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Bronchial hyperresponsiveness

Bronchial hyperresponsiveness (BHR), also referred to as airway hyperresponsiveness (AHR), is defined as an exaggerated narrowing of the airways in response to various stimuli, such as inhaled constrictor agonists, allergens, irritants, or physical challenges like exercise.^[1] This heightened sensitivity leads to excessive bronchoconstriction, manifesting as wheezing, shortness of breath, or cough, and is a hallmark pathophysiological feature of asthma.^[2] BHR is not exclusive to asthma; it occurs in approximately 11–20% of healthy individuals and is also prevalent in chronic obstructive pulmonary disease (COPD) and other respiratory conditions.^[3] The mechanisms underlying BHR involve a combination of airway inflammation, structural changes in the bronchial wall, and altered neural regulation.^[1] Inflammatory cells, including eosinophils and mast cells, release mediators that enhance smooth muscle contractility and epithelial permeability, amplifying the response to stimuli.^[2] Direct stimuli, such as methacholine or histamine, act primarily on airway smooth muscle receptors, while indirect stimuli, like mannitol or cold air, provoke mediator release from inflammatory cells.^[1] These processes are closely linked to atopy, where immunoglobulin E-mediated responses to allergens exacerbate BHR.^[4] Clinically, BHR is assessed through bronchial provocation tests (BPTs), which measure the degree of airway narrowing induced by controlled stimuli, aiding in asthma diagnosis, severity assessment, and treatment monitoring.^[1] For instance, methacholine challenge tests quantify sensitivity by determining the concentration causing a 20% drop in forced expiratory volume in one second (FEV1).^[2] BHR correlates with asthma exacerbations and reduced lung function, particularly in children and athletes, where it may predict the development of persistent asthma.^[5] Treatment strategies focus on reducing inflammation with inhaled corticosteroids and bronchodilators, which can normalize BHR in many cases.^[1]

Definition and Measurement

Definition

Bronchial hyperresponsiveness (BHR), also known as airway hyperresponsiveness, refers to the exaggerated or excessive narrowing of the bronchi and bronchioles in response to various stimuli that typically elicit minimal or no bronchoconstriction in healthy individuals.^[2] This phenomenon is characterized by an increased sensitivity (hyperresponsiveness) and excessive magnitude of response (hyperreactivity) in the airway smooth muscle, leading to heightened airflow obstruction.^[6] It serves as a key physiological feature distinguishing pathological airway behavior from normal responses.^[3] The concept of BHR was first systematically described in the mid-20th century, with early observations in 1945 by Tiffeneau and Beauvallet linking it to asthmatic reactions via histamine challenges, building on broader asthma descriptions from the early 1900s.^[7] Its formal definition evolved during the 1960s through standardized provocation studies using agents like methacholine, which helped quantify the abnormal airway sensitivity in clinical settings.^[8] These developments shifted understanding from anecdotal asthma reports to a measurable trait of respiratory disorders. BHR differs from bronchospasm, which denotes an acute, transient contraction of bronchial smooth muscle often triggered by immediate irritants, whereas BHR represents a chronic predisposition to amplified and prolonged responses across a range of stimuli.^[9] As a hallmark feature of asthma, BHR is assessed via provocation tests that reveal this underlying airway instability.^[10]

