Asthma

• Th2-mediated immune response and eosinophilic inflammation: The pathologic hallmark involves aberrant differentiation of naive CD4+ T cells toward a Th2 phenotype under the influence of epithelial-derived cytokines (IL-25, IL-33, thymic stromal lymphopoietin [TSLP]) and antigen-presenting cells. Th2 cells secrete characteristic cytokines—interleukin-4 (IL-4), IL-5, and IL-13—that promote B cell immunoglobulin E (IgE) class switching, mast cell and eosinophil recruitment, and perpetuation of inflammation. IL-5 specifically drives eosinophil development, recruitment, and survival, making elevated eosinophil counts a marker of Th2-high asthma. IgE-mediated sensitization to environmental antigens (allergens) leads to Fc-epsilon receptor I cross-linking on mast cells and basophils, triggering degranulation and immediate release of preformed mediators (histamine, tryptase, leukotrienes) responsible for acute bronchoconstriction and symptoms. This cascade explains why inhaled corticosteroids (ICS), which suppress Th2 cytokine production, are so effective in asthma management.

• Airway structural remodeling and bronchial hyperresponsiveness: Chronic inflammation drives pathologic changes in airway architecture termed "remodeling," including subepithelial fibrosis with increased collagen deposition, smooth muscle hypertrophy and hyperplasia, neovascularization, and mucus gland hyperplasia. These structural changes increase airway wall thickness, reduce luminal diameter, and enhance the mechanical disadvantage of smooth muscle contraction—a phenomenon explaining why fixed airflow obstruction can develop in long-standing asthma despite optimal therapy. Bronchial hyperresponsiveness (heightened airway reactivity to nonspecific stimuli such as methacholine, histamine, or cold air) develops through multiple mechanisms: increased smooth muscle sensitivity due to altered calcium handling and contractile protein expression, reduced epithelial barrier function allowing irritant penetration, increased neural sensitivity with heightened vagal parasympathetic tone, and enhanced release of inflammatory mediators. BHR is measured objectively by methacholine challenge testing (PC20 value—the provocative concentration of methacholine causing ≥20% FEV1 decline); values <8 mg/mL indicate increased responsiveness and support asthma diagnosis.

• Epithelial barrier dysfunction and innate immunity: The respiratory epithelium, normally a tight barrier maintained by claudins and occludin tight junction proteins, becomes compromised in asthma through multiple mechanisms: direct damage from allergen proteases, oxidative stress, viral infections, and reduced expression of tight junction proteins. This allows enhanced penetration of antigens and irritants into the submucosa, amplifying both adaptive and innate immune responses. Innate lymphoid cells (ILCs), particularly ILC2s, represent an IL-5– and IL-13–producing population activated by epithelial alarmins (IL-33, TSLP, IL-25) and contribute to eosinophilic inflammation independent of adaptive immunity. This mechanism explains non-allergic ("intrinsic") asthma phenotypes and why some patients respond poorly to traditional ICS therapy targeting Th2 responses. Pattern recognition receptors (TLRs) on epithelial and dendritic cells also sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), triggering innate immune responses and bystander inflammation exacerbating asthma symptoms.

• Smooth muscle dysfunction and airway obstruction mechanics: Airway smooth muscle (ASM) exhibits multiple abnormalities in asthma: increased sensitivity to contractile agonists (acetylcholine, histamine, leukotrienes), alterations in calcium regulation with enhanced calcium influx through L-type and T-type calcium channels, increased expression of contractile proteins (actin and myosin), and reduced expression of relaxatory proteins. These intrinsic changes, combined with structural remodeling, result in exaggerated bronchoconstriction in response to stimuli. Additionally, smooth muscle cells secrete inflammatory mediators (cytokines, chemokines, growth factors) in asthma, contributing to recruitment and activation of immune cells and perpetuation of inflammation. β2-adrenergic receptors on smooth muscle mediate relaxation through cyclic AMP–dependent mechanisms; reduced receptor expression, increased phosphodiesterase activity degrading cAMP, and increased Gαi-coupled receptor signaling (via muscarinic receptors and cysteinyl leukotriene receptors) promote a procontractile phenotype.

