The nose, pharynx and larynx

See Chapter 21 (p. 1052).

The trachea, bronchi and bronchioles

The trachea is 10–12 cm in length. It lies slightly to the right of the midline and divides at the carina into right and left main bronchi. The carina lies under the junction of the manubrium sterni and the second right costal cartilage. The right main bronchus is more vertical than the left and, hence, inhaled material is more likely to end up in the right lung.

The right main bronchus divides into the upper lobe bronchus and the intermediate bronchus, which further subdivides into the middle and lower lobe bronchi. On the left the main bronchus divides into upper and lower lobe bronchi only. Each lobar bronchus further divides into segmental and subsegmental bronchi. There are about 25 divisions in all between the trachea and the alveoli.

The first seven divisions are bronchi that have:

The next 16–18 divisions are bronchioles that have:

The ciliated epithelium is a key defence mechanism. Each cell bears approximately 200 cilia beating at 1000 beats per minute in organized waves of contraction. Each cilium consists of nine peripheral parts and two inner longitudinal fibrils in a cytoplasmic matrix (Fig. 15.1). Nexin links join the peripheral pairs. Dynein arms consisting of ATPase protein project towards the adjacent pairs. Bending of the cilia results from a sliding movement between adjacent fibrils powered by an ATP-dependent shearing force developed by the dynein arms (see also p. 22). Absence of dynein arms leads to immotile cilia. Mucus, which contains macrophages, cell debris, inhaled particles and bacteria, is moved by the cilia towards the larynx at about 1.5 cm/min (the ‘mucociliary escalator’, see below).

Figure 15.1 Cross-section of a cilium. Nine outer microtubular doublets and two central single microtubules are linked by spokes, nexin links and dynein arms.

The bronchioles finally divide within the acinus into smaller respiratory bronchioles that have alveoli arising from the surface (Fig. 15.2). Each respiratory bronchiole supplies approximately 200 alveoli via alveolar ducts. The term ‘small airways’ refers to bronchioles of <2 mm; the average lung contains about 30 000 of these.

Figure 15.2 Branches of a terminal bronchiole ending in the alveolar sacs.

The alveoli

There are approximately 300 million alveoli in each lung. Their total surface area is 40–80 m². The epithelial lining consists mainly of type I pneumocytes (Fig. 15.3). These cells have an extremely thin layer of cytoplasm, which only offers a thin barrier to gas exchange. Type I cells are connected to each other by tight junctions that limit the movements of fluid in and out of the alveoli. Alveoli are not completely airtight – many have holes in the alveolar wall allowing communication between alveoli of adjoining lobules (pores of Kohn).

Figure 15.3 The structure of alveoli, showing the pneumocytes and capillaries.

Type II pneumocytes are slightly more numerous than type I cells but cover less of the epithelial lining. They are found generally in the borders of the alveolus and contain distinctive lamellar vacuoles, which are the source of surfactant. Type I pneumocytes are derived from type II cells. Large alveolar macrophages are present within the alveoli and assist in defending the lung.

The lungs

The lungs are separated into lobes by invaginations of the pleura, which are often incomplete. The right lung has three lobes, whereas the left lung has two. The positions of the oblique fissures and the right horizontal fissure are shown in Figure 15.4. The upper lobe lies mainly in front of the lower lobe and therefore physical signs on the right side in the front of the chest are due to lesions of the upper lobe or the middle lobe.

Figure 15.4 Surface anatomy of the chest.

Each lobe is further subdivided into bronchopulmonary segments by fibrous septa that extend inwards from the pleural surface. Each segment receives its own segmental bronchus.

The bronchopulmonary segment is further divided into individual lobules approximately 1 cm in diameter and generally pyramidal in shape, the apex lying towards the bronchiole that supplies it. Within each lobule a terminal bronchus supplies an acinus, and within this structure further divisions of the bronchioles eventually give rise to the alveoli.

The pleura

The pleura is a layer of connective tissue covered by a simple squamous epithelium. The visceral pleura covers the surface of the lung, lines the interlobar fissures, and is continuous at the hilum with the parietal pleura, which lines the inside of the hemithorax. At the hilum the visceral pleura continues alongside the branching bronchial tree for some distance before reflecting back to join the parietal pleura. In health, the pleurae are in apposition apart from a small quantity of lubricating fluid.

The diaphragm

The diaphragm is covered by parietal pleura above and peritoneum below. Its muscle fibres arise from the lower ribs and insert into the central tendon. Motor and sensory nerve fibres go separately to each half of the diaphragm via the phrenic nerves. Fifty per cent of the muscle fibres are of the slow-twitch type with a low glycolytic capacity; they are relatively resistant to fatigue.

Pulmonary vasculature and lymphatics

The lung has a dual blood supply, receiving deoxygenated blood from the right ventricle via the pulmonary artery and oxygenated blood via the bronchial circulation.

The pulmonary artery divides to accompany the bronchi. The arterioles accompanying the respiratory bronchioles are thin-walled and contain little smooth muscle. The pulmonary venules drain laterally to the periphery of the lobules, pass centrally in the interlobular and intersegmental septa, and eventually join to form the four main pulmonary veins.

The bronchial circulation arises from the descending aorta. These bronchial arteries supply tissues down to the level of the respiratory bronchiole. The bronchial veins drain into the pulmonary vein, forming part of the normal physiological shunt.

Lymphatic channels lie in the interstitial space between the alveolar cells and the capillary endothelium of the pulmonary arterioles.

The tracheobronchial lymph nodes are arranged in five main groups: pulmonary, bronchopulmonary, subcarinal, superior tracheobronchial and paratracheal. For all practical purposes these form a continuous network of nodes from the lung substance up to the trachea.

Nerve supply to the lung

The innervation of the lung remains incompletely understood. Parasympathetic and sympathetic fibres (from the vagus and sympathetic chain respectively) accompany the pulmonary arteries and the airways. Airway smooth muscle is innervated by vagal afferents, postganglionic muscarinic vagal efferents and vagally derived non-adrenergic non-cholinergic (NANC) fibres which use a range of neurotransmitters including substance P, neurokinins A and B, calcitonin gene-related peptide, vasoactive intestinal polypeptide and various adenine and guanine phosphates. Three muscarinic receptor subtypes have been identified: M₁ receptors on parasympathetic ganglia, a smaller number of M₂ receptors on muscarinic nerve terminals, and M₃ receptors on airway smooth muscle. The parietal pleura is innervated from intercostal and phrenic nerves but the visceral pleura has no innervation.