Measurement Techniques

Bronchial hyperresponsiveness (BHR) is quantified through standardized bronchial challenge tests that provoke and measure airway narrowing, typically via spirometry to assess forced expiratory volume in one second (FEV1). Direct challenge tests use pharmacological agents that act directly on airway smooth muscle receptors to induce bronchoconstriction, providing a sensitive assessment of airway responsiveness. Methacholine, a synthetic analog of acetylcholine, is the most commonly employed agent, administered in increasing concentrations (e.g., 0.031 to 16 mg/mL) via nebulizer inhalation, with spirometry performed after each dose to monitor FEV1 decline.^[11] Histamine, another direct stimulus, binds to H1 receptors on smooth muscle, causing similar contraction; it was historically used but is less favored today due to greater irritant effects and shorter duration of action compared to methacholine. These tests follow tidal breathing protocols for 1 minute or more per dose to ensure consistent delivery, avoiding deep inhalations that may blunt responses. Indirect challenge tests evaluate BHR by stimulating the release of endogenous mediators from airway inflammatory cells, mimicking physiological triggers and often correlating more closely with clinical symptoms. Exercise challenge involves standardized treadmill or cycle ergometer protocols achieving 80-90% of maximum predicted heart rate for 6-8 minutes, followed by serial FEV1 measurements for up to 30 minutes post-exercise to detect cooling- and drying-induced narrowing. Eucapnic voluntary hyperpnea simulates hyperventilation with dry air while maintaining normal CO2 levels, commonly used in athletes. Mannitol, delivered as a dry powder in escalating doses (0-635 mg), acts as an osmotic agent to draw water into airways and release mediators; it is particularly useful for assessing eosinophilic inflammation. Adenosine monophosphate (AMP) inhalation indirectly stimulates mast cells via A2B receptors, with doses increasing until a 20% FEV1 fall. These methods require specific equipment, such as validated nebulizers for liquids or single-use capsules for mannitol, and are performed in controlled environments to standardize environmental factors like temperature and humidity. The primary metrics for interpreting BHR are the provocative concentration (PC20) or provocative dose (PD20) of the stimulus required to cause a 20% decline in FEV1 from baseline, calculated via dose-response interpolation. PC20 is expressed in mg/mL for concentration-based protocols (e.g., methacholine), while PD20 uses cumulative delivered dose in μg, preferred for its independence from nebulizer output variability. A PC20 below 8 mg/mL or PD20 below 400 μg indicates abnormal BHR, with lower values (e.g., PD20 <25 μg) denoting marked hyperresponsiveness; values above these thresholds suggest normal responsiveness.^[11] These cutoffs establish diagnostic sensitivity, particularly for ruling out asthma when negative, though specificity varies by population.^[12] Safety protocols are essential given the risk of severe bronchospasm, with pre-test screening including baseline FEV1 ≥60-70% predicted, stable asthma control, and withholding of interfering medications (e.g., short-acting beta-agonists for 8 hours). Continuous monitoring of symptoms, oxygen saturation, and ECG in high-risk cases is required, with immediate reversal using inhaled bronchodilators like albuterol; patients must recover to within 10% of baseline FEV1 before discharge. Contraindications include recent myocardial infarction or stroke (within 3 months), uncontrolled hypertension, pregnancy, aortic aneurysm, recent respiratory infection, or conditions raising intracranial pressure (e.g., recent eye surgery).^[13]^[11] Emergency equipment, including oxygen and resuscitation tools, must be readily available, and tests should be supervised by trained personnel. The evolution of these techniques began in the 1940s with Robert Tiffeneau's introduction of histamine inhalation challenges, initially monitored by vital capacity changes, marking the shift from parenteral to aerosolized stimuli for safer, quantifiable assessment. Methacholine emerged in the 1950s as a more stable alternative, with spirometry standardization in the 1970s enabling precise FEV1-based metrics like PC20. Modern protocols, refined through joint American Thoracic Society (ATS) and European Respiratory Society (ERS) efforts, emphasize dosimeter accuracy and PD20 reporting; the 2017 ERS technical standard updated general considerations, incorporating indirect tests and device-specific adjustments for global reproducibility.^[14]

Pathophysiology

Underlying Mechanisms

Airway smooth muscle (ASM) hypercontractility is a central physiological mechanism underlying bronchial hyperresponsiveness (BHR), characterized by exaggerated contractile responses to various stimuli. In asthmatic airways, ASM demonstrates increased calcium sensitivity, enabling enhanced force generation at lower intracellular calcium concentrations through inhibition of myosin light chain phosphatase (MLCP) via the RhoA/Rho kinase pathway, which sustains phosphorylation of regulatory myosin light chain (rMLC).^[15] This hypercontractility is further amplified by upregulated expression of myosin light chain kinase (MLCK), which promotes rMLC phosphorylation and actomyosin cross-bridge cycling, leading to faster shortening velocity and greater overall bronchoconstriction.^[16] These alterations result in a steeper dose-response curve to bronchoconstrictors, contributing to the excessive airway narrowing observed in BHR.^[17] Neural reflexes exacerbate BHR through heightened vagal activity and sensory nerve activation, initiating reflex bronchoconstriction. Parasympathetic efferent nerves release acetylcholine that binds to M3 muscarinic receptors on ASM, inducing contraction, while dysfunction of inhibitory M2 receptors—often due to reduced expression—leads to unchecked acetylcholine accumulation and vagal hyperactivity.^[18] Afferent sensory nerves, particularly C-fibers, become hypersensitive in BHR, depolarizing in response to irritants and signaling via the brainstem (nucleus tractus solitarius) to amplify efferent parasympathetic output, thereby promoting rapid and exaggerated reflex narrowing of the airways.^[19] This neural dysregulation lowers the threshold for bronchoconstrictive responses, distinguishing BHR from normal airway reactivity.^[20] Epithelial barrier dysfunction facilitates BHR by compromising the airway's protective interface, allowing deeper penetration of stimuli. Impaired mucociliary clearance arises from goblet cell metaplasia and hyperplasia, which boost mucus hypersecretion (notably MUC5AC), coupled with reduced numbers of ciliated cells and ciliary beat frequency, hindering effective particle removal and promoting stasis that sensitizes underlying structures.^[21] Concurrently, increased epithelial permeability stems from disrupted tight junctions, including downregulation of occludin and zonula occludens-1 (ZO-1), enabling allergens and irritants to access ASM and sensory nerves more readily, thereby intensifying contractile and reflex responses.^[22] These changes create a permissive environment for stimulus-evoked hyperresponsiveness.^[23] Inflammatory remodeling sustains BHR through persistent structural alterations, notably subepithelial fibrosis and angiogenesis. Subepithelial fibrosis involves extracellular matrix deposition (e.g., collagens I, III, V) beneath the basement membrane, thickening the airway wall and increasing its stiffness, which amplifies the mechanical effects of ASM contraction and contributes to fixed airflow obstruction.^[24] Angiogenesis promotes neovascularization, elevating vascular permeability and edema within the airway wall, further narrowing the lumen and enhancing responsiveness to stimuli in chronic settings.^[25] These remodeling processes, evident early in disease progression, underlie the persistent nature of BHR beyond acute inflammatory episodes.^[26] Dynamic factors, including airway wall thickening and loss of parenchymal tethering, dynamically worsen BHR by altering airway mechanics. Wall thickening from edema, mucus, and fibrosis reduces baseline airway caliber and magnifies the proportional impact of ASM shortening, leading to greater resistance changes during provocation.^[27] Loss of tethering, due to parenchymal elastic tissue degradation, diminishes radial traction on airways, permitting excessive collapse and unchecked bronchoconstriction without the normal stabilizing load from lung parenchyma.^[28] Inflammation amplifies these dynamic effects by accelerating remodeling and neural sensitization.^[7]