• Neurogenic inflammation and parasympathetic dysfunction: The parasympathetic nervous system plays a major role in asthma pathogenesis through vagal preganglionic fibers releasing acetylcholine, which acts on muscarinic M3 receptors on airway smooth muscle to promote contraction. In asthma, enhanced parasympathetic neural tone and increased expression/sensitivity of muscarinic receptors contribute to heightened airway reactivity. Additionally, sensory C-fiber neuropeptides (substance P, neurokinin A) released from afferent nerves mediate neurogenic inflammation through tachykinin receptor activation on mast cells and other inflammatory cells, amplifying the inflammatory cascade. Loss of nitric oxide (NO)-producing neurons in asthmatic airways removes a major bronchorelaxant influence. These mechanisms explain why anticholinergic agents (ipratropium) provide additive benefit in acute asthma and in chronic asthma with prominent muscarinic signaling.

• Leukotriene synthesis and lipid mediator dysregulation: Arachidonic acid released from cell membranes during inflammation is metabolized via the 5-lipoxygenase (5-LO) pathway to generate cysteinyl leukotrienes (CysLTs: LTC4, LTD4, LTE4) and leukotriene B4 (LTB4). CysLTs are among the most potent bronchoconstrictor and inflammatory mediators known, promoting airway smooth muscle contraction, mucus secretion, eosinophil recruitment, and microvascular leakage. Aspirin and NSAIDs can precipitate asthma in susceptible individuals (aspirin-exacerbated respiratory disease [AERD]) through shunting of arachidonic acid metabolism toward leukotriene synthesis. Leukotriene receptor antagonists (montelukast) and 5-lipoxygenase inhibitors (zileuton) target this pathway and provide clinical benefit, particularly in allergic and AERD asthma.

• Genetic susceptibility and environmental gene-environment interactions: Multiple genome-wide association studies (GWAS) have identified susceptibility loci in genes affecting immune regulation (IL4, IL4RA, IL13), T cell development (IL2RA), epithelial barrier function (ORMDL3), and eosinophil biology (GATA3). However, asthma concordance in monozygotic twins is only ~80%, underscoring the primacy of environmental factors in phenotypic expression. Gene-by-environment interactions are critical: children with high genetic risk who are exposed to high allergen burden, respiratory infections (particularly respiratory syncytial virus [RSV] during critical windows), air pollution, or maternal smoking are at substantially elevated risk. The "hygiene hypothesis" and related concepts suggest that reduced childhood microbial exposure and altered microbiota composition favor Th2 differentiation and asthma development. Polymorphisms in β2-adrenergic receptor genes (e.g., Arg16Gly) influence treatment response to β2-agonists and disease severity.

• Allergic sensitization and allergen exposure: Allergic asthma is the most common phenotype (>70% of asthmatics) and occurs when genetic and immunologic predisposition combines with environmental allergen exposure. Common allergens include house dust mites, pet dander, cockroach proteins, mold spores, pollen, and occupational allergens. Primary sensitization typically occurs through the respiratory tract or percutaneously, requiring Th2 priming. Subsequent exposure triggers IgE-mediated mast cell degranulation and immediate hypersensitivity responses. Elevated total and allergen-specific IgE (detected by skin prick testing or serum IgE levels) support allergic asthma diagnosis. Allergic rhinitis frequently coexists (up to 80% of asthmatics have concurrent rhinitis), reflecting common pathophysiology and shared environmental allergen exposure.

• Respiratory infections and viral triggers: Viral respiratory infections, particularly respiratory syncytial virus (RSV), human rhinovirus, and influenza, commonly precipitate asthma exacerbations in both children and adults through multiple mechanisms: direct epithelial damage, enhanced Th2 response polarization, increased IgE production, and temporary elevation of BHR persisting for weeks after viral clearance. Early childhood RSV bronchiolitis is a strong risk factor for subsequent asthma development, particularly in genetically predisposed children. The interaction between viral infection and allergen exposure is synergistic; virus-induced epithelial damage facilitates allergen penetration and amplifies Th2 responses. Bacterial infections less commonly cause asthma exacerbations but may contribute to non-type 2 inflammation via TLR activation.

• Occupational exposures (occupational asthma): Workplace inhalation exposures account for 10-15% of adult-onset asthma and include high-molecular-weight allergens (latex, laboratory animals, grain dust, seafood allergens) and low-molecular-weight sensitizers (isocyanates, plicatic acid from western red cedar, platinum salts, anhydrides). These trigger either IgE-mediated (high-MW) or non-IgE–mediated immune responses with symptom onset typically within 2 years of exposure but potentially after longer latency. Occupational asthma is reversible if exposure ceases early but can become fixed if remodeling occurs. Clinical clue: work-related symptom pattern (improvement on weekends/vacations) should prompt inquiry into occupational exposures.

