Respiratory disease

Clinical examination of the respiratory system

Respiratory disease is responsible for a major burden of morbidity and untimely death, with conditions such as tuberculosis, pandemic influenza and pneumonia the most important in world health terms. The increasing prevalence of allergy, asthma and chronic obstructive pulmonary disease (COPD) contributes to the overall burden of chronic disease in the community. By 2025, the number of cigarette smokers worldwide is anticipated to increase to 1.5 billion, ensuring a growing burden of tobacco-related respiratory conditions.

Respiratory disease covers a breadth of pathologies, including infectious, inflammatory, neoplastic and degenerative processes. The practice of respiratory medicine thus requires collaboration with a range of disciplines. Recent advances have improved the lives of many patients with obstructive lung disease, cystic fibrosis, obstructive sleep apnoea and pulmonary hypertension, but the outlook remains poor for lung and other respiratory cancers, and for some of the fibrosing lung conditions.

Functional anatomy and physiology

The lungs occupy the upper two-thirds of the bony thorax, bounded medially by the spine, the heart and the mediastinum and inferiorly by the diaphragm. During breathing, free movement of the lung surface relative to the chest wall is facilitated by sliding contact between the parietal and visceral pleura, which cover the inner surface of the chest wall and the lung respectively, and are normally in close apposition. Inspiration involves downward contraction of the dome-shaped diaphragm (innervated by the phrenic nerves originating from C3, 4 and 5) and upward, outward movement of the ribs on the costovertebral joints, caused by contraction of the external intercostal muscles (innervated by intercostal nerves originating from the thoracic spinal cord). Expiration is largely passive, driven by elastic recoil of the lungs.

The conducting airways from the nose to the alveoli connect the external environment with the extensive, thin and vulnerable alveolar surface. As air is inhaled through the upper airways, it is filtered in the nose, heated to body temperature and fully saturated with water vapour; partial recovery of this heat and moisture occurs on expiration. Total airway cross-section is smallest in the glottis and trachea, making the central airway particularly vulnerable to obstruction by foreign bodies and tumours. Normal breath sounds originate mainly from the rapid turbulent airflow in the larynx, trachea and main bronchi.

The multitude of small airways within the lung parenchyma has a very large combined cross-sectional area (over 300 cm² in the third-generation respiratory bronchioles), resulting in very slow flow rates. Airflow is normally silent here, and gas transport occurs largely by diffusion in the final generations. Major bronchial and pulmonary divisions are shown in Figure 19.1.

Fig. 19.1 The major bronchial divisions and the fissures, lobes and segments of the lungs.
The angle of the oblique fissure means that the left upper lobe is largely anterior to the lower lobe. On the right, the transverse fissure separates the upper from the anteriorly placed middle lobe, which is matched by the lingular segment on the left side. The site of a lobe determines whether physical signs are mainly anterior or posterior. Each lobe is composed of two or more bronchopulmonary segments that are supplied by the main branches of each lobar bronchus.
*Bronchopulmonary segments*:
**Right** *Upper lobe*: (1) Anterior, (2) Posterior, (3) Apical. *Middle lobe*: (1) Lateral, (2) Medial. *Lower lobe*: (1) Apical, (2) Posterior basal, (3) Lateral basal, (4) Anterior basal, (5) Medial basal.
**Left** *Upper lobe*: (1) Anterior, (2) Apical, (3) Posterior, (4) Lingular. *Lower lobe*: (1) Apical, (2) Posterior basal, (3) Lateral basal, (4) Anterior basal.

The acinus (Fig. 19.2) is the gas exchange unit of the lung and comprises branching respiratory bronchioles and clusters of alveoli. Here the air makes close contact with the blood in the pulmonary capillaries (gas-to-blood distance < 0.4 µm), and oxygen uptake and CO₂ excretion occur. The alveoli are lined with flattened epithelial cells (type I pneumocytes) and a few, more cuboidal, type II pneumocytes. The latter produce surfactant, which is a mixture of phospholipids that reduces surface tension and counteracts the tendency of alveoli to collapse under surface tension. Type II pneumocytes can divide to reconstitute type I pneumocytes after lung injury.

Fig. 19.2 Functional anatomy of the lung.
A The tapering, branching bronchus is armoured against compression by plates of cartilage. The more distal bronchioles are collapsible, but held patent by surrounding elastic tissue. B The unit of lung supplied by a terminal bronchiole is called an acinus. The bronchiolar wall contains smooth muscle and elastin fibres. The latter also run through the alveolar walls. Gas exchange occurs in the alveoli, which are connected to each other by the pores of Kohn. C Vascular anatomy of an acinus. Both the pulmonary artery (carrying desaturated blood) and the bronchial artery (systemic supply to airway tissue) run along the bronchus. The venous drainage to the left atrium follows the interlobular septa. From www.Netter.com – see p. 731.

