Tidal Breathing Analysis Provides a Non-Invasive, Bedside Method for Objectively Assessing Respiratory Mechanics and Bronchodilator Responsiveness in Acute Bronchiolitis

1. Introduction

Bronchiolitis is the most frequent lower respiratory tract infection in infants, characterized by inflammation of the small airways that generates tachypnoea, wheeze, increased work of breathing, and sometimes hospitalization. Respiratory syncytial virus (RSV) predominates, with rhinovirus (RV) and other viruses contributing substantially [1,2]. Airway interactions between viruses, especially rhinoviruses, and potentially pathogenic bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) in early infancy may increase the risk of subsequent wheezing and asthma [3]. While most cases resolve, a certain subset of children materialize recurrent wheeze or asthma, in some prospective-followed cohorts, up to 4 years, being as high as 12% [4]. Hospitalization for severe bronchiolitis is associated with an increased risk of subsequent asthma (commonly reported a two- to three-fold increase across cohorts) [5,6,7,8,9]. Severe bronchiolitis in infancy may trigger development of asthma in genetically susceptible individuals, or it could be a marker of predisposition for future asthma. Genetic variants in CDHR3 and GSDMB modulate susceptibility to bronchiolitis, especially when caused by viruses other than RSV [10,11] Host and environment early-life risk factors are associated with progression of wheezing symptoms over time and several groups of researchers have speculated that dynamic interactions of these factors with an infant’s developing respiratory system are the dominant factor for subsequent wheeze and asthma [12,13,14].

A key unresolved question is whether bronchiolitis causes asthma inception or unmasks pre-existing susceptibility [15,16,17] in certain children.

Current guidelines emphasize supportive care and discourage routine bronchodilator use, in typical bronchiolitis cases, due to inconsistent clinical benefit at general population level [18,19,20]. Nevertheless, subgroups appear bronchodilator or steroid-responsive, potentially signalling airway hyperreactivity akin to early asthma [21,22]. In adults, bronchodilator responsiveness, even in the presence of lung function within normal limits, might be a risk factor for incident chronic airflow obstruction [23]. In young paediatric asthma patients, small airway disfunction (SAD) could be present in spite of normal FEV₁ values [24], so exploring SAD, via tidal breathing analysis (TBA), could unmask future asthma trajectories in infants with severe bronchiolitis. Evidence of SAD was found in almost one-third of subjects who have been ventilated for life-threatening RSV disease, although not always accompanied by respiratory symptoms [25].

TBA is a non-invasive pulmonary function technique that quantifies timing and flow indices from tidal breathing loops (e.g., tPTEF, tPTEF/TE, VT, MV), being validated in various ethnic groups of infants [26,27]. Changes in timing indices after bronchodilator therapy can objectively demonstrate responsiveness, although mild bronchiolitis cases have a rather poor responsiveness in sedated infants [28].

Here we present a wheezing bronchiolitis-like LRTI case with documented salbutamol responsiveness via TBA, synthesize evidence on bronchiolitis–asthma links and treatment response heterogeneity, and propose a testable hypothesis for a research of physiology-defined responsiveness trajectories in these young children.

Case Presentation

A 23-month-old boy presented to the emergency department with a 2-day history of seromucous rhinorrhoea, productive cough, and dyspnoea. Family history was notable for paternal asthma and a sibling with severe bronchiolitis in infancy. Term born (39 weeks’ gestation; birth weight 2,800 g; Apgar score 9) child, was breastfed in early infancy, and had immunizations up to date. Past medical history included a febrile seizure at 9 months, measles at 12 months complicated with pneumonia, and one severe episode of bronchiolitis, with respiratory failure, at 19 months of age, requiring hospitalization. Environmental risk factors include household tobacco smoke exposure, wood-stove heating, and contact with domestic animals (dogs and backyard chicken).

On admission, he weighed 10.3 kg, afebrile, normal appearance. Respiratory findings: nasal obstruction with seromucous rhinorrhoea and productive cough, tachypnoea (54 breaths/min) with intercostal and subcostal retractions and SpO₂ 92% in room air, improving to 99% with low-flow nasal cannula. Chest auscultation revealed diminished vesicular breath sounds with bilateral wheezes and fine crackles. Cardiac examination documented a regular rhythm with tachycardia (150 bpm). The abdomen was non-tender, oral intake was reduced, but bowel movements were normal and urine output was preserved. No meningeal signs were present.