• Environmental air pollutants: Ambient air pollutants—particulate matter (PM2.5, PM10), ozone (O3), nitrogen dioxide (NO2), and sulfur dioxide (SO2)—exacerbate asthma and may contribute to asthma inception through oxidative stress and inflammatory pathway activation. Exposure studies document acute FEV1 decline and symptom exacerbation within hours to days of pollution exposure. Long-term pollutant exposure is associated with accelerated decline in lung function and increased asthma incidence in children. Indoor air pollutants (secondhand smoke, biomass combustion) similarly promote asthma development and exacerbations.

• Maternal/perinatal factors: Maternal smoking during pregnancy increases fetal lung inflammation and alters immune development, increasing offspring asthma risk independent of postnatal smoke exposure. Prematurity and low birth weight, potentially through effects on alveolar development and immune maturation, increase asthma susceptibility. Maternal infections or antibiotic use during pregnancy may alter infant microbiota composition, influencing Th1/Th2 balance. Breastfeeding provides some protective effect through transfer of maternal antibodies and potentially protective microbiota components, though this protection wanes after cessation.

• Obesity: Obesity significantly increases asthma incidence and severity, with obese individuals having 2-3 fold higher risk compared to lean controls. Proposed mechanisms include mechanical effects (reduced functional residual capacity and increased closing volume promoting airway closure), systemic inflammation from adipose tissue (adipokine dysregulation, increased TNF-α and IL-6), and altered immune responses. Notably, obese asthmatics often have non-eosinophilic, "metabolic" asthma with reduced ICS responsiveness, suggesting distinct pathophysiology.

• Hormonal factors and female sex: Women have higher asthma prevalence after age 12 compared to men, and exacerbations frequently correlate with menstrual cycle phases, pregnancy, and menopause, implicating estrogen and progesterone in asthma control. Menstrual-related asthma (symptom exacerbation in perimenstrual window) affects ~35% of reproductive-aged women with asthma. Oral contraceptive use and hormone replacement therapy may modify asthma control through effects on immune tolerance and airway reactivity.

• Genetic predisposition: Family history of asthma or atopy (allergic diseases) substantially increases asthma risk. Twin studies demonstrate ~60-80% heritability for asthma development. Specific genetic polymorphisms (ORMDL3, IL4RA, IL13, GATA3) have been associated with asthma susceptibility; however, multiple genes with small individual effects contribute, and gene-environment interactions are decisive in determining phenotypic expression.

• Atopic dermatitis and food allergies: Patients with atopic dermatitis or IgE-mediated food allergies have elevated asthma risk, reflecting shared Th2-mediated pathophysiology and potential shared epithelial barrier defects (filaggrin mutations in atopic dermatitis also associated with asthma).

• Recurrent cough: Cough is among the most common asthma symptoms, classically described as worse at night, with viral illness, or with cold air exposure. The cough may be persistent and dry or productive of clear mucoid sputum. Cough-variant asthma represents 5-10% of asthma cases with isolated persistent cough as the sole presenting symptom without overt wheezing or dyspnea; this phenotype is often delayed in diagnosis. Pathophysiologically, cough reflects heightened airway reactivity and mucus hypersecretion from goblet cell hyperplasia and mast cell mediator release.

• Dyspnea and chest tightness: Exertional or spontaneous dyspnea develops as airflow obstruction increases intrathoracic pressure swings and increases work of breathing. Patients often describe "tightness" or "heaviness" in the chest. In acute exacerbations, dyspnea escalates rapidly and may progress to inability to speak full sentences, indicating severe obstruction. Exercise-induced asthma (EIA) occurs within 5-20 minutes of vigorous activity, particularly in cold, dry air, due to bronchial cooling and osmotic stress on airways from rapid airway rewarming; notably, warm, humid environments (swimming) provide protection.

• Wheezing: The classic finding is polyphonic (multiple frequencies) expiratory wheezing audible on auscultation, resulting from turbulent airflow through narrowed small airways; however, absence of wheezing does not exclude asthma. In severe obstruction, wheezing may be inaudible ("silent chest") due to profoundly reduced airflow—a sign of critical obstruction. Inspiratory stridor can occur but suggests upper airway pathology or vocal cord dysfunction. Wheezing may be selective (isolated to specific lung fields if obstruction is focal) or diffuse.