Lung mechanics

Healthy alveolar walls contain a fine network of elastin and collagen fibres (see Fig. 19.2). The volume of the lungs at the end of a tidal (‘normal’) breath out is called the functional residual capacity (FRC). At this volume, the inward elastic recoil of the lungs (resulting from elastin fibres and surface tension in the alveolar lining fluid) is balanced by the resistance of the chest wall to inward distortion from its resting shape, causing negative pressure in the pleural space. Elastin fibres allow the lung to be easily distended at physiological lung volumes, but collagen fibres cause increasing stiffness as full inflation is approached so that, in health, the maximum inspiratory volume is limited by the lung (rather than the chest wall). Within the lung, the weight of tissue compresses the dependent regions and distends the uppermost parts, so a greater portion of an inhaled breath passes to the basal regions, which also receive the greatest blood flow as a result of gravity. Elastin fibres in alveolar walls maintain small airway patency by radial traction on the airway walls. Even in health, however, these small airways narrow during expiration because they are surrounded by alveoli at higher pressure, but are prevented from collapsing by radial elastic traction. The volume that can be exhaled is thus limited purely by the capacity of the expiratory muscles to distort the chest wall inwards. In emphysema, loss of alveolar walls leaves the small airways unsupported, and their collapse on expiration causes air trapping and high end-expiratory volume (p. 673).

Control of breathing

The respiratory motor neurons in the posterior medulla oblongata are the origin of the respiratory cycle. Their activity is modulated by multiple external inputs in health and in disease (see Fig. 19.10, p. 657):

Fig. 19.10 Respiratory stimuli contributing to breathlessness.
Mechanisms by which disease can stimulate the respiratory motor neurons in the medulla. Breathlessness is usually felt in proportion to the sum of these stimuli. Further explanation is given on page 543. ( = ventilation/perfusion match)

• Central chemoreceptors in the ventrolateral medulla sense the pH of the cerebrospinal fluid (CSF) and are indirectly stimulated by a rise in arterial PCO₂.

• The carotid bodies sense hypoxaemia but are mainly activated by arterial PO₂ values below 8 KPa (60 mmHg). They are also sensitised to hypoxia by raised arterial PCO₂.

• Muscle spindles in the respiratory muscles sense changes in mechanical load.

• Vagal sensory fibres from the lung may be stimulated by stretch, by inhaled toxins or by disease processes in the interstitium.

• Cortical (volitional) and limbic (emotional) influences can override the automatic control of breathing.

Ventilation/perfusion matching and the pulmonary circulation

To achieve optimal gas exchange within the lungs, the regional distribution of ventilation and perfusion must be matched. At segmental and subsegmental level, hypoxia constricts pulmonary arterioles and airway CO₂ dilates bronchi, helping to maintain good regional matching of ventilation and perfusion. Lung disease may create regions of relative underventilation or underperfusion, which disturb this regional matching, causing respiratory failure (p. 663). In addition to causing ventilation–perfusion mismatch, diseases that destroy capillaries or thicken the alveolar capillary membrane (e.g. emphysema or fibrosis) can impair gas diffusion directly.

The pulmonary circulation in health operates at low pressure (approximately 24/9 mmHg), and can accommodate large increases in flow with minimal rise in pressure, such as during exercise. Pulmonary hypertension occurs when vessels are destroyed by emphysema, obstructed by thrombus, involved in interstitial inflammation or thickened by pulmonary vascular disease. The right ventricle responds by hypertrophy, with right axis deviation and P pulmonale on the ECG. Pulmonary hypertension with hypoxia and hypercapnia is associated with generalised salt and water retention (‘cor pulmonale’), with elevation of the jugular venous pressure (JVP) and peripheral oedema. This is thought to result mainly from a failure of the hypoxic and hypercapnic kidney to excrete sufficient salt and water.

19.1 Respiratory function in old age

• Reserve capacity: a significant reduction in function can occur with ageing with only minimal effect on normal breathing, but the ability to combat acute disease is reduced.

• Decline in FEV₁: the FEV₁/FVC (forced expiratory volume/forced vital capacity, p. 652) ratio falls by around 0.2% per year from 70% at the age of 40–45 years, due to a decline in elastic recoil in the small airways with age. Smoking accelerates this decline threefold on average. Symptoms usually occur only when FEV₁ drops below 50% of predicted.

• Increasing ventilation–perfusion mismatch: the reduction in elastic recoil causes a tendency for the small airways to collapse during expiration, particularly in dependent areas of the lungs, thus reducing ventilation.

• Reduced ventilatory responses to hypoxia and hypercapnia: older people may be less tachypnoeic for any given fall in PaO₂ or rise in PaCO₂.

• Impaired defences against infection: due to reduced numbers of glandular epithelial cells, which lead to a reduction in protective mucus.

• Decline in maximum oxygen uptake: due to a combination of impairments in muscle, and the respiratory and cardiovascular systems. This leads to a reduction in cardiorespiratory reserve and exercise capacity.

• Loss of chest wall compliance: due to reduced intervertebral disc spaces and ossification of the costal cartilages; respiratory muscle strength and endurance also decline. These changes only become important in the presence of other respiratory disease.

Lung defences

Upper airway defences

Large airborne particles are trapped by nasal hairs, and smaller particles settling on the mucosa are cleared towards the oropharynx by the columnar ciliated epithelium which covers the turbinates and septum (Fig. 19.3). During cough, expiratory muscle effort against a closed glottis results in high intrathoracic pressure, which is then released explosively. The flexible posterior tracheal wall is pushed inwards by the high surrounding pressure, which reduces tracheal cross-section and thus maximises the airspeed to achieve effective expectoration. The larynx also acts as a sphincter, protecting the airway during swallowing and vomiting.