The nose

The major functions of nasal breathing are:

About 10 000 L of air are inhaled daily. The relatively low flow rates and turbulence of inspired air in the nose mean that few particles greater than 10 microns (µm) diameter pass through the nose. Particles deposited on the nasal mucosa are removed within 15 minutes, compared with 60–120 days for particles that reach the alveoli. Nasal secretion contains IgA antibodies, lysozyme and interferons. In addition, the cilia of the nasal epithelium move the mucous gel layer rapidly back to the oropharynx where it is swallowed. Bacteria have little chance of settling in the nose. Mucociliary protection is less effective against viral infections because viruses bind to receptors on epithelial cells. The majority of rhinoviruses bind to an adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), which is shared by neutrophils and eosinophils. Many noxious gases, such as SO₂, are almost completely removed by nasal breathing.

Breathing

Lung ventilation can be considered in two parts:

Mechanical process

The lungs have an inherent elastic property that causes them to tend to collapse away from the thoracic wall, generating a negative pressure within the pleural space. The strength of this retractive force relates to the volume of the lung: at higher lung volumes the lung is stretched more, and a greater negative intrapleural pressure is generated. Lung compliance is a measure of the relationship between this retractive force and lung volume. At the end of a quiet expiration, the retractive force exerted by the lungs is balanced by the tendency of the thoracic wall to spring outwards. At this point, respiratory muscles are resting. The volume of air remaining in the lung after a quiet expiration is called the functional residual capacity (FRC).

Inspiration from FRC is an active process: a negative intrapleural pressure is created by descent of the diaphragm and movement of the ribs upwards and outwards through contraction of the intercostal muscles. During tidal breathing in healthy individuals, inspiration is almost entirely due to contraction of the diaphragm. More vigorous inspiration requires the use of accessory muscles of ventilation (sternomastoid and scalene muscles). Respiratory muscles are similar to other skeletal muscles but are less prone to fatigue. However, inspiratory muscle fatigue contributes to respiratory failure in patients with severe chronic airflow limitation and in those with primary neurological and muscle disorders.

At rest or during low-level exercise, expiration is passive and results from the natural tendency of the lung to collapse.

Forced expiration involves activation of accessory muscles, chiefly those of the abdominal wall, which help to push up the diaphragm.

The control of respiration

Coordinated respiratory movements result from rhythmical discharges arising in an anatomically ill-defined group of interconnected neurones in the reticular substance of the brainstem, known as the respiratory centre. Motor discharges from the respiratory centre travel via the phrenic and intercostal nerves to the respiratory musculature.

In healthy individuals, the main driver for respiration is the arterial pH, which is closely related to the partial pressure of carbon dioxide in arterial blood. Oxygen levels in arterial blood are usually above the level which triggers respiratory drive. In a typical normal adult at rest:

The pulmonary blood flow of 5 L/min carries 11 mmol/min (250 mL/min) of oxygen from the lungs to the tissues.

Ventilation at about 6 L/min carries 9 mmol/min (200 mL/min) of carbon dioxide out of the body.

The normal pressure of oxygen in arterial blood (P_aO₂) is between 11 and 13 kPa.

The normal pressure of carbon dioxide in arterial blood (P_aCO₂) is 4.8–6.0 kPa.

Ventilation is controlled by a combination of neurogenic and chemical factors (Fig. 15.5).

Figure 15.5 Chemical and neurogenic factors in the control of ventilation. The strongest stimulant to ventilation is a rise in P_aCO₂ which increases [H⁺] in CSF. Sensitivity to this may be lost in COPD. In these patients hypoxaemia is the chief stimulus to respiratory drive; oxygen treatment may therefore reduce respiratory drive and lead to a further rise in P_aCO₂. An increase in [H⁺] due to metabolic acidosis as in diabetic ketoacidosis will increase ventilation with a fall in P_aCO₂ causing deep sighing (Kussmaul) respiration. The respiratory centre is depressed by severe hypoxaemia and sedatives (e.g. opiates) and stimulated by doxapram, large doses of aspirin and pyrexia. COPD, chronic obstructive pulmonary disease.

Breathlessness on physical exertion is normal and not considered a symptom unless the level of exertion is very light, such as when walking slowly. Surveys of healthy western populations reveal that over 20% of the general population report themselves as breathless on relatively minor exertion. Although breathlessness is a very common symptom, the sensory and neural mechanisms underlying it remain obscure. The sensation of breathlessness is derived from at least three sources:

Changes in lung volume. These are sensed by receptors in thoracic wall muscles signalling changes in their length.

Tension developed by contracting muscles. This is sensed by Golgi tendon organs.

Central perception of the sense of effort.

The airways of the lungs

From the trachea to the periphery, the airways decrease in size but increase in number. Overall, the cross-sectional area available for airflow increases as the total number of airways increases. The airflow rate is greatest in the trachea and slows progressively towards the periphery (since the velocity of airflow depends on the cross-sectional area). In the terminal airways, gas flow occurs solely by diffusion. The resistance to airflow is very low (0.1–0.2 kPa/L in a normal tracheobronchial tree), steadily increasing from the small to the large airways.

Airways expand as the lung volume increases. At full inspiration (total lung capacity, TLC) they are 30–40% larger in calibre than at full expiration (residual volume, RV). In chronic obstructive pulmonary disease (COPD), the small airways are narrowed but this can be partially compensated by breathing closer to TLC.

Control of airway tone

Bronchomotor tone is maintained by vagal efferent nerves and can be reduced by atropine or β-adrenoceptor agonists. Adrenoceptors on the surface of bronchial muscles respond to circulating catecholamines – there is no direct sympathetic innervation. Airway tone shows a circadian rhythm, which is greatest at 04.00 and lowest in the mid-afternoon. Tone can be increased transiently by inhaled stimuli acting on epithelial nerve endings, which trigger reflex bronchoconstriction via the vagus. These stimuli include cigarette smoke, solvents, inert dust and cold air. Airway responsiveness to these stimuli increases following respiratory tract infections even in healthy subjects. In asthma, the airways are very irritable and as the circadian rhythm remains the same, asthmatic symptoms are usually worse in the early morning.

Airflow

Movement of air through the airways results from a difference between atmospheric pressure and the pressure in the alveoli; alveolar pressure is negative in inspiration and positive in expiration. During quiet breathing, the pleural pressure is negative throughout the breathing cycle. With vigorous expiratory efforts (e.g. cough), the pleural pressure becomes positive (up to 10 kPa). This compresses the central airways, but the smaller airways do not close off because the driving pressure for expiratory flow (alveolar pressure) is also increased.

Alveolar pressure (P_ALV) is equal to the pleural pressure (P_PL) plus the elastic recoil pressure (P_el) of the lung.

When there is no airflow (i.e. during a pause in breathing), the tendency of the lungs to collapse (the positive recoil pressure) is exactly balanced by an equivalent negative pleural pressure.