Cellular and Molecular Factors

Bronchial hyperresponsiveness (BHR) involves the activation of key inflammatory cells, including eosinophils, mast cells, and T-helper 2 (Th2) lymphocytes, which release mediators that exacerbate airway sensitivity. Eosinophils contribute to BHR by releasing granule proteins such as major basic protein, which damages airway epithelium and promotes bronchoconstriction.^[29] Mast cells, upon activation, degranulate to release histamine and leukotrienes (e.g., LTC4, LTD4), potent bronchoconstrictors that directly enhance airway responsiveness.^[30] Th2 lymphocytes amplify this process by secreting interleukin-5 (IL-5), which sustains eosinophil survival and recruitment to the airways, thereby perpetuating inflammation and hyperresponsiveness.^[31] At the molecular level, Th2 cytokine skewing plays a central role in BHR pathogenesis, with IL-4 and IL-13 driving IgE production by B cells and inducing goblet cell hyperplasia, leading to mucus hypersecretion and airway narrowing. IL-4 promotes Th2 differentiation and IgE class switching, while IL-13 acts directly on airway smooth muscle and epithelial cells to induce hyperresponsiveness independently of adaptive immunity.^[32] These cytokines synergize to upregulate vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, facilitating eosinophil infiltration.^[33] Protease-activated receptors (PARs), particularly PAR-2 on epithelial cells, are activated by allergens and proteases, triggering signaling cascades that result in epithelial barrier disruption, cytokine release, and enhanced BHR.^[34] Neurogenic inflammation further contributes to BHR through the release of substance P and neurokinin A from sensory C-fibers in the airways, which bind to neurokinin-1 and neurokinin-2 receptors to induce bronchoconstriction, mucus secretion, and vasodilation. These neuropeptides amplify inflammatory responses by stimulating mast cell degranulation and immune cell recruitment, creating a feedback loop that heightens airway reactivity.^[35] Oxidative stress exacerbates BHR via reactive oxygen species (ROS) generated by activated neutrophils, which overwhelm antioxidant defenses and impair beta-adrenergic signaling in airway smooth muscle. ROS oxidize lipids and proteins, reducing beta2-adrenergic receptor responsiveness to bronchodilators like albuterol, thereby promoting sustained bronchoconstriction.^[36] This molecular disruption correlates with increased BHR severity in inflammatory states.^[37] Recent advances highlight the role of innate lymphoid cells type 2 (ILC2s) in sustaining molecular inflammation underlying BHR, as these cells rapidly produce IL-5 and IL-13 in response to epithelial-derived alarmins like IL-33, independent of antigen-specific T cells. Studies post-2020 have shown ILC2s contribute to chronic Th2 skewing and airway remodeling in BHR models.^[38] Additionally, microbiome dysbiosis in the airways and gut promotes BHR by altering molecular inflammation, with reduced microbial diversity leading to enhanced Th2 cytokine production and epithelial permeability via dysregulated short-chain fatty acid signaling. Post-2020 research links this dysbiosis to persistent ILC2 activation and ROS imbalance in BHR pathogenesis.^[39]^[40]