Fig. 19.3 The mucociliary escalator.
Scanning electron micrograph of the respiratory epithelium showing large numbers of cilia (C) overlaid by the mucus ‘raft’ (M).

Lower airway defences

The sterility, structure and function of the lower airways are maintained by close cooperation between the innate and adaptive immune responses (pp. 72 and 76).

The innate response in the lungs is characterised by a number of non-specific defence mechanisms. Inhaled particulate matter is trapped in airway mucus and cleared by the mucociliary escalator. Cigarette smoke increases mucus secretion but reduces mucociliary clearance and predisposes towards lower respiratory tract infections, including pneumonia. Defective mucociliary transport is also a feature of several rare diseases, including Kartagener’s syndrome, Young’s syndrome and ciliary dysmotility syndrome, which are characterised by repeated sino-pulmonary infections and bronchiectasis.

Airway secretions contain an array of antimicrobial peptides (such as defensins, immunoglobulin A (IgA) and lysozyme), antiproteinases and antioxidants. Many assist with the opsonisation and killing of bacteria, and the regulation of the powerful proteolytic enzymes secreted by inflammatory cells. In particular, α₁-antiproteinase (A1Pi) regulates neutrophil elastase, and deficiency of this may be associated with premature emphysema.

Macrophages engulf microbes, organic dusts and other particulate matter. They are unable to digest inorganic agents, such as asbestos or silica, which lead to their death and the release of powerful proteolytic enzymes that cause parenchymal damage. Neutrophil numbers in the airway are low, but the pulmonary circulation contains a marginated pool that may be recruited rapidly in response to bacterial infection. This may explain the prominence of lung injury in sepsis syndromes and trauma.

Adaptive immunity is characterised by the specificity of the response and the development of memory. Lung dendritic cells facilitate antigen presentation to T and B lymphocytes.

Investigation of respiratory disease

A detailed history, thorough examination and basic haematological and biochemical tests usually indicate the likely diagnosis and differential. A number of other investigations are normally required to confirm the diagnosis and/or monitor disease activity.

Imaging

The ‘plain’ chest X-ray

This is performed on the majority of patients suspected of having chest disease. A postero-anterior (PA) film provides information on the lung fields, heart, mediastinum, vascular structures and thoracic cage (Fig. 19.4). Additional information may be obtained from a lateral film, particularly if pathology is suspected behind the heart shadow or deep in the diaphragmatic sulci. An approach to interpreting the chest X-ray is given in Box 19.2, and common abnormalities are listed in Box 19.3.

19.2 How to interpret a chest X-ray

Name, date, orientation	Films are postero-anterior (PA) unless marked AP to denote that they are antero-posterior
Lung fields	Equal translucency? Check horizontal fissure from right hilum to sixth rib at the anterior axillary line Masses? Consolidation? Cavitation?
Lung apices	Check behind the clavicles: Masses? Consolidation? Cavitation?
Trachea	Central? (Midway between the clavicular heads) Paratracheal mass? Goitre?
Heart	Normal shape? Cardiothoracic ratio (should be < half the intrathoracic diameter) Retrocardiac mass?
Hila	Left should be higher than right Shape? (Should be concave laterally; if convex, consider mass or lymphadenopathy) Density?
Diaphragm	Right should be higher than left Hyperinflation? (No more than 10 ribs should be visible posteriorly above the diaphragm)
Costophrenic angles	Acute and well defined? (Pleural fluid or thickening, if not)
Soft tissues	Breast shadows in females Chest wall for masses or subcutaneous emphysema
Bones	Ribs, vertebrae, scapulae and clavicles Any fracture visible at bone margins or lucencies?

19.3 Common chest X-ray abnormalities

Pulmonary and pleural shadowing

• Consolidation: infection, infarction, inflammation, and rarely bronchoalveolar cell carcinoma

• Lobar collapse: mucus plugging, tumour, compression by lymph nodes

• Solitary nodule: see page 660

• Multiple nodules: miliary tuberculosis (TB), dust inhalation, metastatic malignancy, healed varicella pneumonia, rheumatoid disease

• Ring shadows, tramlines and tubular shadows: bronchiectasis

• Cavitating lesions: tumour, abscess, infarct, pneumonia (Staphylococcus/Klebsiella), granulomatosis with polyangiitis

• Reticular, nodular and reticulonodular shadows: diffuse parenchymal lung disease, infection

• Pleural abnormalities: fluid, plaques, tumour

Increased translucency
• Bullae • Pneumothorax	• Oligaemia
Hilar abnormalities
• Unilateral hilar enlargement: TB, bronchial carcinoma, lymphoma
• Bilateral hilar enlargement: sarcoid, lymphoma, TB, silicosis
Other abnormalities
• Hiatus hernia	• Surgical emphysema

Increased shadowing may represent accumulation of fluid, lobar collapse or consolidation. Uncomplicated consolidation should not change the position of the mediastinum and the presence of an air bronchogram means that proximal bronchi are patent. Collapse (implying obstruction of the lobar bronchus) is accompanied by loss of volume and displacement of the mediastinum towards the affected side (Fig. 19.5).