Laboratory evaluation documented leucocytosis with neutrophilia. C-reactive protein was 2 mg/dL. Capillary blood gas analysis evoked respiratory acidosis (pH 7.20, pCO₂ 63 mmHg). The working diagnosis was acute RSV bronchiolitis (RADT documented in Emergency Department) complicated by acute respiratory failure and mild acute dehydration, secondary to reduced intake. Patient underwent non-invasive ventilatory support via HFNC for a total of 7 days.

Tidal-breathing analysis (TBA) was performed with a SpiroScout (Ganshorn Medizin Electronic GmbH, Schiller Group, Germany) pneumotachograph-linked spirometer (see Figure 1) immediately before and ~20 minutes after nebulized salbutamol (0.15 mg/kg). Recordings were gained in non-sedated, quiet-awake state, using a well-fitted facemask with an optimized seal to minimize leak and upper-airway artifacts. At each time point, tidal breathing was recorded for a stable period and ≥3 technically acceptable segments were obtained, in accordance with ERS/ATS infant PFT standards (see Figure 2). Primary indices were derived from a prespecified, artifact-free segment using predefined quality criteria (stable baseline, minimal leak, no cough/swallow/sigh). In cases of uncertainty, segment eligibility was adjudicated by two independent reviewers blinded to test order.

Pre-salbutamol values were: VT 107 mL, RR 28/min, MV 3.0 L/min, TI 0.72 s, TE 1.43 s, Ttot 2.15 s, PEF 0.14 L/s, tPTEF 0.17 s, and tPTEF/TE 0.12.

Post- salbutamol, tidal-breathing indices improved markedly: tPTEF increased from 0.17 to 0.33 s (+94%) and tPTEF/TE from 0.12 to 0.27 (+125%), while TE shortened from 1.43 to 1.25 s (-12.6%) and Ttot from 2.15 to 2.04 s (-5.1%). Minute ventilation rose from 3.0 to 3.55 L/min (+18.3%), mainly through a higher VT (107→120 mL, +12.1%) with a small RR increase (28→30/min, +7.1%). PEF remained unchanged (0.14 L/s). This overall pattern supports bronchodilator responsiveness and is consistent with an improved tidal expiratory profile. Key parameters are summarized in Table 1 and Figure 3.

Management comprised intravenous rehydration for 2 days; high-flow nasal cannula (HFNC) support for 7 days; systemic corticosteroid therapy with methylprednisolone at 2 mg/kg/day for 2 days followed by tapering; inhaled bronchodilator therapy with nebulized salbutamol for 9 days, with adjunctive ipratropium bromide for first 5 days, and inhaled fluticasone propionate. The clinical course was favourable, with progressive improvement in respiratory status and normalization of blood gas measurements.

2. Literature Data

2.1. Aetiology and Epidemiology

Bronchiolitis primarily affects children under 2 years, with RSV responsible for the majority of cases; rhinovirus, parainfluenza, human metapneumovirus, and adenovirus are also involved, and co-infections are common [1,2]. The global burden is substantial, with RSV a leading cause of lower respiratory tract infection in young children [1]. New prevention tools, like long-acting RSV monoclonal antibodies (nirsevimab, clesrovimab) and RSV prefusion F protein-based maternal vaccine during pregnancy had impacted real life burden on hospitalizations or Emergency Department visits in infants [29,30,31,32,33] and will probably generate a more tailored approach of RSV wheezy infants in the foreseeable future, because there is still present a heterogenous approach of these patients [34].

2.2. Association with Asthma

Multiple studies link severe bronchiolitis to increased asthma risk, and rhinovirus-associated bronchiolitis generally carries a higher subsequent risk than RSV [35,36,37,38,39]. One research [35], including 408 children hospitalized for bronchiolitis into a prospective, 3-center, 4-year follow-up study, in Finland, documented at study entry, a median age of 7.5 months. 42% had RSV, 29% RV, 2% both RSV and RV, and 27% had non-RSV/-RV aetiology. The children with RV-A (adjusted hazard ratio, 2.3; P = .01), RV-C (adjusted hazard ratio, 3.5; P < .001), and non-RSV/-RV (adjusted hazard ratio, 2.0; P = .004) bronchiolitis started the asthma control medication earlier than did children with RSV bronchiolitis.

INSPIRE is a large, population-based, birth cohort of healthy infants with non-low birthweight born at term in Tennessee, USA. Children were followed up prospectively for the primary outcome of 5-year current asthma. Not being infected with RSV during infancy was associated with a 26% lower risk of 5-year current asthma than being infected with RSV during infancy (adjusted RR 0·74, 95% CI 0·58–0·94, p=0·014). The estimated proportion of 5-year current asthma cases that could be prevented by avoiding RSV infection during infancy was 15% [40].