As air flows from the alveoli towards the mouth there is a gradual drop of pressure owing to flow resistance (Fig. 15.6a).

Figure 15.6 Diagrams showing ventilatory forces. (a) During resting at functional residual capacity. (b) During forced expiration in normal subjects. (c) During forced expiration in a patient with COPD. The respiratory system is represented as a piston with a single alveolus and the collapsible part of the airways within the piston (see text). C, collapse point; P_ALV, alveolar pressure; P_EL, elastic recoil pressure; P_PL, pleural pressure.

In forced expiration, as mentioned above, the driving pressure raises both the alveolar pressure and the intrapleural pressure. Between the alveolus and the mouth, there is a point (C in Fig. 15.6b) where the airway pressure equals the intrapleural pressure, and the airway collapses. However, this collapse is temporary, as the transient occlusion of the airway results in an increase in pressure behind it (i.e. upstream) and this raises the intra-airway pressure so that the airways open and flow is restored. The airways thus tend to vibrate at this point of ‘dynamic collapse’.

As lung volume decreases during expiration, the elastic recoil pressure of the lungs decreases and the ‘collapse point’ moves upstream (i.e. towards the smaller airways – see Fig. 15.6c). Where there is pathological loss of recoil pressure (as in chronic obstructive pulmonary disease, COPD), the ‘collapse point’ is located even further upstream and causes expiratory flow limitation. The measurement of the forced expiratory volume in 1 second (FEV₁) is a useful clinical index of this phenomenon. To compensate, patients with COPD often ‘purse their lips’ in order to increase airway pressure so that their peripheral airways do not collapse. During inspiration, the intrapleural pressure is always less than the intraluminal pressure within the intrathoracic airways, so increasing effort does not limit airflow. Inspiratory flow is limited only by the power of the inspiratory muscles.

Flow-volume loops

The relationship between maximal flow rates and lung volume is demonstrated by the maximal flow-volume (MFV) loop (Fig. 15.7a).

Figure 15.7 (a, b) Maximal flow-volume loops, showing the relationship between maximal flow rates on expiration and inspiration. (a) In a normal subject. (b) In a patient with severe airflow limitation. Flow-volume loops during tidal breathing at rest (starting from the functional residual capacity (FRC)) and during exercise are also shown. The highest flow rates are achieved when forced expiration begins at total lung capacity (TLC) and represent the peak expiratory flow rate (PEFR). As air is blown out of the lung, so the flow rate decreases until no more air can be forced out, a point known as the residual volume (RV). Because inspiratory airflow is only dependent on effort, the shape of the maximal inspiratory flow-volume loop is quite different, and inspiratory flow remains at a high rate throughout the manoeuvre. (c, d) Flow-volume loops of patients with large airway (tracheal) obstruction, showing plateauing of maximal expiratory flow. (c) Extrathoracic tracheal obstruction with a proportionally greater reduction of maximal inspiratory (as opposed to expiratory) flow rate. (d) Intrathoracic large airway obstruction; the expiratory plateau is more pronounced and inspiratory flow rate is less reduced than in (c). In severe airflow limitation the ventilatory demands of exercise cannot be met (cf. a, b), greatly reducing effort tolerance.

In subjects with healthy lungs, maximal flow rates are rarely achieved even during vigorous exercise. However, in patients with severe COPD, limitation of expiratory flow occurs even during tidal breathing at rest (Fig. 15.7b). To increase ventilation these patients have to breathe at higher lung volumes and allow more time for expiration, both of which reduce the tendency for airway collapse. To compensate they increase flow rates during inspiration, where there is relatively less flow limitation.

The volume that can be forced in from the residual volume in 1 second (FIV₁) will always be greater than that which can be forced out from TLC in 1 second (FEV₁). Thus, the ratio of FEV₁ to FIV₁ is below 1. The only exception to this occurs when there is significant obstruction to the airways outside the thorax, such as tracheal tumour or retrosternal goitre. Expiratory airway narrowing is prevented by tracheal resistance and expiratory airflow becomes more effort-dependent. During forced inspiration this same resistance causes such negative intraluminal pressure that the trachea is compressed by the surrounding atmospheric pressure. Inspiratory flow thus becomes less effort-dependent, and the ratio of FEV₁ to FIV₁ exceeds 1. This phenomenon, and the characteristic flow-volume loop, is diagnostic of extrathoracic airways obstruction (Fig. 15.7c).

Ventilation and perfusion relationships

For optimum gas exchange there must be a match between ventilation of the alveoli () and their perfusion (). However, in reality there is variation in the () ratio in both normal and diseased lungs (Fig. 15.8). In the normal lung both ventilation and perfusion are greater at the bases than at the apices, but the gradient for perfusion is steeper, so the net effect is that ventilation exceeds perfusion towards the apices, while perfusion exceeds ventilation at the bases. Other causes of () mismatch include direct shunting of deoxygenated blood through the lung without passing through alveoli (e.g. the bronchial circulation) and areas of lung that receive no blood (e.g. anatomical deadspace, bullae and areas of underperfusion during acceleration and deceleration, e.g. in aircraft and high performance cars).

Figure 15.8 Relationships between ventilation and perfusion: a schematic diagram showing the alveolar–capillary interface. The centre (b) shows normal ventilation and perfusion. On the left (a) there is a block in perfusion (physiological deadspace), while on the right (c) there is reduced ventilation (physiological shunting).

An increased physiological shunt results in arterial hypoxaemia since it is not possible to compensate for some of the blood being underoxygenated by increasing ventilation of the well-perfused areas. An increased physiological deadspace just increases the work of breathing and has less impact on blood gases since the normally perfused alveoli are well ventilated. In more advanced disease this compensation cannot occur, leading to increased alveolar and arterial PCO₂ (P_aCO₂), together with hypoxaemia which cannot be compensated by increasing ventilation.

Hypoxaemia occurs more readily than hypercapnia because of the different ways in which oxygen and carbon dioxide are carried in the blood. Carbon dioxide can be considered to be in simple solution in the plasma, the volume carried being proportional to the partial pressure. Oxygen is carried in chemical combination with haemoglobin in the red blood cells, with a non-linear relationship between the volume carried and the partial pressure (Fig. 15.5, p. 341). Alveolar hyperventilation reduces the alveolar PCO₂ (P_ACO₂) and diffusion leads to a proportional fall in the carbon dioxide content of the blood (P_aCO₂). However, as the haemoglobin is already saturated with oxygen, there is no significant increase in the blood oxygen content as a result of increasing the alveolar PO₂ through hyperventilation. The hypoxaemia of even a small amount of physiological shunting cannot therefore be compensated for by hyperventilation.

