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Step-by-step diagnostic approach of dyspnea.Clinical historyCareful history-taking is the most useful first step in elucidating the aetiology of dyspnoea. Several factors need to be addressed in the clinical history when constructing the initial differential diagnosis.Time course∙Acute dyspnoea appears suddenly or in a matter of minutes. It typically indicates acute and severe conditions that may belife-threatening. Examples of conditions causing sudden-onsetdyspnoea include acute pulmonary embolism, myocardial infarction, acute heart valve insufficiency, pneumothorax, anaphylaxis,foreign body aspiration, pulmonary oedema, or cardiac tamponade.[16]∙Subacute dyspnoea develops over hours to days. Common causes include acute asthma, exacerbation of COPD, or pulmonary oedema.Less common causes include myocarditis, superior vena cava syndrome, acute eosinophilic pneumonia, or cardiac tamponade.[16] [17] [18] ∙Chronic dyspnoea develops over weeks to months. It is associated with chronic pathology, such as congestive heart failure, COPD,cardiomyopathy, idiopathic pulmonary fibrosis, pulmonary vascular disease, pulmonary hypertension, valvular heart disease, oranaemia. [19] Less common causes include muscular dystrophies,kyphoscoliosis, amyotrophic lateral sclerosis, pulmonary alveolar proteinosis, chronic eosinophilic pneumonia, uraemia, orconstrictive pericarditis. [18] [20] [21] [22] [23] ∙Recurrent dyspnoea may indicate paroxysmal tachycardias or intermittent complete heart block.Severity∙There is no universally agreed measure of dyspnoea; several scales are available in both research and clinical practice. [24] ∙Dyspnoea is highly subjective, and, for a given level of functional impairment, severity varies widely.∙Severe dyspnoea is typically accompanied by associated symptoms and is more likely to be life-threatening. It may be associated with acute asthma, tension pneumothorax, acute upper airway obstruction,massive pulmonary embolism, or myocardial infarction. Milddyspnoea may be a sole symptom and may indicate a benign aetiology.It may be caused by stable COPD, deconditioning, non-criticalairway obstruction, or normal ageing.Associated symptoms∙Dyspnoea often occurs with other symptoms, and their co-existence may help to localise the origin of dyspnoea to the involved organ system and help to narrow the differential diagnosis.∙Fever manifests with dyspnoea in many infectious and inflammatory conditions, including pneumonia, bronchitis, laryngitis, viralsyndromes (e.g., Hantavirus pulmonary syndrome and severe acuterespiratory syndrome [SARS]), vasculitides, and sepsis.[25] [26] Dyspnoea plus fever and cough may indicate community-acquiredpneumonia or opportunistic infection in immunocompromised hosts.A CXR is necessary to exclude pneumonia. Post-obstructive pneumoniais possible in patients with foreign body aspiration or a chestmalignancy.∙Central chest pain may suggest coronary artery disease, pulmonary embolism, pneumothorax, pneumomediastinum, or foreign bodyaspiration. [27] Pleuritic chest pain may indicate pneumonia,pneumothorax, pulmonary embolism, a solitary fibrous tumour of the pleura, or pleuritis.[28] Pericardial constriction and effusions are characterised by typical pericardial pain that is referred to the scapular region, worsened by position and changes inintrathoracic pressure, and relieved by leaning forwards.∙Palpitations may be present in paroxysmal tachyarrhythmias, pulmonary embolism, valvular heart disease, or anxiety attacks.∙Syncope may accompany dyspnoea associated with tachyarrhythmias or pulmonary embolism. [29]∙Wheezing may indicate asthma, COPD, pulmonary oedema, bronchiolitis, or aspiration of a foreign body. Cough may be present in bronchitis, acute infectious pneumonia, acute eosinophilicpneumonia, interstitial lung disease, COPD, asthma, bronchiectasis, or chronic pneumonitis.