• Physical examination findings in stable asthma: Between exacerbations, the physical exam may be unremarkable. However, findings may include prolonged expiratory phase (from air trapping), occasional end-expiratory wheezes on forced expiration, hyperinflation (increased anteroposterior chest diameter, decreased heart sounds due to hyperinflation), and signs of allergic disease (allergic rhinitis with nasal polyps, eczema). Clubbing is not a feature of asthma and suggests alternative diagnoses (cystic fibrosis, bronchiectasis, lung cancer).

• Acute exacerbation presentation: Acute asthma exacerb

Initial test — spirometry with bronchodilator challenge

• Obstruction: reduced FEV1/FVC ratio (below the lower limit of normal for age per ATS/ERS interpretive standards). Mechanism: expiratory flow limitation from smooth muscle contraction, mucus plugging, and wall edema.
• Reversibility: post-bronchodilator rise in FEV1 of ≥12% and ≥200 mL after inhaled short-acting β2-agonist confirms the variable obstruction that separates asthma from fixed COPD.
• Flow-volume loop: scooped/concave expiratory limb. A flattened inspiratory limb instead suggests vocal cord dysfunction or extrathoracic obstruction.

If spirometry is normal (common between attacks)

• Bronchoprovocation testing is the confirmatory study: methacholine challenge with a PC20 below the standard threshold indicates bronchial hyperresponsiveness. Its chief value is a high negative predictive value — a negative challenge largely excludes asthma.
• Peak expiratory flow diurnal variability recorded over roughly two weeks supports the diagnosis when excessive.
• Exercise challenge for suspected exercise-induced bronchoconstriction, showing a post-exercise fall in FEV1.

Supportive and phenotyping studies

• FeNO: elevated in type 2/eosinophilic inflammation; GINA treats it as supportive, not diagnostic, and it also predicts ICS responsiveness.
• Blood eosinophils, total and allergen-specific IgE, skin prick testing: identify allergic phenotype and candidacy for biologics.
• DLCO is normal or high in asthma — a key discriminator from emphysema, where DLCO falls.

Acute exacerbation — stabilise first

• Oxygen titrated to SpO2 ~93–95% in adults (94–98% in children) per GINA.
• Inhaled SABA: albuterol by nebulizer or MDI-with-spacer, repeated/continuous; add ipratropium (SAMA) for severe exacerbations to block M3-mediated vagal tone.
• Systemic corticosteroids (oral prednisone, or IV methylprednisolone if unable to take PO) early — they treat the inflammatory limb and reduce relapse; effect takes hours.
• IV magnesium sulfate (2 g over ~20 minutes) for severe exacerbations not responding to initial therapy; acts as a smooth muscle calcium antagonist.
• Intubation for exhaustion, silent chest, or altered mental status. Ventilate with low respiratory rate and prolonged expiratory time (permissive hypercapnia) to prevent breath stacking, auto-PEEP, and hypotension.

Chronic stepwise therapy (GINA)

• Anti-inflammatory reliever: GINA no longer endorses SABA-only treatment at any step. Preferred Track 1 uses low-dose ICS–formoterol as reliever, and as both maintenance and reliever (MART/SMART) at higher steps. NHLBI/NAEPP 2020 similarly endorses SMART at steps 3–4.
• Step-up options: increase ICS dose; add LAMA (tiotropium); LTRA (montelukast) is an alternative, particularly in AERD and allergic rhinitis.
• Severe/refractory type 2 disease — biologics: anti-IgE (omalizumab), anti–IL-5/5Rα (mepolizumab, benralizumab), anti–IL-4Rα (dupilumab), anti-TSLP (tezepelumab), chosen by eosinophil count, FeNO, and IgE.
• Procedural: bronchial thermoplasty is reserved for selected refractory cases at experienced centers.
• Address modifiable factors: inhaler technique, adherence, allergen and tobacco exposure, GERD, obesity, and vaccination.

Contraindicated / avoid

• LABA monotherapy — increased asthma-related death; a LABA must always be paired with an ICS.
• Aspirin/NSAIDs in AERD; consider aspirin desensitization if needed.
• Nonselective beta blockers; cardioselective agents only when indicated.
• Chronic oral corticosteroids as a maintenance strategy when a biologic is a viable alternative.