In individuals who have mild degrees of mismatch, the P_aO₂ and P_aCO₂ will still be normal at rest. Increasing the requirements for gas exchange by exercise will widen the mismatch and the P_aO₂ will fall. mismatch is by far the most common cause of arterial hypoxaemia.

Alveolar stability

Pulmonary alveoli are essentially hollow spheres. Surface tension acting at the curved internal surface tends to cause the sphere to decrease in size. The surface tension within the alveoli would make the lungs extremely difficult to distend were it not for the presence of surfactant, an insoluble lipoprotein largely consisting of dipalmitoyl lecithin, which forms a thin monomolecular layer at the air-fluid interface. Surfactant is secreted by type II pneumocytes within the alveolus and reduces surface tension so that alveoli remain stable.

Fluid surfaces covered with surfactant exhibit a phenomenon known as hysteresis; that is, the surface-tension-lowering effect of the surfactant can be improved by a transient increase in the size of the surface area of the alveoli. During quiet breathing, small areas of the lung undergo collapse, but it is possible to re-expand these rapidly by a deep breath; hence the importance of sighs or deep breaths as a feature of normal breathing. Failure of this mechanism, e.g. in patients with fractured ribs – gives rise to patchy basal lung collapse. Surfactant levels may be reduced in a number of diseases that cause damage to the lung (e.g. pneumonia). Lack of surfactant plays a central role in the respiratory distress syndrome of the newborn. Severe reduction in perfusion of the lung impairs surfactant activity and this may explain the characteristic areas of collapse associated with pulmonary embolism.

Physical and physiological mechanisms

Humoral and cellular mechanisms

Runny, blocked nose and sneezing

Nasal symptoms (see also p. 691) are extremely common and both common colds and allergic rhinitis cause ‘runny nose’ (rhinorrhoea), nasal blockage and attacks of sneezing. In allergic rhinitis, symptoms may be intermittent, following contact with pollens or animal danders, or persistent, especially when house-dust mite is the allergen. Colds are frequent during the winter but if the symptoms persist for weeks the patient probably has perennial rhinitis rather than persistent viral infection.

Nasal secretions are usually thin and runny in allergic rhinitis but thicker and discoloured with viral infections. Nose bleeds and blood-stained nasal discharge are common and rarely indicate serious pathology. However, a blood-stained nasal discharge associated with nasal obstruction and pain may be the presenting feature of a nasal tumour (p. 1051). Nasal polyps typically present with nasal blockage and loss of smell.

Cough

Cough (see also p. 822) is the commonest symptom of lower respiratory tract disease. It is caused by mechanical or chemical stimulation of cough receptors in the epithelium of the pharynx, larynx, trachea, bronchi and diaphragm. Afferent receptors go to the cough centre in the medulla where efferent signals are generated to the expiratory musculature. Smokers often have a morning cough with a little sputum. A productive cough is the cardinal feature of chronic bronchitis, while dry coughing, particularly at night, can be a symptom of asthma. Cough also occurs in asthmatics after mild exertion or following forced expiration. Cough can also occur for psychological reasons without any definable pathology.

A worsening cough is the most common presenting symptom of lung cancer. The normal explosive character of the cough is lost when a vocal cord is paralysed, usually as a result of lung cancer infiltrating the left recurrent laryngeal nerve – sometimes termed a bovine cough. Cough can be accompanied by stridor in whooping cough or if there is laryngeal or tracheal obstruction.

Sputum

Approximately 100 mL of mucus is produced daily in a healthy, non-smoking individual. This flows gradually up the airways, through the larynx, and is then swallowed. Excess mucus is expectorated as sputum. Cigarette smoking is the commonest cause of excess mucus production.

Mucoid sputum is clear and white but can contain black specks resulting from the inhalation of carbon. Yellow or green sputum is due to the presence of cellular material, including bronchial epithelial cells, or neutrophil or eosinophil granulocytes. Yellow sputum is not necessarily due to infection, as eosinophils in the sputum, as seen in asthma, can give the same appearance. The production of large quantities of yellow or green sputum is characteristic of bronchiectasis.

Haemoptysis (blood-stained sputum) varies from small streaks of blood to massive bleeding.

Haemoptysis should always be investigated. Although a diagnosis can often be made from a chest X-ray, a normal chest X-ray does not exclude disease. However, if the chest X-ray is normal, CT scanning and bronchoscopy are only diagnostic in about 5% of patients with haemoptysis.

Firm plugs of sputum may be coughed up by patients suffering from an exacerbation of allergic bronchopulmonary aspergillosis. Sometimes such sputum looks like casts of inflamed bronchi.

Breathlessness

Dyspnoea is a sense of awareness of increased respiratory effort that is unpleasant and that is recognized by the patient as being inappropriate. Patients often complain of tightness in the chest; this must be differentiated from angina.

Breathlessness should be assessed in relation to the patient’s lifestyle. For example, a moderate degree of breathlessness will be totally disabling if the patient has to climb many flights of stairs to reach home.

Orthopnoea (see p. 675) is breathlessness on lying down. While it is classically linked to heart failure, it is partly due to the weight of the abdominal contents pushing the diaphragm up into the thorax. Such patients may also become breathless on bending over.

Tachypnoea and hyperpnoea are, respectively, an increased rate of breathing and an increased level of ventilation. These may be appropriate responses (e.g. during exercise).

Hyperventilation is inappropriate overbreathing. This may occur at rest or on exertion and results in a lowering of the alveolar and arterial PCO₂ (see p. 1178).

Paroxysmal nocturnal dyspnoea (see p. 798) is acute episodes of breathlessness at night, typically due to heart failure.

Wheezing

Wheezing is a common complaint and results from airflow limitation due to any cause. The symptom of wheezing is not diagnostic of asthma; other causes include vocal chord dysfunction, bronchiolitis and chronic obstructive pulmonary disease (COPD). Conversely, wheeze may be absent in the early stages of asthma.

Chest pain

The most common type of chest pain reported in respiratory disease is a localized sharp pain, often termed pleuritic. It is made worse by deep breathing or coughing and the patient can usually localize it. Localized anterior chest pain with tenderness of a costochondral junction is caused by costochondritis. Shoulder tip pain suggests irritation of the diaphragmatic pleura, while central chest pain radiating to the neck and arms is likely to be cardiac. Retrosternal soreness is associated with tracheitis, while malignant invasion of the chest wall causes a constant, severe, dull pain.

The nose

(see p. 1051)

The chest

Examination of the chest

Inspection

Assess mental alertness, cyanosis, breathlessness at rest, use of accessory muscles, any deformity or scars on the chest and movement on both sides. CO₂ intoxication causes coarse tremor or flap of the outstretched hands. Prominent veins on the chest may imply obstruction of the superior vena cava.