Fig. 19.5 Radiological features of lobar collapse caused by bronchial obstruction.
The dotted line in the drawings represents the normal position of the diaphragm. The dark pink area represents the extent of shadowing seen on the X-ray.

The presence of ring shadows (thickened bronchi seen end-on), tramline shadows (thickened bronchi side-on) or tubular shadows (bronchi filled with secretions) suggests bronchiectasis, but computed tomography is a much more sensitive test than plain X-ray in bronchiectasis. The presence of pleural fluid is suggested by a dense basal shadow, which, in the erect patient, ascends towards the axilla (p. 645). In large pulmonary embolism, relative oligaemia may cause a lung field to appear abnormally dark.

Computed tomography

Computed tomography (CT) provides detailed images of the pulmonary parenchyma, mediastinum, pleura and bony structures. The displayed range of densities can be adjusted to highlight different structures, such as the lung parenchyma, the mediastinal vascular structures or bone. Sophisticated software facilitates three-dimensional reconstruction of the thorax and virtual bronchoscopy.

CT is superior to chest radiography in determining the position and size of a pulmonary lesion and whether calcification or cavitation is present. It is now routinely used in the assessment of patients with suspected lung cancer and facilitates guided percutaneous needle biopsy. Information on tumour stage may be gained by examining the mediastinum, liver and adrenal glands.

High-resolution CT (HRCT) uses thin sections to provide detailed images of the pulmonary parenchyma and is particularly useful in assessing diffuse parenchymal lung disease, identifying bronchiectasis (Fig. 19.30, p. 679), and assessing type and extent of emphysema.

Assessment of the pulmonary circulation

CT pulmonary angiography (CTPA) has become the investigation of choice in the diagnosis of pulmonary thromboembolism (see Fig. 19.69, p. 679), when it may either confirm the suspected embolism or highlight an alternative diagnosis. It has largely replaced the radioisotope-based ventilation–perfusion scan, although the latter continues to provide useful information in the pre-operative assessment of patients being considered for lung resection. In pulmonary hypertension, Doppler echocardiographic assessment of tricuspid regurgitant jets allows accurate non-invasive measurement of pulmonary artery pressure in most cases. Right heart catheterisation is still used in the investigation of patients with pulmonary hypertension in specialised centres, as it permits accurate measurement of response to pulmonary vasodilators.

Positron emission tomography

Positron emission tomography (PET) scanners exploit the ability of malignant tissue to absorb and metabolise glucose avidly. The radiotracer ¹⁸F-fluorodeoxyglucose (FDG) is infused and rapidly taken up by malignant tissue. It is then phosphorylated but cannot be metabolised further, becoming ‘trapped’ in the cell. PET is useful in the investigation of pulmonary nodules, and in staging mediastinal lymph nodes and distal metastatic disease in patients with lung cancer. The negative predictive value is high; however, the positive predictive value is poor. Co-registration of PET and CT (PET-CT) enhances localisation and characterisation of metabolically active deposits (Fig. 19.6). Future advances will see the combination of PET and magnetic resonance imaging (MRI).

Fig. 19.6 Computed tomography and positron emission tomography combined to reveal intrathoracic metastases.
A In a patient with lung cancer, CT shows some posterior pleural thickening. B PET scanning reveals FDG uptake in two pleural lesions (arrows). C The lesions are highlighted in yellow in the combined PET/CT image. From http://radiology.rsnajnls.org – see p. 731.

Ultrasound

Ultrasound is used to assess the pleural space for pleural fluid, which appears as a hypoechoic space. It also allows direct visualisation of the diaphragm and solid organs such as the liver, spleen and kidneys, thereby allowing safe pleural aspiration, biopsy and intercostal chest drain insertion. Ultrasound can also be used to guide needle biopsy of superficial lymph node or chest wall masses and provides useful information on the shape and movement of the diaphragm. Endobronchial ultrasound (EBUS) is described below.

Endoscopic examination

Skin tests

The tuberculin test (p. 695) may be of value in the diagnosis of tuberculosis. Skin hypersensitivity tests are useful in the investigation of allergic diseases (p. 89).

Microbiological investigations

Sputum, pleural fluid, throat swabs, blood, and bronchial washings and aspirates can be examined for bacteria, fungi and viruses. In some cases, as when Mycobacterium tuberculosis is isolated, the information is diagnostically conclusive but, in others, the findings must be interpreted in conjunction with the results of clinical and radiological examination.

The use of hypertonic saline to induce expectoration of sputum is useful in facilitating the collection of specimens for microbiology, particularly in patients in whom more invasive procedures, such as bronchoscopy, are not possible. The technique also allows assessment of the inflammatory cell population of the airway, which is a useful research tool in many conditions, including asthma, COPD and interstitial lung disease.

