Chronic dyspnoea

Chronic dyspnoea is breathlessness lasting more than 4 to 8 weeks, including exertional dyspnoea and shortness of breath as presenting phrases. It is common (up to 25% of adults with cardiac or respiratory disease, 10% of older adults), reduces quality of life more than most symptoms, and independently predicts mortality.

A cause is found in most patients after history, examination, a small set of first line tests and, where needed, specialist physiology.

Clinical relevance. Four conditions explain most cases: asthma, chronic obstructive pulmonary disease, interstitial lung disease and cardiac disease (heart failure, ischaemia, valve disease, arrhythmia). Obesity, deconditioning, anaemia and anxiety contribute in many.

About one third of chronic breathlessness has more than one cause. Persistent breathlessness despite optimal treatment of the cause (chronic breathlessness syndrome) is itself a treatable problem.

Classification.

• Respiratory:
  • Airway: asthma, chronic obstructive pulmonary disease, bronchiectasis, upper airway or tracheal stenosis, vocal cord dysfunction.
  • Parenchymal: interstitial lung disease, pneumoconiosis, sarcoidosis, chronic infection, cancer, lymphangitis.
  • Pulmonary vascular: chronic thromboembolic disease, pulmonary hypertension, arteriovenous malformation.
  • Pleural: effusion, fibrothorax.
  • Chest wall and neuromuscular: kyphoscoliosis, obesity, diaphragm paralysis, neuromuscular disease.
• Cardiac: heart failure (reduced and preserved ejection fraction), coronary disease (angina equivalent), valve disease, arrhythmia (atrial fibrillation), pericardial constriction, congenital disease, pulmonary hypertension.
• Haematological and metabolic: anaemia, thyroid disease, acidosis, renal failure, liver disease with hepatopulmonary syndrome, carboxyhaemoglobin.
• Deconditioning, obesity, pregnancy, and psychological (anxiety, depression, dysfunctional breathing).
• Unexplained after full evaluation.
• By pattern: exertional, at rest, positional (orthopnoea, platypnoea, trepopnoea), episodic (asthma, angina, arrhythmia), progressive (interstitial lung disease, pulmonary hypertension, heart failure).
• By severity: modified Medical Research Council scale grades 0 to 4.

Mechanism. Mismatch between central respiratory drive and the mechanical response of the respiratory system, or the supply of oxygen and removal of carbon dioxide.

Contributions come from increased ventilatory demand (deconditioning, anaemia, acidosis), reduced ventilatory capacity (obstruction, restriction, weakness) and affective factors.

History.

• Time course (months versus years), pattern, diurnal variation, triggers (cold, allergens, exercise, emotion).
• Severity by functional limitation (modified Medical Research Council scale):
  • Grade 0: only on strenuous exercise.
  • Grade 1: hurrying on the level or up a slight hill.
  • Grade 2: slower than peers or stops after walking at own pace.
  • Grade 3: stops after 100 m or a few minutes.
  • Grade 4: too breathless to leave the house or when dressing.
• Orthopnoea, paroxysmal nocturnal dyspnoea, platypnoea, ankle swelling, weight gain, chest pain, palpitations, syncope, cough (dry or productive), wheeze, sputum, haemoptysis, fever, weight loss, night sweats.
• Smoking, vaping, occupation (asbestos, silica, coal, farming, birds, mould, textile), hobbies, pets, hot tub, home damp, travel, prior tuberculosis.
• Family history (lung fibrosis, alpha 1 antitrypsin deficiency, cardiomyopathy).
• Past history: childhood asthma, atopy, heart disease, hypertension, diabetes, thromboembolism, cancer treatment (radiotherapy, bleomycin, anthracyclines), connective tissue disease, HIV, sleep apnoea, reflux, pregnancy.
• Drugs: beta blockers, amiodarone, nitrofurantoin, methotrexate, chemotherapy, checkpoint inhibitors, ACE inhibitors, dasatinib, fenfluramine and appetite suppressants, immunosuppressants, recreational drugs.
• Psychological: anxiety, panic, low mood, sighing, perioral tingling, breathlessness that varies with distraction.
• Impact on activities, sleep, mood and employment.

Examination.