Cyanosis (see p. 676) is a dusky colour of the skin and mucous membranes, due to the presence of more than 50 g/L of desaturated haemoglobin. When due to central causes, cyanosis is visible on the tongue (especially the underside) and lips. Patients with central cyanosis will also be cyanosed peripherally. Peripheral cyanosis without central cyanosis is caused by a reduced peripheral circulation and is noted on the fingernails and skin of the extremities with associated coolness of the skin.

Finger clubbing is present when the normal angle between the base of the nail and the nail fold is lost. The base of the nail is fluctuant owing to increased vascularity, and there is an increased curvature of the nail in all directions, with expansion of the end of the digit. Some causes of clubbing are given in Table 15.1. Clubbing is not a feature of uncomplicated COPD.

Table 15.1 Some causes of finger clubbing

Respiratory Bronchial carcinoma, especially epidermoid (squamous cell) type (major cause) Chronic suppurative lung disease: Bronchiectasis Lung abscess Empyema Pulmonary fibrosis (e.g. idiopathic lung fibrosis) Pleural and mediastinal tumours (e.g. mesothelioma) Cryptogenic organizing pneumonia Cardiovascular Cyanotic heart disease Subacute infective endocarditis Atrial myxoma Miscellaneous Congenital – no disease Cirrhosis Inflammatory bowel disease

Palpation and percussion

Check the position of the trachea and apex beat. Examine the supraclavicular fossa for enlarged lymph nodes. The distance between the sternal notch and the cricoid cartilage (three to four finger breadths in full expiration) is reduced in patients with severe airflow limitation. Check chest expansion. A tape measure is used if precise or serial measurements are needed, e.g. in ankylosing spondylitis. Local discomfort over the sternochondral joints suggests costochondritis. In rib fractures, compression of the chest laterally and anteroposteriorly produces localized pain. On percussion, liver dullness is usually detected anteriorly at the level of the sixth rib. Liver and cardiac dullness disappear when lungs are over-inflated (Table 15.2).

Table 15.2 Physical signs of respiratory disease

Auscultation

Ask the patient to take deep breaths through the mouth. Inspiration should be more prolonged than expiration. Normal breath sounds are caused by turbulent flow in the larynx and sound harsher anteriorly over the upper lobes (particularly on the right). Healthy lungs filter out most of the high-frequency component, and the resulting sounds are called vesicular.

If the lung is consolidated or collapsed, the high-frequency hissing components of breath are not attenuated, and can be heard as ‘bronchial breathing’. Similar sounds may be heard over areas of localized fibrosis or bronchiectasis. Bronchial breathing is accompanied by whispering pectoriloquy (whispered, high-pitched sounds can be heard distinctly through a stethoscope).

Imaging

Radiology is essential in investigating most chest symptoms. Some diseases such as tuberculosis or lung cancer may be undetectable on clinical examination but are obvious on the chest X-ray. Conversely, asthma or chronic bronchitis may be associated with a normal chest X-ray. Always try to get previous films for comparison.

Chest X-ray

When viewing films consider:

Centring of the film. The distance between each clavicular head and the spinal processes should be equal

Penetration (check film is not too dark)

View. Routine films are taken postero-anterior (PA), i.e. the film is placed in front of the patient with the X-ray source behind. Anteroposterior (AP) films are taken only in very ill patients who are unable to stand up or be taken to the radiology department; the cardiac outline appears bigger and the scapulae cannot be moved out of the way. Lateral chest X-rays were often performed in the past to localize pathology, but CT scans have replaced these.

Look at:

The shape and bony structure of the chest wall

Whether the trachea is central

Whether the diaphragm is elevated or flat

The shape, size and position of the heart

The shape and size of the hilar shadows

The size and shape of any lung abnormalities and vascular shadowing.

X-ray abnormalities

Collapse and consolidation

Simple pneumonia is easy to recognize (see Fig. 15.33) but look carefully for any evidence of collapse (Fig. 15.10, Table 15.3). Loss of volume or crowding of the ribs are the best indicators of lobar collapse. The lung lobes collapse in characteristic directions. The lower lobes collapse downwards and towards the mediastinum, the left upper lobe collapses forwards against the anterior chest wall, while the right upper lobe collapses upwards and inwards, forming the appearance of an arch over the remaining lung. The right middle lobe collapses anteriorly and inward, obscuring the right heart border. If a whole lung collapses, the mediastinum will shift towards the side of the collapse. Uncomplicated consolidation does not cause mediastinal shift or loss of lung volume, so any of these features should raise the suspicion of an endobronchial obstruction.

Figure 15.10 Collapse of the left upper lobe. Chest X-ray showing triangular shadow in the left upper zone, next to the mediastinum.

Table 15.3 Causes of collapse of the lung

Enlarged tracheobronchial lymph nodes due to malignant disease, tuberculosis Inhaled foreign bodies (e.g. peanuts) in children, usually in the right main bronchus Bronchial casts or plugs (e.g. allergic bronchopulmonary aspergillosis) Retained secretions – postoperatively and in debilitated patients

Pleural effusion

Pleural effusions (see Fig. 15.45) need to be larger than 500 mL to cause much more than blunting of the costophrenic angle. On an erect film they produce a characteristic shadow with a curved upper edge rising into the axilla. If very large, the whole of one hemithorax may be opaque, with mediastinal shift away from the effusion.

Fibrosis

Localized fibrosis causes streaky shadowing, and the accompanying loss of lung volume causes mediastinal structures to move to the same side. More generalized fibrosis can lead to a honeycomb appearance (see p. 849), seen as diffuse shadows containing multiple circular translucencies a few millimetres in diameter.

Round shadows

Lung cancer is the commonest cause of large round shadows but many other causes are recognized (Table 15.4).

Table 15.4 Causes of round shadows (>3 cm) in the lung

Miliary mottling

This term, derived from the Latin for millet, describes numerous minute opacities, 1–3 mm in size. The commonest causes are tuberculosis, pneumoconiosis, sarcoidosis, idiopathic pulmonary fibrosis and pulmonary oedema (see Fig. 14.15), although pulmonary oedema is usually perihilar and accompanied by larger, fluffy shadows. Pulmonary microlithiasis is a rare but striking cause of miliary mottling.

Computed tomography

CT provides excellent images of the lungs and mediastinal structures (Fig. 15.11). Narrow slice, high-resolution CT scans show the lung parenchyma well, while thicker slice staging CT scans are used for diagnosis of malignant disease. Mediastinal structures are shown more clearly after injecting intravenous contrast medium.