[18] Chronic sputum production may indicate COPD or bronchiectasis, while large amounts of clear secretions may be present in bronchoalveolar carcinoma. [30]∙Change in the pitch of the voice may accompany dyspnoea associated with pneumomediastinum, gastro-oesophageal reflux,retropharyngeal haematoma, aortic aneurysm, or lung cancer. [31] ∙Haemoptysis may accompany dyspnoea in patients with bronchitis, exacerbation of bronchiectasis, chest malignancies, vasculitides, acute infectious pneumonia, cryptogenic organising pneumonia,pulmonary embolism, cocaine toxicity, tuberculosis, or diffusealveolar haemorrhage. [32] [33] [34] [35] [36] [37] ∙Dysphagia or odynophagia may be present in a dyspnoeic patient with granulomatous laryngitis, pneumomediastinum, foreign bodyaspiration, tetanus, and epiglottitis. [38] [39] [40] Inepiglottitis, dyspnoea may be additionally accompanied by drooling.Vomiting and diarrhoea may accompany dyspnoea in thyrotoxicosis or botulism.[41] [42] Heartburn may be present in gastro-oesophageal reflux with aspiration.∙Muscle weakness or myalgias associated with dyspnoea may indicate deconditioning, adverse effects of medications, musculardystrophies, amyotrophic lateral sclerosis, acute polio orpost-polio syndrome, Guillain-Barre syndrome, West Nile and other viral infections, leptospirosis, Cushing's myopathy, or botulism.[20] [26] [43] [44] [45] [46] [47] [48] [41] Visual disturbancesmay occur with dyspnoea in myasthenia and tetanus, and headache may be present in carbon monoxide poisoning. [39] [49] [50] ∙Bone pain may be associated with acute chest syndrome due to sickle cell anaemia or fat embolism associated with long-bone fractures.[51]∙Anxiety may be a reaction to dyspnoea of any aetiology but may also cause dyspnoea in acute panic or anxiety attacks. [52] Dyspnoeaassociated with stress may indicate anxiety, hyperventilation, or takotsubo cardiomyopathy. [53]Positionality∙Orthopnoea is the presence of dyspnoea while supine, with an improvement in the upright position. It is characteristicallylinked with congestive heart failure but may also be present inasthma, COPD, inflammatory and degenerative neurological diseases, gastro-oesophageal reflux, pericardial effusion, or bilateraldiaphragmatic paralysis. [20] [54] [55] [56]∙Platypnoea is the worsening of dyspnoea on assuming an upright position, with alleviation while supine. It is typical of patent foramen ovale, abdominal muscle deficiency, or hepatopulmonarysyndrome. [57] [58]∙Trepopnoea is an infrequent finding in which dyspnoea is present only in the lateral decubitus position. It is associated withcongestive heart failure, sinus of Valsalva aneurysms, or status post-pneumonectomy. [59] [60]∙Variable positional changes in dyspnoea may also be seen in primary and metastatic cardiac tumours. [61] [62]Pattern of dyspnoea∙Dyspnoea that appears during the working week and resolves over periods off work may be related to occupational exposure andsuggests occupational asthma.[63] Occupational exposure may also be implicated in cases of asbestos-related lung disease andhypersensitivity pneumonitis. [64] A history of occupational or leisure exposure to aerosolised solvents, fumes, organic dust,moulds, and animals should be elicited and may be implicated in interstitial lung disease. Dyspnoea developing in indoor hockey players may reflect nitrogen dioxide or carbon monoxide toxicity from faulty ice resurfacing equipment. [65]∙Seasonal dyspnoea or shortness of breath related to cold, pets, exercise, or non-specific irritants may suggest asthma or reactive airway disease. [66]Past medical history∙Dyspnoea may be associated with obesity or occur during a normal pregnancy. In pregnant patients it may also indicate the presence of a previously undiagnosed medical condition, such as valvular heart disease, pulmonary hypertension, alpha-1 protease inhibitor deficiency, pulmonary embolism, spontaneous pneumothorax orpneumomediastinum, progression of a pulmonary arteriovenousmalformation, or deterioration of myasthenia. [67] [68] [69] [70][71] [72] [73]∙In a patient who is