary cortisol measurement has emerged as a reliable, noninvasive biomarker of HPA axis activity that strongly correlates with serum cortisol levels [17, 18].
Given these uncertainties, further research is needed to clarify whether ICS influence the diagnostic accuracy of SPT and whether prolonged ICS therapy contributes to adrenal suppression.
Aim
The aim of this pilot study was to evaluate the impact of ICS therapy on histamine-induced SPT responses and on serum and salivary cortisol levels in adult patients with allergic conditions. We hypothesized that ICS, at standard therapeutic doses, would not significantly suppress skin reactivity on SPT, but prolonged use might be associated with subtle reductions in endogenous cortisol levels.
Material and methods
This observational pilot study enrolled 24 adult patients (aged 18–65 years) with physician-diagnosed asthma or allergic rhinitis, recruited from the outpatient allergy clinic of the Special Hospital for Pulmonary Diseases, Zagreb, between January and June 2024. All participants had been receiving ICS therapy for at least one month before enrollment. Exclusion criteria included systemic corticosteroid use within the last 4 weeks, known adrenal or endocrine disorders, pregnancy, and use of immunosuppressive medications.
The study protocol was reviewed and approved by the Ethics Committee of the Special Hospital for Pulmonary Diseases and the School of Dental Medicine, University of Zagreb. Written informed consent was obtained from all participants, and the study was conducted in accordance with the Declaration of Helsinki.
Detailed ICS exposure history was obtained from both patient interviews and medical records. Data included the specific ICS formulation (fluticasone propionate, budesonide, beclomethasone dipropionate, or ciclesonide), daily dose (range 250–800 µg), frequency of inhalation, and therapy duration (range: 1 month to 7 years). Concomitant use of other corticosteroid-containing therapies (e.g., nasal sprays, dermatologic preparations) was also recorded.
SPT was performed using a standardized aeroallergen panel. Histamine (10 mg/ml) served as the positive control, and saline was used as the negative control. Antihistamines and leukotriene receptor antagonists were discontinued at least 7 days before testing. Wheal diameters were measured after 15 min with digital calipers. A positive response was defined as a wheal at least 3 mm larger than the negative control.
Saliva and serum samples were collected between 8:00–9:00 h on the day of SPT. Saliva was collected at the hospital using the passive drool technique, approximately 30–60 min after awakening, to minimize diurnal variation. Salivary cortisol was analysed using an enzyme immunoassay, with ≤ 11.3 nmol/l considered indicative of reduced adrenal activity. Serum cortisol was measured from venous blood using chemiluminescence immunoassay, with a reference range of 138–690 nmol/l.
Statistical analysis
Statistical analyses were conducted using SPSS version 28.0 (IBM Corp., Armonk, NY, USA). ICS-related variables (dose, duration, frequency) were treated as continuous variables. Correlations between ICS parameters, SPT wheal size, and cortisol levels were evaluated using Pearson correlation coefficients. Comparisons of cortisol levels between patients using ICS alone versus those using additional corticosteroid therapies were performed using independent-sample t-tests. A p-value < 0.05 was considered statistically significant.
Results
All 24 participants successfully completed testing. ICS use varied in type, dose, and duration. No significant differences were observed in histamine wheal surface area, serum cortisol, or salivary cortisol between corticosteroid-sensitive and non-sensitive groups (all p > 0.05). Histamine reactivity was not correlated with ICS dose (r = 0.081, p = 0.68), duration (r = –0.122, p = 0.53), or inhalation frequency (r = –0.091, p = 0.64) (Tables 1–3).
Table 1
Baseline characteristics of study participants
Table 2
Correlations between ICS parameters and cortisol levels
Table 3
Relationship between salivary and serum cortisol levels
| Measure | Correlation coefficient (r) | P-value |
|---|---|---|
| Salivary vs. serum cortisol | 0.719 | < 0.001 |
Salivary cortisol showed a borderline negative correlation with ICS duration (r = –0.405, p = 0.05), while serum cortisol remained unaffected. A strong positive correlation was observed between salivary and serum cortisol levels (r = 0.719, p < 0.001). Participants using additional corticosteroid-containing therapies (e.g., nasal sprays) had significantly lower salivary cortisol levels compared with those on ICS alone (p = 0.049). No significant associations were found between histamine reactivity and total IgE, ACT scores, eosinophil counts, or FEV1 (all p > 0.1).
Discussion
This pilot study investigated the effects of ICS on SPT reactivity and adrenal function in adult patients with allergic conditions. Our findings suggest that standard-dose ICS therapy does not significantly suppress histamine-induced wheal responses, indicating that routine discontinuation of ICS before SPT may be unnecessary. This is clinically relevant as interrupting ICS therapy can risk asthma destabilization and exacerbations [19–54].
Previous studies have shown conflicting results regarding the impact of ICS on skin reactivity. Some investigations reported no significant alteration in SPT responses [9–11], whereas others observed subtle suppression depending on dose, duration, and cumulative corticosteroid exposure [12, 13, 26, 30]. Our data align with the majority of evidence supporting the safety of continuing ICS during allergy diagnostics.
ICS exert their anti-inflammatory effects mainly through local mechanisms, with relatively low systemic bioavailability. However, prolonged therapy or combined use with other corticosteroid formulations (e.g., nasal or topical) may increase systemic exposure. This is supported by our finding that patients using multiple corticosteroid-containing therapies exhibited significantly lower salivary cortisol levels. While serum cortisol remained unaffected, the borderline inverse association between ICS duration and salivary cortisol highlights the sensitivity of salivary cortisol as an early marker of HPA axis suppression.
The strong correlation between serum and salivary cortisol (r = 0.719, p < 0.001) reinforces previous studies validating salivary cortisol as a reliable, noninvasive biomarker of adrenal function. Given its practicality and patient comfort, salivary sampling may be preferable for longitudinal monitoring of patients on prolonged ICS therapy.
Importantly, no significant relationships were observed between histamine reactivity and systemic markers of disease severity such as total IgE, eosinophils, ACT scores, or lung function. This suggests that the preservation of SPT responses under ICS therapy is independent of disease control markers.
Clinical implications of our results include reassurance that ICS therapy at standard doses does not need to be withheld prior to SPT, thereby maintaining asthma control during diagnostic evaluation. At the same time, clinicians should remain vigilant regarding possible adrenal suppression in long-term or high-dose ICS users, particularly when additional corticosteroid therapies are prescribed.
Limitations of this study include the small sample size, which reduces statistical power and prevents subgroup analyses by ICS formulation or cumulative dose. The cross-sectional design also precludes conclusions about causality. Furthermore, adherence was partly self-reported, and dynamic endocrine testing (e.g., ACTH stimulation) was not performed. These factors limit generalizability, and larger prospective studies are required to confirm our findings.
In summary, this pilot study supports the continued use of ICS during allergy testing while also emphasizing the need to monitor long-term ICS users for potential adrenal suppression using simple tools such as salivary cortisol measurement.
Conclusions
ICS at standard therapeutic doses do not impair histamine responsiveness on SPT, supporting their continued use during allergy diagnostics without requiring a washout period. This is particularly important in asthma management, where uninterrupted ICS use is critical to maintaining disease control. However, prolonged ICS therapy may lead to subtle HPA axis suppression, as indicated by lower salivary cortisol levels. Clinicians should be vigilant in monitoring long-term or high-dose ICS users, especially those receiving multiple corticosteroid preparations. Salivary cortisol provides a reliable, noninvasive tool for such monitoring. Larger prospective studies are warranted to establish thresholds for clinically significant adrenal suppression and to refine recommendations for ICS use before allergy testing [19–54].