Figure 15.11 CT scans of the lung. (a) Lung setting – showing normal lung markings. 1, right hilum; 2, mediastinum; 3, left hilum; 4, lung vessels; 5, left main bronchus; 6, right main bronchus; 7, peripheral lung vessels. (b) Mediastinal (soft tissue) setting – showing normal mediastinal structures following intravenous contrast enhancement. 1, rib; 2, descending left pulmonary artery; 3, scapula; 4, subcutaneous fat; 5, left main bronchus; 6, descending aorta; 7, spinal canal; 8, vertebral body; 9, oesophagus; 10, right main bronchus; 11, right pulmonary artery; 12, muscle; 13, right superior pulmonary vein; 14, superior vena cava; 15, costal cartilage; 16, ascending aorta; 17, sternum; 18, thymic remnant; 19, pulmonary trunk; 20, left superior pulmonary vein. (c) Post-contrast scan showing large right upper zone carcinoma with enlarged lymph nodes in the mediastinum surrounding the trachea.

CT is essential in staging bronchial carcinoma by demonstrating tumour size, nodal involvement, metastases and invasion of mediastinum, pleura or chest wall. CT-guided needle biopsy allows samples to be obtained from peripheral masses. Staging scans should assess liver and adrenals, which are common sites for metastatic disease.

High-resolution CT (HRCT) scanning samples lung parenchyma with 1–2 mm thickness scans at 10–20 mm intervals and are used to assess diffuse inflammatory and infective parenchymal processes. It is valuable in:

Multi-slice CT scanners can produce detailed images in two or three dimensions in any plane. This detail is particularly useful for the detection of pulmonary emboli. Pulmonary nodules and airway disease are more easily defined and the technique makes HRCT less necessary.

Magnetic resonance imaging

MRI is less valuable than CT in assessing the lung parenchyma. In the mediastinum, MRI with ECG-gating allows accurate imaging of the heart and aortic aneurysms, and MRI has been used in staging lung cancer, for assessing tumour invasion in the mediastinum, chest wall and at the lung apex, because it produces good images in the sagittal and coronal planes. Vascular structures can be clearly differentiated as flowing blood produces a signal void on MRI.

Positron emission tomography (PET)

Tumours take up labelled fluorodeoxyglucose (FDG), which emits positrons that can be imaged and helps to differentiate benign from malignant tumours. In bronchial carcinoma, PET scanning combined with CT is now the investigation of choice for assessing lymph nodes and metastatic disease.

Scintigraphic imaging

Isotopic lung scans were used widely for the detection of pulmonary emboli but are now performed less often owing to widespread use of D-dimer measurements and CT pulmonary angiography.

Ultrasound (USS)

Ultrasound is useful for diagnosing and aspirating small pleural effusions, and for the safe placement of intercostal drains. Ultrasound guided biopsy is used for lung masses that abut the pleura, but ultrasound is not useful for lung parenchymal disease as ultrasound energy is scattered by air. Endobronchial ultrasound is helpful.

Respiratory function tests (Table 15.5)

In clinical practice, airflow limitation can be assessed by relatively simple tests that have good intra-subject repeatability. Results must be compared with predicted values for healthy subjects as normal ranges vary with sex, age and height. Moreover, there is considerable variation between healthy individuals of the same size and age; the standard deviation for the peak expiratory flow rate is approximately 50 L/min, and for the FEV₁ it is approximately 0.4 L. Repeated measurements of lung function are useful for assessing the progression of disease in individual patients.

Table 15.5 Respiratory function tests and exercise tests

Tests of ventilatory function

These tests are used mainly to assess the degree of airflow limitation during expiration.

Spirometry

The patient takes a maximum inspiration followed by a forced expiration (for as long as possible) into the spirometer. The spirometer measures the one second forced expiratory volume (FEV₁) and the total volume of exhaled gas (forced vital capacity, FVC). Both FEV₁ and FVC are related to height, age and sex (Fig. 15.12).

Figure 15.12 Spirometry. Volume–time curves showing (a) normal patterns for age and sex, (b) restrictive pattern (FEV₁ and FVC reduced), (c) airflow limitation (FEV₁ only reduced).

In airflow limitation, the FEV₁ is reduced as a percentage of FVC. In normal health the FEV₁/FVC ratio is around 75%. With increasing airflow limitation FEV₁ falls proportionately more than FVC, so the FEV₁/FVC ratio is reduced. With restrictive lung disease FEV₁ and FVC are reduced proportionately and the FEV₁/FVC ratio remains normal or may even increase because of enhanced elastic recoil.

In chronic airflow limitation (particularly in COPD and asthma) the total lung capacity (TLC) is usually increased, yet there is nearly always some reduction in the FVC. This is due to collapse of small airways causing obstruction to airflow before the normal residual volume (RV) is reached. This trapping of air within the lung is a characteristic feature of these diseases.

Peak expiratory flow rate (PEFR)

This is an extremely simple and cheap test. Subjects take a full inspiration to total lung capacity and then blow out forcefully into the peak flow meter (Fig. 15.13). The best of three attempts is recorded.

Figure 15.13 Peak flow measurements. (a) Peak flow meter: the lips should be tight around the mouthpiece. (b) Graph of normal readings for men and women.

Although reproducible, PEFR is mainly dependent on the flow rate in larger airways and it may be falsely reassuring in patients with moderate airflow limitation. PEFR is mainly used to diagnose asthma, and to monitor exacerbations of asthma and response to treatment. Regular measurements of peak flow rates on waking, during the afternoon, and before going to bed demonstrate the wide diurnal variations in airflow limitation that characterize asthma and allow objective assessment of response to treatment (Fig. 15.14).

Figure 15.14 Diurnal variability in PEFR in asthma, showing the effect of steroids. M, morning; N, noon; E, evening.

Other ventilatory function tests

Measurement of airways resistance in a body box (plethysmograph) is more sensitive but the equipment is expensive and the necessary manoeuvres are too exhausting for many patients with chronic airflow limitation.

Flow-volume loops

Plotting flow rates against expired volume (flow-volume loops, see Fig. 15.7) shows the site of airflow limitation within the lung. At the start of expiration from TLC, maximum resistance is from the large airways, and this affects the flow rate for the first 25% of the curve. As air is exhaled, lung volume reduces and the flow rate becomes dependent on the resistance of smaller airways. In chronic obstructive pulmonary disease (COPD), where the disease mainly affects the smaller airways, expiratory flow rates at 50% or 25% of the vital capacity are disproportionately reduced when compared with flow rates at larger lung volumes. Flow-volume loops will also show obstruction of large airways, e.g. tracheal narrowing due to tumour or retrosternal goitre.