Causes and Risk Factors

Genetic Influences

Bronchial hyperresponsiveness (BHR) exhibits a significant genetic component, with twin studies estimating heritability at 35-50%. For instance, analysis of 8- to 18-year-old twins from the Australian Twin Registry in the 1990s revealed substantial genetic overlap between BHR, asthma, and atopy, supporting a polygenic inheritance pattern where genetic factors account for a moderate to high proportion of phenotypic variance.^[41] Several candidate genes have been implicated in BHR pathogenesis. The ADAM33 gene, located on chromosome 20p13, influences airway remodeling and smooth muscle contractility, with polymorphisms associated with increased BHR risk in asthmatic populations. Variants in the IL4 and IL13 loci on chromosome 5q31 promote Th2-mediated inflammation, elevating IgE levels and eosinophil activity that exacerbate bronchial responsiveness. Similarly, the ORMDL3 gene at the 17q21 locus regulates sphingolipid synthesis, impacting airway smooth muscle proliferation and contributing to BHR susceptibility, particularly in early-onset cases. The GSTM1 null genotype, resulting from a homozygous deletion of the glutathione S-transferase mu 1 gene, heightens vulnerability to oxidative stress, amplifying BHR in response to environmental irritants such as nitrogen dioxide from gas cooking.^[42] Individuals with this genotype exhibit reduced detoxification capacity, leading to persistent airway inflammation and heightened responsiveness.^[43] Advancements in genomics have introduced polygenic risk scores (PRS) derived from genome-wide association studies (GWAS), which aggregate effects of multiple variants to predict BHR in at-risk groups; the 2024 study using SNPs from drug metabolism pathways demonstrated improved accuracy for childhood asthma susceptibility and severity.^[44] A 2025 analysis further showed that cumulative genetic risk contributes to asthma disease severity.^[45] Epigenetic modifications, such as DNA methylation in promoter regions of inflammatory genes like those encoding IL-4 and IL-13, further modulate BHR heritability, often triggered by early-life exposures that alter gene expression without changing the DNA sequence.^[46] These genetic and epigenetic factors interact with environmental triggers to shape overall BHR risk.

Environmental and Lifestyle Factors

Bronchial hyperresponsiveness (BHR) can be induced or exacerbated by various environmental allergens and irritants that trigger airway inflammation and sensitivity. Common allergens such as pollen and dust mites provoke immune responses leading to mast cell degranulation and release of mediators like histamine, which narrow the airways and heighten responsiveness.^[47] Tobacco smoke acts as a potent irritant, causing oxidative stress and epithelial injury that directly enhances BHR in exposed individuals.^[48] Occupational exposures, particularly to isocyanates used in paints and coatings, are linked to the development of BHR through sensitization and inflammatory cascades, affecting workers in industries like automotive painting.^[49] Viral respiratory infections, including respiratory syncytial virus (RSV) and rhinovirus, often cause transient BHR by damaging the airway epithelium and disrupting barrier function, allowing inflammatory cells to infiltrate and amplify responsiveness.^[50] These infections induce cytokine release and neurogenic inflammation, leading to heightened bronchial sensitivity that can persist for weeks post-infection.^[51] Lifestyle factors significantly contribute to BHR risk. Active smoking increases the odds of BHR by approximately 2-3 times through chronic irritation and impaired mucociliary clearance, with dose-dependent effects observed across pack-years.^[52] Obesity promotes BHR via elevated adipokines such as leptin, which enhance airway smooth muscle contractility and inflammation.^[53] Diets low in antioxidants, like vitamins C and E, fail to counter oxidative stress from environmental exposures, thereby increasing bronchial reactivity.^[54] Climatic conditions and air pollution further sensitize airways to BHR. Inhalation of cold air induces bronchoconstriction by cooling and drying the airways, triggering hyperresponsiveness in susceptible individuals.^[55] Ozone exposure generates reactive oxygen species that inflame the epithelium and amplify BHR, while fine particulate matter (PM2.5) deposits in airways, promoting persistent sensitivity.^[47] Urban environments, with higher pollution levels, show greater BHR prevalence compared to rural areas, highlighting the role of ambient pollutants in exacerbating this condition.^[56] Recent studies on post-COVID-19 effects indicate persistent BHR in a notable subset of recovered patients, with one analysis reporting airway hyperresponsiveness in most individuals with ongoing respiratory symptoms, and another finding positive methacholine challenge tests in 43% of post-infection cases.^[57]^[58] These findings underscore viral-induced epithelial damage as a mechanism for long-term airway dysfunction in 20-30% of those experiencing prolonged symptoms, based on broader long COVID cohorts.^[59]

Clinical Associations

In Asthma

Bronchial hyperresponsiveness (BHR) is a hallmark feature of asthma, present in the majority of patients, with prevalence rates ranging from 70% to 90% depending on the study population and diagnostic criteria used for asthma and BHR assessment.^[60] The degree of BHR correlates with asthma severity, being more pronounced in severe persistent asthma compared to mild intermittent forms, where it often reflects the extent of underlying airway inflammation and remodeling.^[61] In asthma, BHR is characteristically reversible, distinguishing it from fixed airway obstruction seen in other conditions; this reversibility is demonstrated by a significant improvement in forced expiratory volume in 1 second (FEV1) of greater than 12% and 200 mL following bronchodilator administration, such as albuterol, which helps confirm the diagnosis and guides management.^[62] Among asthma phenotypes, early-onset allergic asthma exhibits heightened BHR largely attributable to atopy, with elevated IgE levels and allergen sensitization contributing to exaggerated airway responses.^[5] In contrast, non-allergic asthma phenotypes, such as exercise-induced asthma, display BHR triggered by non-immunologic stimuli like physical activity or cold air, often without prominent atopic features. Persistent BHR serves as a prognostic indicator in asthma, predicting an increased risk of future exacerbations and accelerated decline in lung function over periods of 5 to 10 years, with longitudinal studies showing associations between ongoing BHR and greater annual loss of FEV1.^[63] This predictive value underscores the importance of monitoring BHR in clinical follow-up to identify patients at risk for disease progression.^[64] A specific subtype, aspirin-exacerbated respiratory disease (AERD), features particularly heightened BHR to nonsteroidal anti-inflammatory drugs (NSAIDs), leading to severe bronchospasm and increased asthma morbidity upon exposure.^[65]