• General: body mass index, ability to speak, cyanosis, pallor, clubbing, nail changes, lymph nodes, thyroid, signs of anaemia, skin rash, mouth ulcers, Raynaud phenomenon, sclerodactyly.
• Respiratory: respiratory rate and pattern (pursed lip breathing, tripod posture), chest shape (hyperinflation, barrel chest, kyphoscoliosis), expansion, percussion, stridor.
• Auscultation: wheeze, prolonged expiration, basal fine end inspiratory crackles in fibrosis, coarse crackles, pleural rub, reduced breath sounds, dullness.
• Cardiac: pulse (rate, rhythm, volume), blood pressure, jugular venous pressure, apex beat, heart sounds (loud P2, third sound, murmurs), right ventricular heave, peripheral oedema, hepatomegaly, ascites.
• Neuromuscular: respiratory muscle weakness (paradoxical abdominal movement when supine), bulbar signs, limb power.
• Vital signs at rest and after exertion (walk test, saturation fall).
• Functional or psychological signs: sighing, upper chest breathing, normal examination, normal exercise saturation.

Red flags.

• Rapid progression over weeks, haemoptysis, weight loss, night sweats, hoarseness (cancer, tuberculosis, vasculitis).
• Resting hypoxia, new cyanosis, desaturation on exertion.
• Orthopnoea with oedema (heart failure), syncope or presyncope on exertion (aortic stenosis, pulmonary hypertension, arrhythmia).
• Chest pain on exertion (ischaemia).
• Clubbing with crackles (interstitial lung disease, cancer).
• Unilateral signs, stridor, new hoarseness, wheeze that does not change (central airway lesion, tumour).
• Unilateral leg swelling, previous thrombosis, cancer (chronic thromboembolic disease).
• Neuromuscular signs, orthopnoea without heart failure (diaphragm weakness).
• Pulmonary hypertension signs: loud P2, right ventricular heave, raised jugular venous pressure.
• Pregnancy or postpartum breathlessness.

Airway disease. Asthma, chronic obstructive pulmonary disease and emphysema, bronchiectasis, cystic fibrosis, bronchiolitis obliterans, alpha 1 antitrypsin deficiency, tracheal and large airway stenosis, vocal cord dysfunction, tracheobronchomalacia, obstructive sleep apnoea.

Parenchymal and pleural disease.

• Idiopathic pulmonary fibrosis and other fibrosing interstitial lung diseases.
• Hypersensitivity pneumonitis and sarcoidosis.
• Connective tissue disease lung (systemic sclerosis, rheumatoid arthritis) and drug induced lung disease.
• Pneumoconiosis (asbestosis, silicosis, coal workers).
• Pulmonary eosinophilia, organising pneumonia, pulmonary alveolar proteinosis, lymphangioleiomyomatosis.
• Lung cancer and lymphangitis carcinomatosa, chronic infection.
• Pleural effusion, mesothelioma, fibrothorax, previous radiotherapy.

Pulmonary vascular. Chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, pulmonary hypertension from left heart or lung disease, pulmonary arteriovenous malformations, hepatopulmonary syndrome, portopulmonary hypertension.

Cardiac. Heart failure (reduced and preserved ejection fraction), coronary artery disease, aortic stenosis, mitral stenosis and regurgitation, cardiomyopathy (hypertrophic, amyloid, restrictive), atrial fibrillation, constrictive pericarditis, pericardial effusion, congenital heart disease.

Haematological and metabolic. Anaemia, thyrotoxicosis and hypothyroidism, chronic kidney disease, metabolic acidosis, hepatic hydrothorax, carbon monoxide.

Neuromuscular and chest wall. Diaphragm paralysis, motor neurone disease, myasthenia gravis, myopathy, muscular dystrophy, post polio syndrome, kyphoscoliosis, ankylosing spondylitis, obesity hypoventilation syndrome.

Others. Deconditioning, obesity, pregnancy, high altitude, anxiety and dysfunctional breathing, chronic breathlessness syndrome, fever.