Several studies on non-invasive biomarkers for assessing asthma in preschool children have been published [41,42,43]. Specimens that can be easily obtained by non-invasive methods are blood, exhaled breath and urine. Eosinophils, eosinophil cationic protein and eosinophil-derived neurotoxin (EDN) in blood are helpful in evaluating eosinophilic inflammation of the airways. Exhaled breath contains nitric oxide, volatile organic compounds, various cytokines and mediators as analytical components. Fraction of exhaled nitric oxide has been used to assess the degree of eosinophil inflammation and has been standardized in school-age children and adults, but not yet in preschool children. Exhaled breath condensate (EBC) pH and various cytokines/mediators that are detected in EBC seem to be promising biomarkers for assessing asthma, but need more standardization and validation.

Dysregulated interferon responses (changes in gene transcription during cold-associated asthma exacerbations) are important contributors to this risk in children. Low baseline interferon expression followed by greater upregulation of interferon pathways in airway and blood during respiratory illnesses increased exacerbation risk [44].

Bronchiolitis cohort studies have identified early-life environmental exposure [45], genetic [46,47,48,49] and immune risk factors [50] for childhood asthma development by carrying out analysis at single level (e.g., associations with respiratory virus types, host immune response or the microbiome composition of the host) [51]. Multi-omics technologies have elucidated certain mechanisms underlying the gut-lung axis, numerous pathways remain to be fully delineated [52]. Severe bronchiolitis pathogenesis involves interaction of factors at multiple levels (e.g., genome, epigenome, transcriptome, metabolome, microbiome) [53,54,55]. Proposed mechanisms through which early-life RSV infection might contribute to asthma include epithelial injury, immune dysregulation with Th2-skewed responses, and airway/microbiome remodelling, superimposed on host susceptibility [56].

Bronchodilator Response in Bronchiolitis

Guidelines discourage routine β₂-agonists in typical bronchiolitis due to absent or inconsistent clinical benefit [18,19]. Nonetheless, subgroup patients may respond, potentially indicating asthma-like airway hyperreactivity [21]. An old meta-analysis [57] is documenting no overall clinical benefits in infants treated with bronchodilators: they do not improve oxygen saturation, do not reduce hospital admission after outpatient treatment, do not shorten the duration of hospitalization and do not reduce the time to resolution of illness at home. Some trials suggest that epinephrine may transiently reduce early admissions in emergency settings, especially in combination with dexamethasone, as in BIPED study [58].

2.3. Tidal Breathing Analysis

TBA can be used to identify potential responders via meaningful improvements in timing indices (e.g., tPTEF/TE), supporting physiology-based phenotyping. TBA is feasible in non-sedated children and quantifies airflow obstruction through timing and flow indices [59,60]. In wheezing infants, lower tPTEF/TE has been reported in those with more persistent symptoms, although variability necessitates standardized acquisition and loop selection [61].

2.4. Treatment Reviews for Acute Bronchiolitis

Supportive care is cornerstone: hydration, oxygen, and suctioning [62,63].

Hypertonic saline may modestly reduce hospital length of stay and may slightly improve clinical severity score (CSS). Treatment with nebulised hypertonic saline may also reduce the risk of hospitalisation amongst outpatients and ED patients, although a randomized clinical trial of 777 healthy infants, the hospital admission rate in the hypertonic saline group was 48.1% compared with 52.2% in the normal saline group [64]. Nebulised hypertonic saline seems to be a safe treatment in infants with bronchiolitis with only minor and spontaneously resolved adverse events, especially when administered in conjunction with a bronchodilator as documented in a recent review; total number of included trials was 34, involving 5205 infants with acute bronchiolitis, of whom 2727 infants received hypertonic saline [65]. In studies that explored combination of medication, low-quality evidence suggests that nebulized epinephrine plus hypertonic saline may be considered as a safe and efficient therapy for decreasing length of stay and CSS in infants with acute bronchiolitis, especially in those who require hospitalization for more than 48 h [66].

Corticosteroids generally show no consistent benefit in typical bronchiolitis; evidence for benefit in combination regimens (e.g., with epinephrine) has been mixed across trials [67], but in children with severe bronchiolitis, the duration of clinician-managed pressure support in intensive care (defined as high-flow nasal-prong oxygen, nasopharyngeal continuous positive airway pressure, or mechanical ventilation), was reduced by regular treatment with systemic corticosteroids and inhaled epinephrine compared with standard care [68].

Antibiotics are ineffective in absence of bacterial co-infection [69], excepting azithromycin that may reduce hospitalization time in acute bronchiolitis and wheezing episodes among children aged less than two. Azithromycin administrated during the acute wheezing period, does not have preventive effect on wheezing recurrence [70].