In Other Respiratory Diseases

Bronchial hyperresponsiveness (BHR) is observed in approximately 40-60% of patients with chronic obstructive pulmonary disease (COPD), particularly those with emphysema and small airway disease, where it contributes to airflow limitation but shows limited reversibility in response to bronchodilators.^[66]^[2] This prevalence was notably documented in the Lung Health Study, a multicenter trial conducted from the 1980s through the early 2000s, which identified BHR in about 60% of participants with early COPD using methacholine challenge testing.^[66] Unlike in asthma, BHR in COPD often reflects structural changes in the airways rather than primarily reversible inflammation, influencing disease progression and symptom severity.^[67] Post-infectious BHR commonly arises following viral upper respiratory infections or pertussis, manifesting as transient airway sensitivity that typically resolves within weeks to months.^[68] Studies indicate that this hyperresponsiveness persists for an average of three weeks after symptom onset in adults, with durations extending up to 5-11 weeks in children experiencing a single viral episode.^[69]^[70] In pertussis cases, the associated cough hypersensitivity can prolong BHR, sometimes contributing to extrathoracic airway involvement, but it generally subsides without long-term sequelae in otherwise healthy individuals.^[71] In allergic rhinitis, mild BHR occurs as a comorbidity in 24-40% of patients, often linked to shared inflammatory pathways with asthma, such as eosinophilic airway involvement, though it presents with subtler symptoms like episodic wheezing during allergen exposure.^[72]^[73] Vocal cord dysfunction frequently coexists with mild BHR in up to 11-40% of cases, leading to frequent misdiagnosis as asthma due to overlapping symptoms of dyspnea and inspiratory stridor, with prior asthma labeling in over 40% of affected individuals.^[74]^[75] This misdiagnosis can result in unnecessary asthma therapies, as the primary issue involves laryngeal rather than bronchial hyperreactivity.^[76] BHR affects 30-50% of patients with cystic fibrosis, where it is exacerbated by chronic mucus plugging, recurrent infections, and airway remodeling, leading to variable airflow obstruction beyond the primary structural defects.^[77]^[78] In bronchiectasis, prevalence ranges from 18-29%, similarly worsened by persistent infections and bronchial inflammation, which heighten sensitivity to nonspecific stimuli and complicate management.^[79]^[80] These features distinguish BHR in cystic fibrosis and bronchiectasis from isolated asthma, as it often correlates with disease severity and infectious exacerbations rather than atopy alone.^[81] Among occupational lung diseases, BHR is prominent in hypersensitivity pneumonitis, where acute and subacute forms present with wheezing and increased airway responsiveness due to immune-mediated alveolar and bronchial inflammation from inhaled antigens.^[82] In byssinosis, caused by cotton dust exposure, BHR affects the majority of symptomatic workers, manifesting as acute chest tightness and reversible bronchoconstriction during shifts, with hyperreactivity persisting in chronic cases.^[83]^[84] These conditions highlight BHR as a secondary response to environmental irritants, differing from intrinsic asthmatic mechanisms.^[85]

Diagnosis

Bronchial Provocation Tests

Bronchial provocation tests serve as a key diagnostic method to assess bronchial hyperresponsiveness by intentionally inducing bronchoconstriction in a controlled setting, often confirming suspected asthma when baseline lung function is normal. These tests are categorized into direct and indirect types. Direct challenges involve agonists like methacholine or histamine that act directly on airway smooth muscle receptors to cause constriction, offering high sensitivity for detecting hyperresponsiveness.^[86] Indirect challenges, such as exercise, cold dry air inhalation, mannitol, or hypertonic saline, stimulate the release of endogenous mediators from inflammatory cells, better reflecting real-world triggers and correlating more closely with airway inflammation; the choice depends on the suspected underlying mechanism, with indirect tests preferred when exercise-induced symptoms are prominent.^[86]^[87] The standard protocol for a methacholine challenge test begins with baseline spirometry to measure forced expiratory volume in 1 second (FEV1), ensuring it is at least 70% of predicted and stable (variation <10% between trials). Patients then inhale nebulized diluent (saline) for control, followed by stepwise increasing concentrations of methacholine, typically using doubling doses from 0.0625 mg/mL up to 16 mg/mL, administered via tidal breathing for 1 minute per dose or 5 vital capacity breaths.^[13] FEV1 is measured 30 seconds after each inhalation, with measurements repeated every 30-90 seconds if needed until a 20% fall from baseline occurs or the maximum dose is reached; the test is terminated early if FEV1 drops by 20%. Equipment must adhere to standardization guidelines to ensure reproducibility. Nebulizers, such as the Wright or DeVilbiss models, are calibrated for consistent aerosol output of approximately 0.13 mL/min (with ±10% variation) during the inhalation period, verified by weighing the nebulizer before and after use.^[13] The 2017 ERS technical standard, endorsed by the ATS, recommends using provocative dose (PD20) metrics based on delivered aerosol mass, with nebulizers characterized accordingly; the 2021 ERS guidelines for asthma diagnosis in children aged 5-16 years recommend direct bronchial challenge testing with methacholine when first-line tests are inconclusive, and indirect challenges such as exercise for those with exercise-related symptoms, noting feasibility considerations in pediatrics.^[88]^[89] Patient preparation is essential to avoid false negatives or safety risks. Inhaled corticosteroids and leukotriene modifiers do not need to be withheld, as they have little effect on the test. Short-acting beta-agonists should be withheld for at least 8 hours, long-acting beta-agonists for 48 hours, theophylline for 24 hours, and oral beta-agonists for 12 hours. Patients must avoid caffeine-containing beverages and heavy meals for 4 hours prior, refrain from smoking or alcohol for 1-4 hours, and report recent respiratory infections or heart conditions that contraindicate testing.^[90]^[13]^[88] Adverse events are generally mild and transient, including throat irritation, cough, wheezing, or dyspnea, resolving spontaneously or with bronchodilators. Severe reactions, such as significant bronchospasm requiring epinephrine, occur in less than 1% of tests, with thousands of procedures performed annually without serious complications when protocols are followed.^[91]