1. Characterise severity (modified Medical Research Council grade), pattern and associated features. Look for red flags. Identify cardiac versus respiratory versus other features.
2. First line tests in all:
   • Pulse oximetry at rest and after walking.
   • Full blood count (anaemia, polycythaemia, eosinophilia), urea, creatinine and electrolytes, liver function, thyroid stimulating hormone, glucose and HbA1c, ferritin.
   • 12 lead ECG.
   • Chest radiograph (hyperinflation, infiltrates, effusion, mass, cardiomegaly, pulmonary hypertension, raised hemidiaphragm).
   • Spirometry (forced expiratory volume in 1 second, forced vital capacity, ratio; with bronchodilator reversibility).
   • Peak expiratory flow chart if asthma is suspected.
   • Natriuretic peptide (N-terminal pro B-type natriuretic peptide under 125 pg/mL makes heart failure unlikely in the community).
3. Second line:
   • Echocardiography.
   • Full lung function (lung volumes, gas transfer, DLCO): restriction with low transfer factor in interstitial disease; high transfer in asthma and polycythaemia; low in emphysema, pulmonary vascular disease and anaemia.
   • Fractional exhaled nitric oxide; blood eosinophils; IgE and allergy tests; alpha 1 antitrypsin level; HIV test.
   • Autoimmune screen (antinuclear antibody, extractable nuclear antigens, rheumatoid factor, anti cyclic citrullinated peptide, myositis and scleroderma antibodies, antineutrophil cytoplasmic antibody).
   • Angiotensin converting enzyme; precipitins for hypersensitivity pneumonitis; D-dimer.
4. High resolution CT chest for interstitial or airway disease and unexplained dyspnoea with normal radiograph. CT pulmonary angiography or V/Q scan for suspected thromboembolic disease (V/Q is more sensitive for chronic thromboembolic disease).
5. Exercise testing: six minute walk with saturation, shuttle test, cardiopulmonary exercise test. The cardiopulmonary exercise test separates cardiac, ventilatory, pulmonary vascular, deconditioning and dysfunctional breathing (peak oxygen uptake, anaerobic threshold, ventilatory equivalents, breathing reserve).
6. Cardiac: stress imaging, coronary angiography or CT coronary angiography, cardiac MRI, ambulatory ECG, right heart catheterisation. Mean pulmonary artery pressure over 20 mmHg with wedge pressure 15 mmHg or less and pulmonary vascular resistance over 2 Wood units indicates pre capillary pulmonary hypertension.
7. Upper airway: laryngoscopy during symptoms or continuous laryngoscopy during exercise for vocal cord dysfunction; flow volume loop (flattened inspiratory limb).
8. Neuromuscular: supine and upright vital capacity (fall over 20% supine suggests diaphragm weakness), maximal inspiratory and expiratory pressures, sniff nasal pressure, diaphragm ultrasound, phrenic nerve studies, nocturnal oximetry and capnography, sleep study.
9. Invasive tests as needed: bronchoscopy with bronchoalveolar lavage and transbronchial or cryobiopsy, surgical lung biopsy, endobronchial ultrasound for nodes, pleural aspiration.
10. If the work up is negative: consider deconditioning, obesity, anxiety, dysfunctional breathing (Nijmegen questionnaire over 23, breathing pattern assessment), with multidisciplinary review. Repeat evaluation if symptoms progress.

Limits. No single test is sensitive enough. Spirometry is normal in early interstitial disease, pulmonary vascular disease, heart failure with preserved ejection fraction and between asthma attacks.

Chest radiograph is normal in a substantial minority of interstitial lung disease and in chronic thromboembolic disease. Natriuretic peptides are raised in atrial fibrillation, renal failure and age and are low in obesity. Cardiopulmonary exercise testing needs expertise. Up to 20% remain unexplained after full investigation.

General principles. Treat the underlying cause first. Correct anaemia, hypoxia and cardiac failure. Optimise comorbidities. Address smoking, obesity, deconditioning and anxiety. Provide a written action plan and review.

Asthma.

• Stepwise: low dose inhaled corticosteroid with formoterol as needed at the start (budesonide with formoterol 200/6 micrograms 1 to 2 inhalations as needed, maximum 12 in 24 hours).
• Maintenance and reliever therapy: budesonide with formoterol 200/6 micrograms 1 inhalation twice daily plus as needed. Increase to 2 inhalations twice daily.
• Add montelukast 10 mg at night or a long acting muscarinic antagonist (tiotropium 2.5 micrograms 2 puffs daily).
• Biologic therapy for severe eosinophilic or allergic asthma: omalizumab, mepolizumab 100 mg subcutaneously every 4 weeks, benralizumab 30 mg every 4 weeks then every 8 weeks, dupilumab 300 mg every 2 weeks, tezepelumab 210 mg every 4 weeks.
• Check inhaler technique, adherence, triggers and comorbidities; written plan; vaccinations.