Lung volumes

The subdivisions of lung volume are shown in Figure 15.15. Tidal volume and vital capacity can be measured using a simple spirometer, but alternative techniques are needed to measure TLC and RV. TLC is measured by inhaling air containing a known concentration of helium and measuring its dilution in the exhaled air. RV can be calculated by subtracting the vital capacity from the TLC.

Figure 15.15 The subdivisions of the lung volume.

TLC measurements using this technique are inaccurate if there are large cystic spaces in the lung, because helium cannot diffuse into them. Under these circumstances the thoracic gas volume can be measured more accurately using a body plethysmograph. The difference between measurements made by these two methods shows the extent of non-communicating air space within the lungs.

Transfer factor

To measure the efficiency of gas transfer across the alveolar-capillary membrane carbon monoxide is used as a surrogate, since its diffusion rate is similar to oxygen. A low concentration of carbon monoxide is inhaled and the rate of absorption calculated. In normal lungs the transfer factor accurately reflects the diffusing capacity of the lungs for oxygen and depends on the thickness of the alveolar-capillary membrane. In lung disease the diffusing capacity (D_CO) is also affected by the ventilation–perfusion relationship. To control for differences in lung volume, the uptake of carbon monoxide is expressed relative to lung volume as a transfer coefficient (K_CO).

Gas transfer is reduced in patients with severe degrees of emphysema and fibrosis, but also in heart failure and anaemia. Although relatively nonspecific, gas transfer is particularly useful in the detection and monitoring of diseases affecting the lung parenchyma (e.g. idiopathic pulmonary fibrosis, sarcoidosis, asbestosis).

Measurement of blood gases

This technique is described on page 891.

Measurement of the partial pressures of oxygen and carbon dioxide in arterial blood is essential in managing respiratory failure and severe asthma, when repeated measurements are often the best guide to therapy.

Peripheral oxygen saturation (S_pO₂) can be continuously measured using an oximeter with either ear or finger probes. Pulse oximetry has become an essential part of routine monitoring of patients in hospital and clinics. It is also useful in exercise testing and reduces the need to measure arterial blood gases.

Exhaled nitric oxide

Nitric oxide is produced by the bronchial epithelium and increases in asthma and other forms of airway inflammation. Measuring exhaled NO can guide therapy in asthma that is difficult to control.

Haematological and biochemical tests

It is useful to measure:

Other blood investigations sometimes required include α₁-antitrypsin levels, Aspergillus antibodies, viral and mycoplasma serology, autoantibody profiles and specific IgE measurements.

Sputum

Sputum should be inspected for colour:

Microbiological studies (e.g. Gram-stain and culture) are rarely helpful in upper respiratory tract infections or in acute or chronic bronchitis. They are of value in:

Exercise tests

The predominant symptom in respiratory medicine is breathlessness. The degree of disability produced by breathlessness can be assessed by asking the patient to walk for 6 minutes along a measured track. This has been shown to be a reproducible and useful test once the patient has undergone an initial training walk to overcome the learning effect. Additional information can be obtained by using pulse oximetry during exercise to assess desaturation.

More sophisticated cardiopulmonary exercise tests are useful in investigating unexplained breathlessness. Measurement of uptake of oxygen (), work performed, heart rate and blood pressure together with serial ECGs allows the following:

Pleural aspiration

Diagnostic aspiration is necessary for all but very small effusions. Nowadays this is usually done under ultrasound guidance, using full aspetic precautions. A needle attached to a 20 mL syringe is inserted under local anaesthesia through an intercostal space towards the top of an area of dullness. Fluid is withdrawn and the presence of any blood is noted. Samples are sent for protein estimation, lactate dehydrogenase (LDH), cytology and bacteriological examination, including culture and Ziehl–Neelsen/auramine stain for tuberculosis. Large amounts of fluid can be aspirated through a large-bore needle to help relieve extreme breathlessness.

Pleural biopsy

Pleural biopsy used to be performed at the bedside, but is now generally done under direct vision using video-assisted thoracoscopy.

Intercostal drainage

This is carried out when large effusions are present, producing severe breathlessness, or for drainage of an empyema (see Practical Box 15.1). Drains should be inserted with ultrasound guidance. Pleurodesis is performed for recurrent/malignant effusion.

Mediastinoscopy and scalene node biopsy

Mediastinoscopy is used in the diagnosis of mediastinal masses and in staging nodal disease in carcinoma of the bronchus. An incision is made just above the sternum and a mediastinoscope inserted by blunt dissection.

Fibreoptic bronchoscopy

See Practical Box 15.2 and Fig. 15.16.

Figure 15.16 Normal endobronchial appearances as seen at fibreoptic bronchoscopy.

Under local anaesthesia and sedation, the central airways can be visualized down to subsegmental level and biopsies taken for histology. More distal lesions may be sampled by washing or blind brushing. Diffuse inflammatory and infective lung processes may be sampled by bronchoalveolar lavage and transbronchial biopsy. The yield is best in sarcoidosis, lymphangitis carcinomatosa and hypersensitivity pneumonitis. Other fibrotic lung diseases usually yield non-diagnostic samples so it may be more relevant to proceed directly to open or thoracoscopic lung biopsy. Endoscopic bronchoscopic ultrasound enables direct sampling of lymph nodes for diagnostic staging of lung cancer.

Video-assisted thoracoscopic (VATS) lung biopsy

This technique has largely replaced open thoracotomy when a lung biopsy is required (p. 850).

Skin-prick tests

Allergen solutions are placed on the skin (usually the volar surface of the forearm) and the epidermis is broken using a 1 mm tipped lancet. A separate lancet should be used for each allergen. If the patient is sensitive to the allergen a wheal develops. The wheal diameter is measured after 10 minutes. A wheal of at least 3 mm diameter is regarded as positive provided that the control test is negative. The results should always be interpreted in the light of the history. Skin tests are not affected by bronchodilators or corticosteroids but antihistamines should be discontinued at least 48 hours before testing.

Prevalence

Cigarette smoking is declining in the western world. In 1974 in the UK, 51% of men and 41% of women smoked cigarettes – nearly half the adult population. Now 22% of men and 21% of women aged 16 years and over smoke. The highest rates are in women aged 20–24, 31% of whom smoke, and men aged 25–34, 30% of whom smoke. The highest rates of cigarette consumption per capita are in Greece, Russia and parts of Eastern Europe. In global terms the USA ranks 39th and the UK is now down to 65th, close to the rates in Sweden and Malaysia. Smoking continues to increase in many developing countries, particularly among women.

Toxic effects

Cigarette smoke contains polycyclic aromatic hydrocarbons and nitrosamines, which are potent carcinogens and mutagens in animals. It causes release of enzymes from neutrophil granulocytes and macrophages that are capable of destroying elastin and leading to lung damage. Pulmonary epithelial permeability increases even in symptomless cigarette smokers, and correlates with the concentration of carboxyhaemoglobin in blood. This altered permeability may allow easier access for carcinogens.