Interpretation and Limitations

The interpretation of bronchial provocation test results for assessing bronchial hyperresponsiveness (BHR) primarily relies on the provocative concentration of methacholine (PC₂₀) that causes a 20% fall in forced expiratory volume in 1 second (FEV₁). A PC₂₀ of ≤8 mg/mL is typically considered positive for BHR, indicating significant airway responsiveness, while values between 8 and 16 mg/mL are classified as borderline and necessitate correlation with clinical history and other diagnostic findings to avoid misdiagnosis. Guidelines increasingly recommend reporting provocative dose (PD₂₀) in micrograms for greater standardization across devices.^[92]^[11]^[88] Bronchial provocation tests exhibit high sensitivity for detecting asthma, approximately 90%, making a negative result (PC₂₀ >16 mg/mL) reliable for excluding current asthma in patients with recent symptoms. However, specificity is lower, ranging from 30% to 50%, due to overlap with conditions like allergic rhinitis or chronic obstructive pulmonary disease (COPD), which can mimic BHR without confirming asthma.^[92] Several limitations affect the reliability of these tests. False-positive results, where non-asthmatic individuals show heightened responsiveness, are common in current smokers due to chronic airway irritation and following upper respiratory infections (URIs), which transiently increase airway sensitivity. Conversely, false negatives can occur in patients with severe airflow obstruction (baseline FEV₁ <60% predicted), as the test may not detect underlying BHR, or in those recently treated with systemic corticosteroids or long-acting bronchodilators, which suppress responsiveness.^[92] Results can also be influenced by confounders such as age, sex, and atopy. BHR is more prevalent in females than males, potentially due to hormonal or anatomical differences in airway caliber, and atopy amplifies responsiveness through IgE-mediated inflammation. Age-related changes in lung function may alter thresholds, with younger individuals showing higher variability. To monitor disease progression or treatment efficacy, serial testing is recommended, as single measurements may not capture fluctuations in responsiveness.^[93]^[94] When bronchial provocation tests are contraindicated, such as during pregnancy due to risks of inducing bronchospasm, alternative diagnostics like peak flow variability monitoring (e.g., >20% diurnal variation suggestive of asthma) or fractional exhaled nitric oxide (FeNO) measurement serve as adjuncts to assess airway inflammation and variability.^[95]^[96]^[97]