or recently was in labour, dyspnoea may indicate pulmonary embolism, septic or toxic shock, amniotic fluid ortrophoblastic embolism, pneumothorax, or pneumomediastinum. [9][74]∙Dyspnoea in the post-operative period may indicate pulmonary embolism, an acute coronary event, or pulmonary oedema related to fluid resuscitation. Less frequently a pneumothorax or previously unrecognised muscular dystrophy may be implicated. [75] Specific surgical interventions may be followed by dyspnoea due to fatembolism (liposuction, long-bone surgery), talc-induced acute lung injury (pleurodesis), or pulmonary vein stenosis (mitral valvesurgery). [10] [76] [77] A history of previous venothromboembolic disease, inadequate anticoagulation, immobilisation, admission to hospital, long-distance travel, vascular access, or leg injury may indicate pulmonary embolism as the cause of dyspnoea.∙The presence of a known autoimmune or rheumatological disease predisposes the patient to dyspnoea resulting from pulmonaryembolism, pulmonary hypertension, interstitial lung disease,pleural effusion, or pulmonary haemorrhage.[78] Known malignancy may cause dyspnoea through airway obstruction by the primary ormetastatic tumour, malignant effusion, post-obstructive pneumonia, pulmonary tumour embolism, lymphangitic spread into the lung, or pericardial or endocardial involvement. [79] [80] History ofrheumatological diseases, uncorrected obstructive sleep apnoea,and obesity may indicate pulmonary hypertension. Recurrentpneumonia may indicate gastro-oesophageal reflux with aspiration,a retained foreign body, benign or malignant tumours, or a vascularring. [81] [82] [83] Pleural effusions can accompany pneumonia,heart failure, pleural tuberculosis, malignancy, rheumatological diseases, or mesothelioma.∙ A history of thoracic radiation for malignancy should be elicited.Dyspnoea due to radiation pneumonitis typically appears 1 to 6months after the radiation treatments. [84]Drug history∙Medications may cause dyspnoea or contribute to it through a variety of mechanisms, including several forms of pulmonary toxicity(interstitial disease, pulmonary oedema, pulmonary haemorrhage,airways disease, pleural effusion, pulmonary vascular changes),induction of metabolic acidosis (nucleoside reverse-transcriptase inhibitors, topiramate), or induction of bradycardia andchronotropic insufficiency (digoxin, calcium-channel blockers,beta-blockers). [The drug-induced lung diseases] [85] [86] ∙Beta-blockers may worsen airway obstruction in COPD and asthma.Social history∙ A smoking history with documentation of the number of pack-years smoked is essential. Several smoking-related conditions, including COPD, lung cancer, and certain forms of interstitial lung disease, may produce dyspnoea.Dyspnoea scales∙Although dyspnoea is by its nature a subjective complaint, attempts have been made to grade it. Several dyspnoea scales exist, although their use in everyday practice is limited.∙The Veterans Specific Activity Questionnaire (VSAQ) assesses the functional capability of the patient and estimates the aerobiccapacity in metres. [87] The degree of impairment can then beinferred. The approach and testing for a 25-year-old with trouble running an 8-minute mile is different from that of an 80-year-old with trouble climbing a 12-step staircase. The VSAQ establishes thebaseline function and provides an objective measure forlongitudinal assessment of progress or the lack thereof.∙Other classification schemes are the New York Heart Association functional classification and the Medical Research Councildyspnoea scale. [88] [89]Physical examCareful physical exam helps to narrow the differential and rule in or out life-threatening conditions. Generally, dyspnoea with the presence of signs of acute distress ("dyspnoea that a doctor can see") fares worse than dyspnoea reported by a patient with a normal or near-normal physical exam.Vital signs∙Hypotension, tachycardia, and tachypnoea may indicate acute myocardial infarction, pulmonary embolism, aortic dissection,acute valvular insufficiency, cardiac tamponade, or an acuteinfectious process with sepsis. [90]∙Hypertension in a dyspnoeic patient may point tohypertension-related diastolic heart failure with pulmonary oedema, hyperthyroidism, or phaeochromocytoma. [91]∙Pulsus paradoxus may be a sign of asthma, COPD, or cardiac tamponade.