DNase has been explored for mucus clearance but evidence is limited [71].

3. Future Research

3.1. Study Question

Does acute bronchodilator responsiveness during an acute bronchiolitis episode, defined by prespecified TBA criteria, predict higher 5-year asthma risk compared with non-responsiveness?

3.2. Objectives

Primary: Compare physician-diagnosed asthma at 5 years (as per GINA 2026 criteria for asthma in children 5 years and younger) [73] among salbutamol-responders and non-responders (TBA-defined).

Secondary: (i) acute changes in TBA after salbutamol; (ii) proportion classified as responders; (iii) predictors of response (family history, viral aetiology, smoke exposure, biomarkers); (iv) associations between response and acute severity (PRESS, oxygen/HFNC, length of stay, PICU) [71,72].

4. Discussion

The majority of infants with wheezing have transient conditions associated with diminished airway function at birth and do not have increased risks of asthma later in life. In a substantial minority of infants, however, wheezing episodes are probably related to a predisposition to asthma [4,5,6].

Although recent guidelines recommend a minimalist approach to bronchiolitis, there are some issues with this approach. First, there are concerns about the precise definition of the disease, the quality and uniformity of the guidelines, the method of administration of bronchodilators, and the availability of tools to evaluate the response to therapies. Second, for decades it has been assumed that all cases of viral bronchiolitis are similar, but recent evidence has shown that this is not the case. Distinct bronchiolitis phenotypes have been described, with heterogeneity in clinical presentation, molecular immune signatures and clinically relevant outcomes such as respiratory failure and recurrent wheezing [77]. All these limitations are more stringent in primary care settings, even in developed countries [78].

The physiological changes observed after salbutamol are compatible with bronchodilator responsiveness, objectively assessed by TBA, in a child presenting with a second episode of recurrent wheezing triggered by respiratory syncytial virus lower respiratory tract infection. During the initial episode three months earlier, which required hospitalization in our unit for severe bronchiolitis (Paediatric Respiratory Severity Score [PRESS] = 5), the patient exhibited a clinically significant response to inhaled salbutamol. However, TBA was not performed at that time to objectively quantify changes in lung function parameters.

During this second major broncho-obstructive episode, with hospitalization, nebulized salbutamol administration resulted in a marked increase in respiratory timing indices (tPTEF and tPTEF/TE), shortening of expiratory duration, and increased minute ventilation, while peak expiratory flow (PEF) remained unchanged. The observed alterations in TBA waveform morphology were consistent with an improved tidal expiratory pattern in the absence of an increase in peak flow, supporting the presence of pharmacologically mediated bronchodilation. In this patient, who appears to follow a recurrent wheezing trajectory compatible with a viral-induced asthma phenotype, responsiveness to short-acting β₂-agonists was objectively documented. This interpretation accounts for potential state-dependent physiological variability and measurement-related fluctuations that may influence respiratory timing indices in young children.

This pattern seems similar to findings of a group of researchers that monitored 76 children presenting with their first wheezing episode at the ages of 3 to 23 months. At study entry, viral aetiology, rhinovirus genome load, atopic and clinical characteristics, and standardized questionnaire were analysed. At 4-year follow-up visit, impulse oscillometry with exercise challenge was performed. Bronchial reactivity (≥35% change in mean crude values of resistance) after exercise challenge or bronchodilation was present in nine (12%) children [79].

This paper has several limitations: it presents only one case of TBA usage for description of bronchodilator responsiveness in a 23 old months child with previous wheezing episodes. This scenario could be used as hypothesis generating and we have evoked potential future research, as strength of this case, we can state that to our knowledge, this is among the first reports using bedside TBA to characterize acute bronchodilator responsiveness in severe bronchiolitis-like illness.

Future precision-medicine strategies integrating validated asthma prediction models and pulmonary function tests with artificial intelligence–based platforms that incorporate electronic health records, genomic data, and molecular biomarkers may further optimize individualized management and improve long-term quality of life in some high-risk populations.

5. Conclusions

Bedside physiological assessment can reveal clinically relevant heterogeneity within phenotypically typical bronchiolitis presentations.

Although routine bronchodilator therapy is not recommended at the population level, physiology-guided bedside trials may provide a pragmatic and evidence-based approach for identifying selected potential responders without reliance on empirical trial-and-error management strategies.

TBA-based phenotyping by future research could refine acute therapeutic decision-making, enable risk-stratified surveillance during early childhood, and potentially will be incorporated into artificial intelligence–driven personalized treatment algorithms.