Disease-related — emergencies flagged

• Status asthmaticus / near-fatal asthma (EMERGENCY): severe obstruction refractory to bronchodilators. Signals: inability to speak in phrases, accessory muscle use, silent chest (airflow too low to generate wheeze), altered mental status, and pulsus paradoxus from exaggerated inspiratory fall in left ventricular filling. A normal or rising PaCO2 in a tachypneic asthmatic means respiratory muscle fatigue — intubate, do not reassure.
• Dynamic hyperinflation and auto-PEEP (EMERGENCY when ventilated): incomplete exhalation stacks breaths, raising intrathoracic pressure, impeding venous return, and causing hypotension. Management: disconnect the circuit and allow exhalation.
• Pneumothorax / pneumomediastinum (EMERGENCY if tension): alveolar rupture from high transpulmonary pressures; sudden unilateral pain, tracheal deviation, unilaterally absent breath sounds.
• Mucus plugging with lobar atelectasis: goblet cell hyperplasia and inspissated secretions; segmental collapse on radiograph.
• Allergic bronchopulmonary aspergillosis: hypersensitivity to Aspergillus colonization; recurrent infiltrates, markedly elevated total IgE, central bronchiectasis, brown mucus plugs.
• Airway remodeling with fixed obstruction: chronic inflammation drives subepithelial fibrosis and smooth muscle hypertrophy; loss of bronchodilator reversibility over years.

Treatment-related

• Inhaled corticosteroids: local immunosuppression causing oropharyngeal candidiasis and dysphonia (myopathy of laryngeal muscles) — prevented by spacer use and mouth rinsing. High cumulative dose may modestly slow childhood growth velocity and, rarely, suppress the HPA axis.
• β2-agonists: extrapulmonary β2 stimulation causes tremor, tachycardia, hypokalemia (intracellular potassium shift), hyperglycemia, and lactic acidosis with high-dose continuous therapy.
• Systemic corticosteroids: hyperglycemia, hypertension, mood change acutely; osteoporosis, cataracts, adrenal suppression with repeated courses.
• Theophylline: narrow therapeutic index — nausea, seizures, and tachyarrhythmias; interacts with CYP1A2 inhibitors.
• Montelukast: FDA boxed warning for serious neuropsychiatric events, including agitation and suicidality.
• Omalizumab: boxed warning for anaphylaxis — observation after dosing is required.

• Reversibility is the diagnosis: post-bronchodilator FEV1 rise of ≥12% and ≥200 mL. If spirometry is normal and asthma is still suspected, the single best next step is a methacholine challenge, valued for its high negative predictive value.
• DLCO is normal or increased in asthma. The common distractor is choosing a reduced DLCO — that points to emphysema, not asthma.
• A normal or rising PaCO2 in an acutely dyspneic, tachypneic asthmatic is ominous, not reassuring. Early attacks show respiratory alkalosis with hypocapnia; "normalization" reflects fatigue and heralds respiratory arrest. Combined with silent chest and pulsus paradoxus, this mandates ICU care and intubation preparation.
• Sputum buzzwords: Curschmann spirals (shed epithelium in mucus casts), Charcot-Leyden crystals (galectin-10 from eosinophil breakdown), and Creola bodies (sloughed epithelial clusters).
• Samter triad / AERD: asthma + nasal polyposis + aspirin or NSAID sensitivity, mechanistically from COX-1 inhibition shunting arachidonic acid toward cysteinyl leukotrienes. Best therapy additions are leukotriene modifiers (montelukast, zileuton) and, in refractory disease, aspirin desensitization.
• Never LABA monotherapy — it carries an increased risk of asthma-related death; a LABA must be paired with an ICS. Likewise, GINA no longer endorses SABA-only treatment at any step; low-dose ICS–formoterol is the preferred reliever.
• The examiner's favorite association: exercise-induced bronchoconstriction is worst in cold, dry air and mildest with swimming; pretreat with SABA before activity, but recurrent need signals inadequate controller therapy, not a SABA problem.
• Mimic to exclude: vocal cord dysfunction presents with inspiratory stridor, a flattened inspiratory flow-volume loop, and no response to bronchodilators — diagnosed by laryngoscopy during symptoms, treated with speech therapy, not escalating steroids.