[16]General exam∙Mental status change may be present with dyspnoea in some conditions, including stroke, hypoxaemic or hypercarbic respiratory failurerelated to congestive heart failure, pulmonary oedema, asthma, COPD, pneumonia, sepsis, or CNS infections. [92]∙Frequent sighing may accompany hyperventilation and anxiety states.[93]∙Cyanosis may indicate acute respiratory failure caused by exacerbated COPD, pulmonary embolism, acute airway obstruction,acute drug toxicity, congenital cyanotic valvular disease,mechanical valve malfunction, cardiac tamponade, pulmonaryarteriovenous malformations, aspiration, or methaemoglobinaemia.[90] [94] [95] [96] [97]∙Jaundice may accompany dyspnoea in liver failure or leptospirosis.[47]∙Facial oedema may be present in dyspnoeic patients with superior vena cava syndrome or anaphylaxis.∙ A goitre may accompany retrosternal goitre causing airway obstruction or may be the sign of Graves' disease withthyrotoxicosis. [98] [99]∙Laryngeal height of 4 cm or more is associated with a diagnosis of COPD. [100]∙Kyphoscoliosis, either idiopathic or resulting from a neuromuscular process, may cause restriction of chest movement and subsequent dyspnoea. [21]∙Clubbing may be present in lung cancer, interstitial lung disease, portopulmonary hypertension, or pulmonary arteriovenous fistulas.[101] [102] [103] [104]∙Increased abdominal girth may indicate congestive heart failure, hepatic cirrhosis with ascites and pleural effusions, orconstrictive pericarditis. [105]∙Urticarial rash may accompany dyspnoea in systemic anaphylaxis.[106] Purpura may indicate thrombotic thrombocytopenic purpura,meningococcaemia, or vasculitis. [107]Cardiovascular exam∙Neck vein engorgement may present in dyspnoeic patients with congestive heart failure, COPD, pneumothorax, or cardiac tamponade.Elevated neck veins, extra heart sound (S3 gallop rhythm), and fluid retention indicate congestive heart failure. Chronic dyspnoearesulting from pericardial constriction and effusions may beaccompanied by elevated neck veins, pulsus paradoxus, a pericardial knock, pericardial rub, and the Kussmaul's sign. [108] ∙An irregular or fast heart beat may lead to a diagnosis of a tachyarrhythmia or atrial fibrillation. A loud S2 may be associated with pulmonary hypertension and cor pulmonale. A systolic heartmurmur may indicate acute valvular insufficiency, mechanical valve malfunction, or congenital or rheumatic valvular disease. [95] ∙Lower extremity oedema may indicate congestive heart failure with pulmonary oedema, volume overload, pulmonary thromboembolism,myocardial infarction, arrhythmias, constrictive pericarditis,pulmonary hypertension, inferior vena cava thrombosis,hypothyroidism, or cardiac tumours. [105] [109]Respiratory exam∙Pursed lip breathing may be present in a patient with COPD.∙Stridor in a dyspnoeic patient is usually caused by upper airway obstruction with a foreign body, infectious or inflammatory oedema(e.g., diphtheria, tetanus, epiglottitis, angio-oedema),[39] [40][110] [111] dysfunction of the upper airway structures (vocal corddysfunction, tetany),[112] [113] tumours of the airway wall (base of the tongue, larynx, oesophagus, trachea, and airwaypapillomatosis), or airway limitation by its extrinsic compression (retrosternal goitre, thyroid cancer, lymphoma).[98] [114] [115] Associated fever and difficulty in swallowing may indicateepiglottitis, while a characteristic cough in a child with an upper respiratory tract infection may indicate croup. Hoarseness mayaccompany dyspnoea in laryngitis, laryngeal tumours, relapsingpolychondritis, [38] [116] or unilateral idiopathic and benign(aortic aneurysm, Ortner's syndrome) or malignant vocal cordparalysis. [117]∙ A barrel chest (increased anteroposterior diameter) is seen in emphysema and cystic fibrosis.