Special Asthma Syndromes & Asthma Mimics
When the wheeze has a trigger, a twist, or a different cause entirely
Aspirin-exacerbated respiratory disease
The triad. AERD combines asthma, chronic rhinosinusitis with nasal polyps, and respiratory reactions to aspirin and other COX-1-inhibiting NSAIDs. It usually begins in adulthood, often with loss of smell, and affects about 7% of adults with asthma and a larger share of those with severe asthma. Bronchospasm, nasal congestion, rhinorrhea, and flushing start 30–180 minutes after a dose. The reaction is not IgE-mediated, so skin testing is useless and every nonselective NSAID carries the risk. Nasal polyps in a child suggest cystic fibrosis instead.
Mechanism. PGE2, a COX-1 product, normally restrains 5-lipoxygenase and mast cells. Blocking COX-1 lowers PGE2 and shunts arachidonic acid toward the cysteinyl leukotrienes (LTC4, LTD4, LTE4), which cause bronchoconstriction, mucus secretion, and nasal symptoms; urinary LTE4 rises during reactions.
Management.
- Avoid aspirin and nonselective NSAIDs such as ibuprofen, naproxen, and ketorolac.
- Selective COX-2 inhibitors (celecoxib) and modest doses of acetaminophen are generally tolerated; high-dose acetaminophen occasionally cross-reacts.
- Add a leukotriene modifier to ICS: montelukast (CysLT1 receptor antagonist; boxed warning for neuropsychiatric effects) or zileuton (5-lipoxygenase inhibitor; monitor liver enzymes).
- Treat the sinuses with intranasal corticosteroids and endoscopic surgery; polyps often recur, and biologics against type 2 inflammation such as dupilumab help refractory polyposis.
Aspirin desensitization. Graded oral doses under monitoring induce tolerance that persists only with uninterrupted daily aspirin; a lapse of more than about 48 hours can restore sensitivity. It is indicated when aspirin is needed for coronary disease or a stent (allowing standard dual antiplatelet therapy), and for refractory polyps, because high-dose maintenance slows polyp regrowth and reduces steroid needs. A leukotriene modifier is often started beforehand to soften reactions, but no premedication replaces desensitization.
Exercise-induced bronchoconstriction
Mechanism and timing. High ventilation dries and cools the airway lining, and the osmotic change triggers mast-cell mediator release. Airways often dilate during exercise itself; bronchoconstriction peaks about 5–15 minutes after stopping and resolves within 30–60 minutes. Cold, dry air (winter sports, ice rinks) worsens it. Many patients then have a refractory period of 1–3 hours in which repeat exertion causes less bronchoconstriction.
Diagnosis. Resting spirometry is often normal. An exercise challenge or eucapnic voluntary hyperventilation with serial spirometry confirms EIB when FEV1 falls ≥10% from baseline. VCD, deconditioning, and cardiac disease are alternative causes of exertional dyspnea.
- Warm up10–15 minutes of lighter exercise uses the refractory period.
- PretreatInhaled SABA 5–20 minutes before exercise protects for 2–4 hours; low-dose ICS-formoterol before exercise is an alternative (GINA).
- Shield from cold airA mask or scarf warms and humidifies inspired air.
- Add a controllerIf pretreatment is needed daily or symptoms occur beyond exercise, start a daily ICS; montelukast is an alternative.
Daily SABA or LABA use blunts the protective effect, and a LABA is never used without an ICS in asthma.
Occupational asthma
The clue. Asthma that improves on weekends and vacations and worsens on return to work. Work-exacerbated asthma, in which preexisting asthma is aggravated by workplace conditions, is distinguished from asthma caused by work.
| Feature | Sensitizer-induced | Irritant-induced (RADS) |
|---|---|---|
| Onset | After a latent period of months to years | Within 24 hours of a single high-level exposure |
| Mechanism | Immunologic sensitization | Nonimmunologic airway injury |
| Examples | Isocyanates (spray paints, foams), flour, latex, laboratory animals, western red cedar | Chlorine, ammonia, smoke, acid fumes |
| Afterward | Once sensitized, trace exposure provokes attacks | Persistent airway hyperresponsiveness |
Diagnosis and management. Confirm asthma, then link it to work objectively with serial peak expiratory flow recorded several times daily for weeks at work and away from work. Specific inhalation challenge is the reference standard at specialized centers. Early, complete removal from a sensitizer gives the best chance of remission; respirators and exposure reduction are less effective, and continued exposure leads to persistent asthma.