Management and Treatment

Pharmacological Interventions

Pharmacological interventions for bronchial hyperresponsiveness (BHR) primarily aim to alleviate acute symptoms, reduce airway inflammation, and improve long-term airway responsiveness through targeted medications. These therapies, including bronchodilators, inhaled corticosteroids, leukotriene modifiers, biologics, and anticholinergics, are selected based on the severity and underlying mechanisms of BHR, often demonstrating measurable improvements in provocative concentration causing a 20% fall in FEV1 (PC20) and symptom control.^[98] Short-acting beta-agonists (SABAs), such as albuterol, provide rapid bronchodilation for acute relief of BHR-induced bronchospasm by stimulating beta-2 adrenergic receptors, leading to smooth muscle relaxation within minutes.^[98] Long-acting beta-agonists (LABAs), like salmeterol, are used for maintenance therapy in persistent BHR, offering sustained bronchodilation over 12 hours and reducing airway hyperresponsiveness by approximately 1-2 doubling dilutions in PC20 after regular use.^[99] When combined with inhaled corticosteroids, LABAs enhance overall control without increasing adverse events.^[100] Inhaled corticosteroids (ICS), such as beclomethasone or fluticasone, are cornerstone therapies that decrease airway inflammation by inhibiting inflammatory cell recruitment and cytokine production, thereby normalizing PC20 in many patients within 4-6 weeks of initiation.^[101] A meta-analysis of placebo-controlled trials confirmed a dose-dependent improvement in BHR, with higher doses yielding greater shifts in PC20 compared to low doses.^[102] These agents are particularly effective in reducing eosinophilic inflammation associated with BHR.^[103] Leukotriene modifiers, exemplified by montelukast, inhibit cysteinyl leukotriene receptors, blocking the proinflammatory effects of leukotrienes that exacerbate BHR, and are especially effective in aspirin-sensitive cases where they attenuate bronchoconstriction provoked by aspirin challenge.^[104] Clinical trials have shown montelukast reduces BHR in aspirin-exacerbated respiratory disease by partially protecting against lysine-aspirin-induced responses, with benefits observed after 10 mg doses.^[105] Biologics target specific pathways in severe eosinophilic BHR. Omalizumab, an anti-IgE monoclonal antibody, binds free IgE to prevent mast cell activation, achieving response rates of around 58% in patients with elevated eosinophils (≥300 cells/µL), as measured by reduced exacerbations and improved lung function in allergic asthma phenotypes.^[106] Mepolizumab, an anti-IL-5 antibody, depletes eosinophils by neutralizing IL-5, leading to 47-53% reductions in exacerbation rates and significant improvements in BHR in severe eosinophilic cases, with real-world response rates exceeding 50% for symptom control in 2020s trials.^[107] Other biologics include benralizumab, reslizumab, dupilumab, and tezepelumab, which target IL-5/IL-5R, IL-4Rα, and TSLP pathways, respectively, in severe Type 2 asthma.^[108] Both agents are reserved for refractory BHR unresponsive to standard therapies.^[109] Anticholinergics like tiotropium block muscarinic receptors to inhibit vagally mediated bronchoconstriction, providing additive benefits when added to LABA/ICS regimens in persistent BHR, with improvements in lung function comparable to adding a LABA alone.^[110] In patients with uncontrolled severe asthma, tiotropium enhances 24-hour bronchodilation and reduces BHR to methacholine, supporting its role in step-up therapy.^[111] Preventive measures, such as allergen avoidance, complement these interventions to sustain efficacy.

Preventive Measures

Preventive measures for bronchial hyperresponsiveness (BHR) primarily involve avoiding known triggers and modifying environmental and lifestyle factors to reduce airway inflammation and sensitivity. These strategies aim to mitigate the onset or progression of BHR, particularly in individuals with asthma or at risk due to occupational exposures or infections. By targeting allergens, irritants, and modifiable risk factors, such approaches can improve lung function and decrease symptom severity without relying on pharmacological interventions alone. Allergen avoidance is a cornerstone of BHR prevention, especially for those sensitized to house dust mites or pollen. Using allergen-proof encasements on mattresses and pillows significantly reduces exposure to dust mite allergens, thereby decreasing bronchial hyperreactivity in sensitive individuals. High-efficiency particulate air (HEPA) filters in vacuum cleaners and air purifiers further lower indoor allergen levels, helping to alleviate respiratory symptoms and potentially reduce BHR in atopic patients. For pollen sensitivity, allergen immunotherapy modifies immune responses to specific allergens, reducing airway hyperresponsiveness and the risk of asthma development in allergic rhinitic individuals. Smoking cessation is essential for preventing and reversing BHR, as tobacco smoke directly exacerbates airway inflammation. Quitting smoking leads to improvements in bronchial hyperresponsiveness within months, with studies showing reduced airway sensitivity to stimuli like methacholine after 4-6 months of abstinence. Counseling combined with nicotine replacement therapy achieves quit rates of approximately 25-30% at one year, supporting sustained respiratory benefits in former smokers with BHR. Environmental controls play a key role in minimizing irritant exposure that can trigger BHR. Air purifiers equipped with HEPA filters effectively reduce airborne pollutants and particulate matter, decreasing airway inflammation in susceptible individuals. In dry climates or during heating seasons, humidifiers maintain optimal indoor humidity levels (40-50%), preventing mucosal drying that can worsen airway responsiveness. For occupational settings, such as chemical industries, personal protective equipment like N95 masks or respirators limits inhalation of irritants, reducing the incidence of work-related BHR. Vaccination and infection prevention are critical to avoid post-viral exacerbations of BHR. Annual influenza vaccination is recommended for individuals with chronic respiratory conditions, as it prevents flu-related lower respiratory infections that can induce or aggravate bronchial hyperresponsiveness. In high-risk groups, such as infants or those with underlying lung disease, respiratory syncytial virus (RSV) prophylaxis with monoclonal antibodies like nirsevimab reduces severe RSV infections, thereby mitigating the risk of subsequent airway hyperreactivity. Lifestyle modifications offer additional avenues for BHR management. Weight loss in obese patients with asthma improves airway responsiveness, with studies showing improvements following significant body weight reduction through diet and exercise. Breathing exercises, such as the Buteyko method, promote nasal breathing and reduce hyperventilation, leading to better asthma control and decreased bronchial sensitivity in practitioners.