∙The trachea may deviate away from the lesion in tension pneumothorax or a large pleural effusion.∙Unilateral dullness to percussion may be due to pleural effusion, atelectasis, foreign body aspiration, pleural tumours, orpneumonia. [118] Hyper-resonance may indicate pneumothorax orsevere emphysema. Subcutaneous emphysema may indicate the presence of pneumomediastinum. [27]∙Unilateral decreased or absent breath sounds may be due to pleural effusion, atelectasis, foreign body aspiration, or pneumothorax.Pulmonary hypertension is suggested by a loud P2 on auscultation.Distant breath sounds suggest a pleural effusion. [119] Wheezing accompanies dyspnoea in asthma, COPD, anaphylaxis, vocal corddysfunction, pulmonary congestion and oedema, cystic fibrosis, or pulmonary embolism. In COPD, wheeze is associated with acutedyspnoea and a laryngeal descent of at least 4 cm. [19] Pulmonary rales may indicate pulmonary congestion (fine, bibasal) or oedema, acute or chronic pneumonia, or some interstitial lung diseases, including sarcoidosis, hypersensitivity pneumonitis, oridiopathic pneumonitides. Velcro crackles should alert theclinician to the possibility of interstitial lung disease. Aprolonged expiratory phase may be observed in asthma, COPD, cystic fibrosis, bronchiectasis, or bronchiolitis.Neurological exam∙Cranial nerve palsies may accompany dyspnoea in botulism. [41] ∙Ptosis may be present in myasthenia gravis, myotonic dystrophy, or botulism. [41] [49] [75]InvestigationsResults of preliminary laboratory testing and radiographic investigations help to narrow the diagnosis and focus on only some of the numerous differential diagnoses of dyspnoea. Initial investigations for dyspnoea include pulse oximetry and ABG; an FBC; D-dimer, B-type natriuretic peptide (BNP), and TSH levels; a 12-lead ECG and CXR; and spirometry (including carbon monoxide diffusing capacity [DLCO]) and cardiopulmonary exercise testing. [120] [121] [122] The choice of investigations is dictated by the clinical history and physical exam findings.∙Pulse oximetry: this allows detection and ongoing monitoring of hypoxaemia with initiation of oxygen supplementation as necessary, while undertaking diagnostic work-up for its cause.∙ABG: not all patients with dyspnoea display abnormal findings on ABG, and not all abnormal ABG results manifest with dyspnoea.However, the ABG results may help in constructing a differential diagnosis and, along with exertional oximetry, may be indicated to evaluate gas exchange abnormalities in conditions associated with hypoxaemia. Hypercapnia (PaCO2 >45 mmHg) may accompany dyspnoea in exacerbation of COPD, neuromuscular disease, stroke, upper airway obstruction, or obesity-hypoventilation syndrome. Hypocapnia may be present in anxiety states and accompany any process that presents with hyperventilation, such as pulmonary embolism. Hypoxaemia(PaO2 <70 mmHg at sea level) has a broader differential, including conditions causing shunting (acute respiratory distress syndrome, pneumonia, pulmonary oedema, cyanotic valvular disease), V/Qmismatching (COPD, asthma, pulmonary embolism), diffusionimpairment (interstitial lung disease), or hypoventilation (COPD exacerbation, neuromuscular disease, stroke, upper airwayobstruction, or obesity-hypoventilation syndrome). The dyspnoea differentiation index, which combines the PaO2 with the PEFR ([PEFR x PaO2]/1000), has a reported diagnostic accuracy of 79% indifferentiating cardiac from pulmonary causes of dyspnoea. [123] Acidosis (pH <7.36) is a potent stimulus of breathing and mayaccompany dyspnoea in the late phases of almost any processpresenting with dyspnoea, including sepsis, pulmonary oedema,exacerbation of COPD, and cyanide toxicity. [124] It may also be present in idiopathic or medication-induced renal tubular acidosis and thiamine deficiency. [125] Acidosis may result from usingmedications such as nucleoside reverse-transcriptase inhibitors and topiramate.