Vocal cord dysfunction
Presentation. Paradoxical adduction of the vocal folds during inspiration, also called inducible laryngeal obstruction, classically affects young women, athletes, and health care workers. Triggers include exercise, irritants, GERD, postnasal drip, and anxiety. Episodes start and stop abruptly with throat tightness, inspiratory stridor loudest over the larynx, and voice change, and bronchodilators do not help. Many patients carry a label of refractory asthma with repeated steroid bursts and even intubations, yet SpO2 and the A-a gradient stay normal and ventilation is easy once the tube bypasses the cords. VCD and asthma can coexist.
| Feature | Asthma | Vocal cord dysfunction |
|---|---|---|
| Sound | Expiratory, polyphonic wheeze over the chest | Inspiratory stridor over the neck |
| Oxygenation | Hypoxemia and widened A-a gradient when severe | Normal SpO2 and A-a gradient |
| Flow-volume loop | Scooped expiratory limb | Flattened inspiratory limb, normal expiratory limb |
| Confirmation | Reversible obstruction or positive methacholine test | Laryngoscopy showing inspiratory adduction |
| Treatment | ICS-based therapy and bronchodilators | Speech therapy and trigger control |
Diagnosis and treatment. The flow-volume loop shows a variable extrathoracic obstruction pattern. Laryngoscopy during symptoms, or after provocation with exercise or methacholine, shows the cords closing on inspiration with a small posterior chink. Treatment is speech-language therapy with breathing retraining, control of GERD, postnasal drip, and anxiety, and reassurance; heliox or CPAP can ease a severe episode. More corticosteroids only add toxicity.
Asthma in pregnancy
Course and risk. About a third of women improve, a third worsen, and a third are unchanged. Poorly controlled asthma and maternal hypoxemia raise the risks of preeclampsia, preterm birth, low birth weight, and perinatal death far more than asthma medications do.
- Continue controllers that work; never stop an effective ICS because of pregnancy.
- Budesonide has the most safety data and is preferred when an ICS is started.
- Albuterol is the preferred reliever; LABAs and montelukast may continue if needed.
Exacerbations. Treat as in any adult: oxygen to keep SpO2 ≥95%, inhaled SABA with ipratropium, early systemic corticosteroids, and fetal monitoring. Progesterone-driven hyperventilation sets the normal pregnant PaCO2 near 28–32 mm Hg, so a "normal" 40 mm Hg during an attack signals CO2 retention and impending respiratory failure.
Withholding systemic corticosteroids from a pregnant patient having an exacerbation is a classic error; maternal hypoxemia is the real threat to the fetus.
When the wheeze is not asthma
Cardiac asthma. Peribronchial edema narrows small airways, so decompensated heart failure can wheeze. Clues are older age, orthopnea, PND, crackles, S3, JVD, edema, and elevated BNP. Treat the congestion with loop diuretics and nitrates; new wheezing after about age 50 deserves a cardiac evaluation.
Central airway obstruction. A fixed, localized, monophonic wheeze that does not change with coughing or bronchodilators suggests a tumor (carcinoid, bronchogenic carcinoma), a foreign body (toddlers and older adults, often the right mainstem bronchus), post-intubation tracheal stenosis, or goiter compression. CT and bronchoscopy establish the cause, and bronchoscopy can remove a foreign body. A fixed tracheal or laryngeal lesion flattens both limbs of the flow-volume loop.
Bronchiolitis obliterans. Concentric fibrosis obliterates the bronchioles, producing progressive airflow obstruction without bronchodilator response. Causes include chronic rejection after lung transplantation (bronchiolitis obliterans syndrome), chronic GVHD after allogeneic stem cell transplantation, toxic inhalation (diacetyl "popcorn lung," nitrogen dioxide in silo fillers), severe childhood viral infection, and rheumatoid arthritis. The chest radiograph is often normal; expiratory HRCT shows mosaic attenuation and air trapping.