Epidemiology

Prevalence and Distribution

Bronchial hyperresponsiveness (BHR) affects approximately 11-20% of healthy individuals in the general population, with prevalence estimates varying based on testing methods and populations studied.^[3] In individuals with asthma, BHR is present in 80-95% of cases, depending on disease severity and diagnostic criteria.^[112] Prevalence is generally higher in children than adults, with up to 17% in pediatric cohorts compared to 10-15% in adults, reflecting differences in airway development and environmental exposures.^[113] Demographic patterns show BHR is more common in females, with odds ratios of 1.5-2 compared to males, particularly after puberty when gender differences in airway responsiveness emerge.^[114] It is also more prevalent among urban dwellers and atopic individuals, where atopy strongly correlates with increased BHR risk across populations.^[4] Regional variations indicate higher BHR prevalence in developed countries compared to rural areas in developing regions, attributed to urbanization, pollution, and the hygiene hypothesis.^[115] In developing regions like Southeast Asia, rates are rising but remain below those in Western countries, with urban areas showing elevated levels due to environmental pollutants.^[116] Comorbidity rates highlight BHR in 50-66% of individuals with non-severe chronic obstructive pulmonary disease (COPD), as observed in the Lung Health Study cohort of smokers with mild airflow limitation.^[117] Post-viral BHR occurs in 20-30% of the general population following respiratory infections, often persisting as a transient but significant feature.^[118] Over time, BHR incidence has shown variable trends globally, linked to allergic disease burdens. As of 2025, recent studies indicate stable or slightly decreasing prevalence in some populations, such as 4-21% in adolescents, influenced by air pollution and urbanization.^[119]^[120]

Prognostic Implications

Bronchial hyperresponsiveness (BHR) serves as a significant predictor of new-onset asthma, particularly in at-risk pediatric populations. In the Tucson Children's Respiratory Study, a longitudinal birth cohort, BHR identified through cold air challenge at age 6 years was associated with a markedly elevated risk of subsequent asthma diagnosis by age 13, with a cumulative incidence of 13.4% in hyperresponsive children compared to 3.4% in those without, yielding a relative risk of 3.76.^[121] This predictive value extends into early adulthood, where early childhood BHR independently increased the odds of newly diagnosed asthma by 2.91-fold after adjusting for confounders like wheezing and atopy.^[122] Such findings underscore BHR's role in identifying children at 3- to 4-fold higher risk over 5- to 10-year follow-ups, informing targeted monitoring in high-prevalence cohorts. In chronic obstructive pulmonary disease (COPD), BHR correlates with accelerated disease progression, including steeper declines in lung function and heightened exacerbation rates. Patients with COPD and BHR exhibit an annual forced expiratory volume in 1 second (FEV1) decline approximately 50 mL greater than those without.^[63] This hyperresponsiveness also amplifies exacerbation frequency, with affected individuals experiencing 1.5- to 2-fold more events annually, often linked to underlying airway inflammation that exacerbates airflow obstruction.^[123] These associations highlight BHR as a marker for poorer long-term trajectories in COPD, beyond baseline severity. Remission of BHR is feasible in a subset of cases, particularly mild asthma managed with early intervention, though persistence often signals irreversible airway remodeling. In mild persistent asthma, early initiation of inhaled corticosteroids achieves BHR resolution in 30-50% of patients within 2-5 years, restoring normal airway responsiveness and preventing structural changes like subepithelial fibrosis.^[124] Conversely, sustained BHR despite treatment is tied to ongoing remodeling, with studies showing persistent hyperresponsiveness in 50-70% of moderate-to-severe cases leading to fixed airflow limitation.^[125] This differential outcome emphasizes timely therapy to maximize remission potential and mitigate chronic alterations. BHR elevates morbidity and mortality risks in asthma, manifesting as doubled hospitalization rates and heightened cardiovascular comorbidities. Asthmatics with documented BHR face approximately twice the risk of asthma-related hospitalizations compared to those with normal responsiveness, driven by severe exacerbations and reduced treatment adherence.^[126] Furthermore, BHR in severe asthma is linked to a 1.5- to 2-fold increase in cardiovascular events, including coronary heart disease and stroke, due to shared inflammatory pathways affecting vascular endothelium.^[127] These comorbidities compound overall mortality, with BHR-positive patients showing 20-30% higher all-cause death rates over 10 years in population studies.^[128] Recent research positions BHR as a valuable biomarker for gauging response to biologic therapies in severe asthma, particularly anti-IL5 agents. In trials from 2022-2024, baseline BHR levels predicted enhanced outcomes with anti-IL5/IL5Rα monoclonal antibodies, such as a 40% greater reduction in exacerbation rates and improved FEV1 in hyperresponsive subgroups compared to non-responders.^[129] For instance, real-world data on mepolizumab and benralizumab demonstrated that patients with elevated BHR achieved 35-45% better lung function gains and remission of symptoms after 12 months, supporting BHR's utility in personalizing biologic selection.^[130] These insights, from phase III and observational studies, advocate integrating BHR assessment to optimize therapy efficacy and long-term prognosis.

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