[85] [86] Alkalosis may be a consequence of anxiety, panic attacks, dehydration, pulmonary embolism, ovarianhyperstimulation syndrome, or pulmonary leukostasis. [126] [14]∙PEFR: this simple bedside test may help to differentiate between pulmonary and cardiac causes of dyspnoea. Low peak flow rates are associated with obstructive lung disease such as asthma, COPD, and cystic fibrosis. [123]∙FBC: leukocytosis may accompany dyspnoea in any infectious process involving the respiratory system, as well as in sepsis, autoimmune disease, parasitic infections, and leukemia. [14] [127]Eosinophilia may be present in a dyspnoeic patient with parasitic disease, certain vasculitides (e.g., Churg-Strauss syndrome), asthma, eosinophilic pneumonia, or cocaine use. [127] [128] [129] [130] Anaemia may be the primary reason for dyspnoea or mayaccompany it in drug-related lung injury, hereditary haemorrhagic telangiectasia, acute chest syndrome of sickle cell disease, pulmonary alveolar haemorrhage, or widespread infectious processes.[131] [132] Thrombocytopenia may be present with dyspnoea in viral infections, including influenza, SARS, and Hantavirus pulmonary syndrome. [25] [26] It may also be due to adverse drug reactions, especially with chemotherapy.∙Electrolytes: hyponatraemia may accompany dyspnoea in congestive heart failure, chronic kidney disease, liver failure, orhypothyroidism.∙Liver function tests: bilirubin may be elevated in dyspnoeic patients with liver failure, congestive heart failure,leptospirosis, and thoracic amoebiasis. [47] [133] [134]Transaminases may be elevated in liver failure, acute myocardial infarction, atypical pneumonia (especially Legionella pneumonia), and viral infections such as SARS and Hantavirus pulmonary syndrome.[25] [26]∙Kidney function tests: dyspnoea accompanied by laboratory evidence of renal insufficiency may be due to uraemic pleurisy, long-term volume overload with pleural effusions, pneumonia, and several types of acute vasculitis. [135] [136] [137] [138]∙Cardiac enzymes: elevated troponin I/T, myoglobin, and CK-MB may accompany acute myocardial infarction, myocarditis, takotsubo cardiomyopathy, or hypothyroidism. [53] [139] It may also reflect chronic coronary artery disease with superimposed physiological stress (e.g., sepsis).∙BNP: elevated B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) have been associated with congestive heart failure, but also sepsis, coronary artery disease, pulmonary embolism, COPD with cor pulmonale, renal failure, liver cirrhosis, and hyperthyroidism.[140] [141] [142] A low normal BNP level (<100 nanograms/L [<100 picograms/mL]) is helpful in excludingcongestive heart failure.∙CXR: this is important to exclude spontaneous or secondary pneumothorax. Pulmonary venous congestion and an enlarged heart suggest congestive heart failure. An enlarged cardiac silhouette may also indicate valvular heart disease, a pericardial cyst, or cardiac tamponade.[16] [143] Dyspnoea accompanied by parenchymal infiltrates may be present in infectious pneumonia, pulmonary oedema, eosinophilic pneumonitis, radiation pneumonitis, [144] some interstitial lung diseases (sarcoidosis, usual interstitial pneumonitis, non-specific interstitial pneumonitis, cryptogenic interstitial pneumonitis, lymphoid interstitial pneumonitis, acute interstitial pneumonitis), [145] [146] [147] [148] [149] pneumoconioses (silicosis, asbestosis, berylliosis), drug-related lung disease, autoimmune disease-related lung disease (lupus, rheumatoid arthritis, scleroderma, polymyositis, vasculitis), or metastatic lung disease. Pleural effusion may accompany congestive heart failure, liver failure, uraemia, nephrotic syndrome,malignancy, pneumonia, pulmonary embolism, or pleuritis. Pleural thickening and nodularity may be seen in pleural tumours.