Chronic obstructive pulmonary disease.

• Stop smoking: nicotine replacement patch 21 mg daily for 6 weeks, 14 mg for 2 weeks, 7 mg for 2 weeks, with gum or lozenge; or varenicline 0.5 mg daily for 3 days, 0.5 mg twice daily for 4 days, then 1 mg twice daily for 12 weeks.
• Long acting muscarinic antagonist (tiotropium 18 micrograms daily or umeclidinium 62.5 micrograms daily) and/or long acting beta agonist (indacaterol 150 micrograms daily, formoterol 12 micrograms twice daily). Combine as dual therapy for persistent breathlessness.
• Add inhaled corticosteroid (beclometasone, budesonide or fluticasone furoate) if frequent exacerbations and blood eosinophils over 0.3 x 10^9/L.
• Roflumilast 500 micrograms daily or azithromycin 250 mg daily for frequent exacerbations.
• Pulmonary rehabilitation (6 to 8 weeks, twice weekly).
• Long term oxygen for resting saturation 88% or less (at least 15 hours daily).
• Vaccinations (influenza, pneumococcal, COVID-19, RSV).
• Lung volume reduction in selected emphysema; palliative measures in advanced disease.

Interstitial lung disease.

• Multidisciplinary diagnosis; stop causative drugs and exposures.
• Idiopathic pulmonary fibrosis: nintedanib 150 mg twice daily or pirfenidone 801 mg three times daily with food (titrated over 2 weeks).
• Hypersensitivity pneumonitis, sarcoidosis, organising pneumonia and connective tissue disease: prednisolone 0.5 mg/kg daily (maximum 40 mg) reducing over months with steroid sparing agent (mycophenolate mofetil 1 to 1.5 g twice daily, azathioprine 2 mg/kg, or rituximab).
• Oxygen for hypoxia; pulmonary rehabilitation; treat reflux; transplant assessment; antifibrotics for progressive fibrosing disease; palliative care.

Heart failure and cardiac causes.

• ACE inhibitor (ramipril 2.5 mg twice daily increasing to 5 mg twice daily) or sacubitril-valsartan 24/26 mg twice daily increasing to 97/103 mg twice daily.
• Beta blocker (bisoprolol 1.25 mg daily increasing to 10 mg); spironolactone 25 mg daily; dapagliflozin or empagliflozin 10 mg daily; furosemide 20 to 80 mg daily for congestion.
• For preserved ejection fraction: SGLT2 inhibitor, diuretic, control of blood pressure and atrial fibrillation.
• Coronary disease: aspirin 75 mg, atorvastatin 40 to 80 mg, beta blocker, nitrate (glyceryl trinitrate 400 micrograms sublingual as needed; isosorbide mononitrate 30 to 60 mg daily), revascularisation.
• Atrial fibrillation: rate control (bisoprolol 2.5 to 10 mg daily, diltiazem 120 to 360 mg daily, digoxin 62.5 to 250 micrograms daily), anticoagulation (CHA2DS2-VASc 2 or more in men, 3 or more in women; apixaban 5 mg twice daily).
• Valve disease: surgery or transcatheter treatment by symptom and echocardiographic thresholds.

Pulmonary hypertension.

• Treat the left heart and lung disease and hypoxia.
• Chronic thromboembolic: lifelong anticoagulation, pulmonary endarterectomy or balloon pulmonary angioplasty, riociguat 1 mg three times daily titrated to 2.5 mg three times daily.
• Pulmonary arterial hypertension: specialist centre, combination therapy (ambrisentan 5 to 10 mg daily with tadalafil 20 to 40 mg daily; macitentan 10 mg daily; selexipag; treprostinil).
• Diuretics, oxygen, avoid pregnancy.

Anaemia and metabolic causes.