Histopathology and cytology

Histopathological examination of biopsies of pleura, lymph node or lung often allows a ‘tissue diagnosis’ to be made. This is particularly important in suspected malignancy or in characterising the pathological changes in interstitial lung disease. Important causative organisms, such as M. tuberculosis, Pneumocystis jirovecii or fungi, may be identified in bronchial washings, brushings or transbronchial biopsies.

Cytological examination of exfoliated cells in pleural fluid or bronchial brushings and washings, or of fine needle aspirates from lymph nodes or pulmonary lesions, can support a diagnosis of malignancy but, if this is indeterminate, a larger tissue biopsy is often necessary. Differential cell counts in bronchial lavage fluid may help to distinguish pulmonary changes due to sarcoidosis (p. 709) from those caused by idiopathic pulmonary fibrosis (p. 706) or hypersensitivity pneumonitis (p. 719).

Respiratory function testing

Respiratory function tests are used to aid diagnosis, assess functional impairment, and monitor treatment or progression of disease. Airway narrowing, lung volume and gas exchange capacity are quantified and compared with normal values adjusted for age, gender, height and ethnic origin. In diseases characterised by airway narrowing (e.g. asthma, bronchitis and emphysema), maximum expiratory flow is limited by dynamic compression of small intrathoracic airways, some of which may close completely during expiration, limiting the volume that can be expired (‘obstructive’ defect). Hyperinflation of the chest results, and can become extreme if elastic recoil is also lost due to parenchymal destruction, as in emphysema. In contrast, diseases that cause interstitial inflammation and/or fibrosis lead to progressive loss of lung volume (‘restrictive’ defect) with normal expiratory flow rates. Typical laboratory traces are illustrated in Figure 19.7.

Fig. 19.7 Respiratory function tests in health and disease.
A Volume/time traces from forced expiration in a normal subject, in COPD and in fibrosis. COPD causes slow, prolonged and limited exhalation. In fibrosis, forced expiration results in rapid expulsion of a reduced forced vital capacity (FVC). Forced expiratory volume (FEV₁) is reduced in both diseases but is disproportionately reduced, compared to FVC, in COPD. B The same data plotted as flow/volume loops. In COPD, collapse of intrathoracic airways limits flow, particularly during mid- and late expiration. The blue trace illustrates large airway obstruction, which particularly limits peak flow rates. C Lung volume measurement. Volume/time graphs during quiet breathing with a single maximal breath in and out. COPD causes hyperinflation with increased residual volume. Fibrosis causes a proportional reduction in all lung volumes.

Measurement of airway obstruction

Airway narrowing is assessed by asking patients to blow out as hard and as fast as they can into a peak flow meter or a spirometer. Peak flow meters are cheap and convenient for home monitoring of peak expiratory flow (PEF) in the detection and monitoring of asthma, but results are effort-dependent. More accurate and reproducible measures are obtained by inhaling fully, then exhaling at maximum effort into a spirometer. The forced expired volume in 1 second (FEV₁) is the volume exhaled in the first second, and the forced vital capacity (FVC) is the total volume exhaled. FEV₁ is disproportionately reduced in airflow obstruction, resulting in FEV₁/FVC ratios of less than 70%. In this situation, spirometry should be repeated following inhaled short-acting β₂-adrenoceptor agonists (e.g. salbutamol); a large improvement in FEV₁ (over 400 mL) and variability in peak flow over time are features of asthma (p. 668).

To distinguish large airway narrowing (e.g. tracheal stenosis or compression) from small airway narrowing, flow/volume loops are recorded using spirometry. These display flow in relation to lung volume (rather than time) during maximum expiration and inspiration, and the pattern of flow reveals the site of airflow obstruction (see Fig. 19.7).

Lung volumes

Tidal volume and vital capacity (VC – the maximum amount of air that can be expelled from the lungs after the deepest possible breath) can be measured by spirometry. Total lung capacity (TLC – the total amount of air in the lungs after taking the deepest breath possible) can be measured by asking the patient to rebreathe an inert non-absorbed gas (usually helium) and recording how much the test gas is diluted by lung gas. This measures the volume of intrathoracic gas that mixes with tidal breaths. Alternatively, lung volume may be measured by body plethysmography, which determines the pressure/volume relationship of the thorax. This method measures total intrathoracic gas volume, including poorly ventilated areas such as bullae.

Transfer factor

To measure the capacity of the lungs to exchange gas, patients inhale a test mixture of 0.3% carbon monoxide, which is taken up avidly by haemoglobin in pulmonary capillaries. After a short breath-hold, the rate of disappearance of CO into the circulation is calculated from a sample of expirate, and expressed as the TL_CO or carbon monoxide transfer factor. Helium is also included in the test breath to allow calculation of the volume of lung examined by the test breath. Transfer factor expressed per unit lung volume is termed K_CO. Common respiratory function abnormalities are summarised in Box 19.4.