[28] Lung hyperinflation may be present in COPD, exacerbation of asthma, or foreign body aspiration. Elevation of the hemidiaphragm mayindicate its paralysis. Unilateral lucidity may indicatepneumothorax or a diaphragmatic hernia. [150] Prominent hilar vessels may be apparent in pulmonary hypertension.∙ECG: this helps to diagnose acute coronary syndromes as the cause of dyspnoea with ST-T-segment changes. It also identifies complete heart block, bradycardias, and tachyarrhythmias, and detects changes suggestive of pericarditis, cardiac tamponade (lowvoltage), and pulmonary embolism. Changes in the p-wave morphology may help diagnose right atrial enlargement (typical of a chronic pulmonary process) or left atrial enlargement (typical of valvular heart disease). Change in the QRS axis may indicate right (COPD, pulmonary hypertension) or left (hypertension, valvular heart disease) ventricular enlargement or hypertrophy.∙Echocardiogram: this can detect pericardial disease and pulmonary hypertension. It can also be used to delineate valvular heart disease, measure diastolic dysfunction, and differentiate between systolic and diastolic failure. The diagnosis of constrictive and restrictive heart diseases with heart failure requiresechocardiographic study.∙Holter monitoring: continuous monitoring of the heart rate over a period of days or weeks allows for the detection of intermittent arrhythmias.∙ A negative D-dimer by ELISA has a negative predictive ratio of 0.1 for the presence of venothromboembolism, similar to that of a lowerextremity duplex ultrasound scan, and a normal to near-normal V/Q lung scan. [13]∙CT angiography of the chest: this is the best investigation for diagnosing and excluding pulmonary embolism and may be indicated if the D-dimer is abnormal. CT of the chest can also detect and help define the extent of pulmonary parenchymal disease (infectious and non-infectious infiltrates), suggest the presence of pulmonary oedema, define airway (benign stenoses, foreign body, malignancy) and vascular (congenital and acquired stenoses of the intrathoracic blood vessels, aneurysms) abnormalities, confirm the presence of pleural effusion, or evaluate other intrathoracic (thymus,retrosternal goitre) structures.∙High resolution CT chest: this imaging study is necessary in evaluating interstitial lung disease, which is not excluded by a normal CXR. [151]∙Ventilation-perfusion (V/Q) scan: unmatched perfusion defects on V/Q scan suggest pulmonary embolism in an appropriate clinical setting. Three-dimensional single-photon emission CT (SPECT) technology improves sensitivity and specificity of the V/Q scan.[152]∙Lateral X-ray of the neck may show an enlarged epiglottis, the “thumb sign”, which in an appropriate clinical scenario is suggestive of epiglottitis.∙Lung biopsy: a thoracoscopic lung biopsy is the mainstay of diagnosis for many interstitial lung diseases. It may also be used in diagnosing autoimmune or vascular diseases of the lung.Transthoracic needle aspiration may be useful in confirming the malignant aetiology of intrathoracic nodules.∙Spirometry: this simple clinic-based test allows the detection of an obstructive deficit, which is revealed by a disproportionate reduction in the FEV1 in relation to the FVC. Obstructive deficits are characteristic of asthma, emphysema, or chronic bronchitis.More symmetrical reduction in FEV1 and FVC may suggest restriction and warrants full pulmonary function testing, with measurement of lung volumes and carbon monoxide diffusing capacity (DLCO). [153] ∙Pulmonary function testing: this involves spirometry, measuring lung volumes, and evaluating DLCO. The 2 most common patterns of ventilatory defect are an obstructive deficit (low FEV1/FVC ratio, increased residual volume, increased total lung capacity), seen in asthma, bronchitis, and emphysema, and a restrictive deficit (symmetrical reduction of FEV1 and FVC, high FEV1/FVC ratio, low total lung capacity), seen in interstitial lung disease. Less common patterns include a fixed or variable extrathoracic flow limitation in vocal cord obstruction and tumours, an isolated。