• Iron replacement (ferrous sulphate 200 mg once daily or on alternate days; intravenous ferric carboxymaltose 1,000 mg when oral fails, in heart failure or in malabsorption).
• Vitamin B12 (hydroxocobalamin 1 mg intramuscularly); erythropoiesis agents in kidney disease.
• Thyroid disease: levothyroxine 1.6 micrograms/kg (25 micrograms start in older adults or coronary disease), carbimazole 20 to 40 mg daily.
• Kidney disease: dialysis, correct acidosis.

Neuromuscular and chest wall causes.

• Non invasive ventilation (nocturnal) for hypercapnia, vital capacity under 50% predicted, or nocturnal desaturation; cough assist.
• Riluzole 50 mg twice daily and specialist care in motor neurone disease.
• Obesity hypoventilation: weight loss, continuous positive airway pressure or bilevel support.
• Diaphragm plication in selected unilateral paralysis.

Obstructive sleep apnoea. Continuous positive airway pressure, weight loss, mandibular advancement device, avoid alcohol and sedatives.

Dysfunctional breathing and vocal cord dysfunction. Specialist physiotherapy (diaphragmatic breathing retraining, Buteyko or Papworth methods), speech and language therapy, cognitive behavioural therapy, treat coexisting asthma and reflux.

Chronic breathlessness syndrome (symptomatic management after cause is optimised).

• Hand held fan directed to the face, pacing, positioning (forward lean), pursed lip breathing, breathing control, walking aids, energy conservation.
• Pulmonary or cardiac rehabilitation and exercise training.
• Low dose sustained release morphine 5 mg once daily (titrate to 10 mg twice daily; add a regular laxative: senna 15 mg at night or macrogol 1 to 2 sachets daily) for severe breathlessness despite optimal treatment. Monitor for sedation and constipation. Use caution in renal impairment (use lower dose or alternative) and hypercapnia.
• Benzodiazepines (lorazepam 0.5 to 1 mg sublingual as needed) only for panic when other measures fail.
• Oxygen only when hypoxaemic (not for breathlessness alone with normal saturation).
• Treat anxiety and depression (sertraline 50 mg daily, cognitive behavioural therapy).
• Palliative care referral when progressive and life limiting.

General health. Weight management, exercise programme, vaccinations (influenza, pneumococcal, COVID-19, RSV), smoking cessation, avoidance of occupational and environmental triggers, treat sleep apnoea.

Monitoring. Symptoms (modified Medical Research Council grade), exercise tolerance, spirometry and transfer factor at 3 to 6 months. Weight, oxygen saturation, blood pressure, heart rate. Natriuretic peptide for heart failure. Exacerbation count. Annual review. Assess adherence and inhaler technique. Echocardiography for pulmonary hypertension or heart failure change.

Referral and escalation.

• Respiratory clinic for unexplained dyspnoea, abnormal imaging, interstitial lung disease and severe airway disease.
• Cardiology for suspected cardiac causes and pulmonary hypertension; pulmonary hypertension centre.
• Neurology for neuromuscular disease; sleep medicine; rehabilitation; palliative care.
• ENT and speech therapy for vocal cord dysfunction; psychology.
• Urgent referral (urgent suspected cancer referral) for haemoptysis, abnormal imaging suggesting cancer or unexplained weight loss.

Admission. Resting hypoxia, respiratory failure, suspected pulmonary embolism, acute heart failure, arrhythmia, syncope, rapid progression, haemoptysis with instability, or need for urgent invasive tests.

Safety netting. Return urgently for breathlessness at rest, chest pain, fainting, coughing blood, new leg swelling, blue lips, or sudden worsening. Follow the written action plan, use inhalers correctly and keep appointments.

Special groups.

• Children: asthma, congenital heart disease, cystic fibrosis, anaemia, exercise induced laryngeal obstruction.
• Pregnancy: physiological breathlessness (up to 75%); exclude peripartum cardiomyopathy, embolism, mitral stenosis and asthma.
• Older adults: multiple contributors (heart failure with preserved ejection fraction, chronic obstructive pulmonary disease, anaemia, deconditioning); frailty assessment.
• Athletes: exercise induced bronchoconstriction, laryngeal obstruction, cardiomyopathy.
• High altitude and travellers.
• Endemic regions: tuberculosis, rheumatic heart disease, schistosomiasis, severe anaemia, HIV related lung disease, sickle cell lung disease and biomass fuel exposure are common causes.