19.4 How to interpret respiratory function abnormalities

	Asthma	Chronic bronchitis	Emphysema	Pulmonary fibrosis
FEV₁	↓↓	↓↓	↓↓	↓
VC	↓	↓	↓	↓↓
FEV₁/VC	↓	↓	↓	→/↑
TL_CO	→	→	↓↓	↓↓
K_CO	→/↑	→	↓	→/↓
TLC	→/↑	↑	↑↑	↓
RV	→/↑	↑	↑↑	↓

(RV = residual volume; see text for other abbreviations)

Arterial blood gases and oximetry

The measurement of hydrogen ion concentration, PaO₂ and PaCO₂, and derived bicarbonate concentration in an arterial blood sample is essential to assess the degree and type of respiratory failure, and for measuring acid–base status. This is discussed in detail on pages 663 and 442. Interpretation of results is made easier by blood gas diagrams (Fig. 19.8), which indicate whether any acidosis or alkalosis is due to acute or chronic respiratory derangements of PaCO₂, or to metabolic causes. Pulse oximeters with finger or ear probes measure the difference in absorbance of light by oxygenated and deoxygenated blood to calculate its oxygen saturation (SaO₂). This allows non-invasive continuous assessment of oxygen saturation in patients, which is useful in assessing hypoxaemia and its response to therapy.

Fig. 19.8 Changes in blood [H⁺], PaCO₂ and plasma [HCO₃⁻] in acid–base disorders.
The rectangle indicates normal limits for [H⁺] and PaCO₂. The bands represent 95% confidence limits of single disturbances in human blood. To determine the likely cause of an acid–base disorder, plot the values of [H⁺] and PaCO₂ from an arterial blood gas measurement._. The diagram indicates whether any acidosis or alkalosis results primarily from a respiratory disorder of PaCO₂ or from a metabolic derangement. Adapted from Flenley 1971 – see p. 732.

Exercise tests

Resting measurements may be unhelpful in early disease or in patients complaining only of exercise-induced symptoms. Exercise testing with spirometry before and after can help demonstrate exercise-induced asthma. Walk tests include the self-paced 6-minute walk and the externally paced incremental ‘shuttle’ test, where patients walk at increasing pace between two cones 10 m apart. These provide simple, repeatable assessments of disability and response to treatment. Cardiopulmonary bicycle exercise testing, with measurement of metabolic gas exchange, ventilation and ECG changes, is useful for quantifying exercise limitation and detecting occult cardiovascular or respiratory limitation in a breathless patient.

Presenting problems in respiratory disease

Cough

Cough is the most frequent symptom of respiratory disease and is caused by stimulation of sensory nerves in the mucosa of the pharynx, larynx, trachea and bronchi. Acute sensitisation of the normal cough reflex occurs in a number of conditions, and it is typically induced by changes in air temperature or exposure to irritants, such as cigarette smoke or perfumes. The characteristics of cough originating at various levels of the respiratory tract are detailed in Box 19.5.

19.5 Cough

Origin	Common causes	Clinical features
Pharynx	Post-nasal drip	History of chronic rhinitis
Larynx	Laryngitis, tumour, whooping cough, croup	Voice or swallowing altered, harsh or painful cough Paroxysms of cough, often associated with stridor
Trachea	Tracheitis	Raw retrosternal pain with cough
Bronchi	Bronchitis (acute) and COPD	Dry or productive, worse in mornings
	Asthma	Usually dry, worse at night
	Eosinophilic bronchitis	Features similar to asthma but AHR absent
	Bronchial carcinoma	Persistent (often with haemoptysis)
Lung parenchyma	Tuberculosis	Productive (often with haemoptysis)
	Pneumonia Bronchiectasis	Dry initially, productive later Productive, changes in posture induce sputum production
	Pulmonary oedema	Often at night (may be productive of pink, frothy sputum)
	Interstitial fibrosis	Dry and distressing
Drug side-effect	ACE inhibitors	Dry cough

(ACE = angiotensin-converting enzyme; AHR = airway hyper-reactivity; COPD = chronic obstructive pulmonary disease)

Based on Crompton GK. The respiratory system. In: Munro JF, Campbell IW. Macleod’s clinical examination. 10th edn. Edinburgh: Churchill Livingstone; 2000 (p. 119); copyright Elsevier.

The explosive quality of a normal cough is lost in patients with respiratory muscle paralysis or vocal cord palsy. Paralysis of a single vocal cord gives rise to a prolonged, low-pitched, inefficient ‘bovine’ cough accompanied by hoarseness. Coexistence of an inspiratory noise (stridor) indicates partial obstruction of a major airway (e.g. laryngeal oedema, tracheal tumour, scarring, compression or inhaled foreign body) and requires urgent investigation and treatment. Sputum production is common in patients with acute or chronic cough, and its nature and appearance can provide clues to the aetiology (p. 644).

Causes of cough

Acute transient cough is most commonly caused by viral lower respiratory tract infection, post-nasal drip resulting from rhinitis or sinusitis, aspiration of a foreign body, or throat-clearing secondary to laryngitis or pharyngitis. When cough occurs in the context of more serious diseases, such as pneumonia, aspiration, congestive heart failure or pulmonary embolism, it is usually easy to diagnose from other clinical features.

Patients with chronic cough present more of a challenge, especially when physical examination, chest X-ray and lung function studies are normal. In this context, it is most often explained by cough-variant asthma (where cough may be the principal or exclusive clinical manifestation), post-nasal drip secondary to nasal or sinus disease, or gastro-oesophageal reflux with aspiration. Diagnosis of the latter may require ambulatory oesophageal pH monitoring or a prolonged trial of anti-reflux therapy (p. 865). Between 10% and 15% of patients (particularly women) taking angiotensin-converting enzyme (ACE) inhibitors develop a drug-induced chronic cough. Bordetella pertussis infection in adults (p. 682) can also result in protracted cough and should be suspected in those in close contact with children. While most patients with a bronchogenic carcinoma have an abnormal chest X-ray on presentation, fibreoptic bronchoscopy or thoracic CT is advisable in most adults (especially smokers) with otherwise unexplained cough of recent onset, as this may reveal a small endobronchial tumour or unexpected foreign body (Fig. 19.9). In a small percentage of patients, dry cough may be the presenting feature of interstitial lung disease.

Fig. 19.9 Inhaled foreign body.
A Chest X-ray showing a tooth lodged in a main bronchus. B Bronchoscopic appearance of inhaled foreign body (tooth) with a covering mucous film.

Breathlessness

Breathlessness or dyspnoea can be defined as the feeling of an uncomfortable need to breathe. It is unusual among sensations, as it has no defined receptors, no localised representation in the brain, and multiple causes both in health (e.g. exercise) and in diseases of the lungs, heart or muscles.

Pathophysiology

Stimuli to breathing resulting from disease processes are shown in Figure 19.10. Respiratory diseases can stimulate breathing and dyspnoea by:

• stimulating intrapulmonary sensory nerves (e.g. pneumothorax, interstitial inflammation and pulmonary embolus)

• increasing the mechanical load on the respiratory muscles (e.g. airflow obstruction or pulmonary fibrosis)

• causing hypoxia, hypercapnia or acidosis, which stimulate chemoreceptors.

In cardiac failure, pulmonary congestion reduces lung compliance and can also obstruct the small airways. Reduced cardiac output also limits oxygen supply to the skeletal muscles during exercise, causing early lactic acidaemia and further stimulating breathing via the central chemoreceptors.

Breathlessness and the effects of treatment can be quantified using a symptom scale. Patients tend to report breathlessness in proportion to the sum of the above stimuli to breathe. Individual patients differ greatly in the intensity of breathlessness reported for a given set of circumstances, but breathlessness scores during exercise within individuals are reproducible, and can be used to monitor the effects of therapy.

Differential diagnosis

Patients with breathlessness present either with chronic exertional symptoms or as an emergency with acute breathlessness, when symptoms are prominent even at rest. The causes can be classified accordingly (Box 19.6).

19.6 Causes of breathlessness

System	Acute dyspnoea	Chronic exertional dyspnoea
Cardiovascular	*Acute pulmonary oedema (p. 543)	Chronic heart failure (p. 543) Myocardial ischaemia (angina equivalent) (p. 544)
Respiratory	Acute severe asthma Acute exacerbation of COPD Pneumothorax Pneumonia *Pulmonary embolus ARDS Inhaled foreign body (especially in children) Lobar collapse Laryngeal oedema (e.g. anaphylaxis)	COPD Chronic asthma Bronchial carcinoma Interstitial lung disease (sarcoidosis, fibrosing alveolitis, extrinsic allergic alveolitis, pneumoconiosis) Chronic pulmonary thromboembolism Lymphatic carcinomatosis (may cause intolerable breathlessness) Large pleural effusion(s)
Others	Metabolic acidosis (e.g. diabetic ketoacidosis, lactic acidosis, uraemia, overdose of salicylates, ethylene glycol poisoning) Psychogenic hyperventilation (anxiety or panic-related)	Severe anaemia Obesity Deconditioning

^*Denotes a common cause. (ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease)

Chronic exertional breathlessness

The cause of breathlessness is often apparent from a careful clinical history. Key questions include:

How is your breathing at rest and overnight?

In COPD, there is a fixed, structural limit to maximum ventilation, and a tendency for progressive hyperinflation during exercise. Breathlessness is mainly apparent when walking, and patients usually report minimal symptoms at rest and overnight. In contrast, patients with significant asthma are often woken from their sleep by breathlessness with chest tightness and wheeze.

Orthopnoea, however, is common in COPD, as well as in heart disease, because airflow obstruction is made worse by cranial displacement of the diaphragm by the abdominal contents when recumbent, so many patients choose to sleep propped up. It may thus not be a useful differentiating symptom, unless there is a clear history of previous angina or infarction to suggest cardiac disease.

How much can you do on a good day?

Noting ‘breathless on exertion’ is not enough; the approximate distance the patient can walk on the level should be documented, along with capacity to climb inclines or stairs. Variability within and between days is a hallmark of asthma; in mild asthma, the patient may be free of symptoms and signs when well. Gradual, progressive loss of exercise capacity over months and years, with consistent disability over days, is typical of COPD. When asthma is suspected, the degree of variability is best documented by home peak flow monitoring.

Relentless, progressive breathlessness that is also present at rest, often accompanied by a dry cough, suggests interstitial fibrosis. Impaired left ventricular function can also cause chronic exertional breathlessness, cough and wheeze. A history of angina, hypertension or myocardial infarction raises the possibility of a cardiac cause. This may be confirmed by a displaced apex beat, a raised JVP and cardiac murmurs (although these signs can occur in severe cor pulmonale). The chest X-ray may show cardiomegaly, and an electrocardiogram (ECG) and echocardiogram may provide evidence of left ventricular disease. Measurement of arterial blood gases may help, as, in the absence of an intracardiac shunt or pulmonary oedema, the PaO₂ in cardiac disease is normal and the PaCO₂ is low or normal.

Did you have breathing problems in childhood or at school?

When present, a history of childhood wheeze increases the likelihood of asthma, although this history may be absent in late-onset asthma. A history of atopic allergy also increases the likelihood of asthma.

Do you have other symptoms along with your breathlessness?

Digital or perioral paraesthesiae and a feeling that ‘I cannot get a deep enough breath in’ are typical features of psychogenic hyperventilation, but this cannot be diagnosed until investigations have excluded other potential causes. Additional symptoms include lightheadedness, central chest discomfort or even carpopedal spasm due to acute respiratory alkalosis. These alarming symptoms may provoke further anxiety and exacerbate hyperventilation. Psychogenic breathlessness rarely disturbs sleep, frequently occurs at rest, may be provoked by stressful situations and may even be relieved by exercise. The Nijmegen questionnaire can be used to score some of the typical symptoms of hyperventilation (Box 19.7). Arterial blood gases show normal PO₂, low PCO₂ and alkalosis.

19.7 Factors suggesting psychogenic hyperventilation

• ‘Inability to take a deep breath’

• Frequent sighing/erratic ventilation at rest

• Short breath-holding time in the absence of severe respiratory disease

• Difficulty in performing and/or inconsistent spirometry measures

• High score (over 26) on Nijmegen questionnaire

• Induction of symptoms during submaximal hyperventilation

• Resting end-tidal CO₂ < 4.5%

• Associated digital paraesthesiae

Pleuritic chest pain in a patient with chronic breathlessness, particularly if it occurs in more than one site over time, should raise suspicion of thromboembolic disease. Thromboembolism may occasionally present as chronic breathlessness with no other specific features, and should always be considered before a diagnosis of psychogenic hyperventilation is made.

Morning headache is an important symptom in patients with breathlessness, as it may signal the onset of carbon dioxide retention and respiratory failure. This is particularly significant in patients with musculoskeletal disease impairing respiratory function (e.g. kyphoscoliosis or muscular dystrophy).

Acute severe breathlessness

This is one of the most common and dramatic medical emergencies. The history and a rapid but careful examination will usually suggest a diagnosis which can be confirmed by routine investigations, including chest X-ray, ECG and arterial blood gases. Specific features that aid the diagnosis of the important causes are shown in Box 19.8.

19.8 Differential diagnosis of acute breathlessness

Condition	History	Signs	CXR	ABG	ECG
Pulmonary oedema	Chest pain, palpitations, orthopnoea, cardiac history*	Central cyanosis, ↑JVP, sweating, cool extremities, basal crackles*	Cardiomegaly, oedema/pleural effusions*	↓PaO₂ ↓PaCO₂	Sinus tachycardia, ischaemia*, arrhythmia
Massive pulmonary embolus	Risk factors, chest pain, pleurisy, syncope, dizziness	Central cyanosis, ↑JVP, absence of signs in the lung, shock (tachycardia, hypotension)	Often normal Prominent hilar vessels, oligaemic lung fields*	↓PaO₂ ↓PaCO₂	Sinus tachycardia, RBBB, S₁Q₃T₃ pattern ↑T(V₁–V₄)
Acute severe asthma	History of asthma, asthma medications, wheeze*	Tachycardia, pulsus paradoxus, cyanosis (late), JVP →, ↓peak flow, wheeze	Hyperinflation only (unless complicated by pneumothorax)*	↓PaO₂ ↓PaCO₂ (↑PaCO₂ in extremis)	Sinus tachycardia (bradycardia in extremis)
Acute exacerbation of COPD	Previous episodes*, smoker. If in type II respiratory failure, may be drowsy	Cyanosis, hyperinflation, signs of CO₂ retention (flapping tremor, bounding pulses)	Hyperinflation*, bullae, complicating pneumothorax	↓ or ↓↓PaO₂ ↑PaCO₂ in type II failure ± ↑H⁺, ↑HCO₃ in chronic type II failure	Normal, or signs of right ventricular strain
Pneumonia	Prodromal illness, fever, rigors, pleurisy	Fever, confusion, pleural rub, consolidation, cyanosis (if severe)	Pneumonic consolidation*	↓PaO₂ ↓PaCO₂ (↑ in extremis)	Tachycardia
Metabolic acidosis	Evidence of diabetes mellitus or renal disease, aspirin or ethylene glycol overdose	Fetor (ketones), hyperventilation without heart or lung signs, dehydration, air hunger	Normal	PaO₂ normal ↓↓PaCO₂, ↑H⁺
Psychogenic	Previous episodes, digital or perioral dysaesthesia	No cyanosis, no heart or lung signs, carpopedal spasm	Normal	PaO₂ normal* ↓↓PaCO₂, ↓H⁺*