The dangers

Cigarette smoking is addictive and harmful to health (Table 15.6). People usually start smoking in adolescence for psychosocial reasons and, once they smoke regularly, the pharmacological properties of nicotine encourage persistence, by their effect on the smoker’s mood. Very few cigarette smokers (<2%) can limit themselves to occasional or intermittent smoking.

Table 15.6 The dangers of cigarette smoking

Significant dose–response relationships exist between cigarette consumption, airway inflammation (Table 15.7) and lung cancer mortality. Sputum production and airflow limitation increase with daily cigarette consumption, and effort tolerance decreases. Smoking 20 cigarettes daily for 20 years increases the lifetime risk of lung cancer by about 10 times compared to a lifelong non-smoker. Smoking and asbestos exposure are synergistic risk factors for lung cancer, with a combined risk of about 90 times that of unexposed non-smokers.

Table 15.7 Effects of smoking on the lung

Cigarette smokers who change to cigars or pipe-smoking can reduce their risk of lung cancer. However, pipe and cigar smokers remain at greater risk of lung cancer than lifelong non-smokers or former smokers.

Environmental tobacco smoke (‘passive smoking’) has been shown to increase the frequency and severity of asthma attacks in children and may also increase the incidence of asthma. It is also associated with a small but definite increase in lung cancer. Worldwide, second hand smoke was estimated to affect 40% of children, 33% of non-smoking males and 35% of non-smoking females in 2004. This caused a 1% worldwide mortality and 0.7% of the total worldwide burden of disease in DALYs (disability-adjusted life years).

Stopping smoking

If the entire population could be persuaded to stop smoking, the effect on healthcare use would be enormous. National campaigns, bans on advertising and a substantial increase in the cost of cigarettes are the best ways of achieving this at the population level. Smoking bans in the workplace, pubs and public spaces have also helped. Meanwhile, active encouragement to stop smoking remains a useful approach for individuals. Smokers who want to stop should have access to smoking cessation clinics to provide behavioural support. Nicotine replacement therapy (NRT) and bupropion are effective aids to smoking cessation in those smoking >10 cigarettes/day. Both should only be used in smokers who commit to a target stop date, and the initial prescription should be for 2 weeks beyond the target stop date. NRT is the preferred choice; there is no evidence that combined therapy offers any advantage. Therapy should be changed after 3 months if abstinence is not achieved.

Varenicline is an oral partial agonist on the α₄β₂ subtype of the nicotinic acetylcholine receptor. It stimulates the nicotine receptor and reduces withdrawal symptoms and also the craving for cigarettes. A 12-week course increases the chance of stopping smoking four times; its main side-effects are nausea and sometimes severe depression. Cytisine, which has high affinity for the same receptor, also aids smoking cessation.

The common cold (acute coryza)

This highly infectious illness causes a mild systemic upset and prominent nasal symptoms. It is due to infection by a wide range of respiratory viruses, of which the rhinoviruses are the most common. Other common cold viruses include coronaviruses and adenoviruses. Infectivity from close personal contact (nasal mucus on hands) or droplets is high in the early stages of the infection, and spread is facilitated by overcrowding and poor ventilation. There are at least 100 different antigenic strains of rhinovirus, making it difficult for the immune system to confer protection. On average, individuals suffer two to three colds per year, but the incidence lessens with age, presumably as a result of accumulating immunity to different virus strains. The incubation period varies from 12 hours to 5 days.

The clinical features are tiredness, slight pyrexia, malaise and a sore nose and pharynx. Sneezing and profuse, watery nasal discharge are followed by thick mucopurulent secretions which may persist for up to a week. Secondary bacterial infection occurs only in a minority of cases.

Sinusitis

(see p. 1052)

Rhinitis

Rhinitis is defined clinically as sneezing attacks, nasal discharge or blockage occurring for more than an hour on most days:

Seasonal rhinitis

This is the commonest allergic disorder. It is often called ‘hayfever’ but as this implies that only grass pollen is responsible, it is better described as seasonal (or intermittent) allergic rhinitis. Worldwide prevalence rates vary from 2% to 20%. Prevalence is maximal in the 2nd decade, and up to 30% of UK teenagers and young adults are affected each June and July.

Nasal irritation, sneezing and watery rhinorrhoea are the most troublesome symptoms, but many also suffer from itching of the eyes and soft palate and occasionally even itching of the ears because of the common innervation of the pharyngeal mucosa and the ear. In addition, approximately 20% suffer from seasonal wheezing. The common seasonal allergens are shown in Figure 15.17. Since pollination of plants that give rise to high pollen counts varies from country to country, seasonal rhinoconjunctivitis and accompanying wheeze may occur at different times of year in different regions.

Figure 15.17 Seasonal allergic rhinitis. Bar graph showing the proportion of patients whose symptoms are worst in the month or months indicated. The causative agents are also shown.

FURTHER READING

Booth S, Dudgeon D. Dyspnoea in Advanced Disease. A Guide to Clinical Management. Oxford: Oxford University Press; 2006.

Greiner AN et al. Allergic rhinitis. Lancet 2011; 378:2112–2122.

Perennial rhinitis

Patients with perennial rhinitis rarely have symptoms that affect the eyes or throat. Half have symptoms predominantly of sneezing and watery rhinorrhoea, whilst the other half complain mostly of nasal blockage. The patient may lose the sense of smell and taste. Sinusitis occurs in about 50% of cases, due to mucosal swelling that obstructs drainage from the sinuses. Perennial rhinitis is most frequent in the 2nd and 3rd decades, decreasing with age, and can be divided into four main types.

Perennial allergic rhinitis

The commonest cause is allergy to the faecal particles of the house-dust mite Dermatophagoides pteronyssinus or D. farinae; these are under 0.5 mm in size, invisible to the naked eye (Fig. 15.18), and found in dust throughout the house, particularly in older, damp dwellings. Mites live off desquamated human skin scales and the highest concentrations (4000 mites/g of surface dust) are found in human bedding. Their faecal particles are approximately 20 µm in diameter (Fig. 15.18), and impact in the nose rather than the lungs, unless the patient breathes through their mouth.

Figure 15.18 Common allergens causing allergic rhinitis and asthma. The house-dust mite, faeces of house-dust mites, pollen grains, domestic pets and moulds. Percentages are those of positive skin-prick tests to these allergens in patients with allergic rhinitis.

The next most common allergens come from domestic pets (especially cats) and are proteins derived from urine or saliva spread over the surface of the animal as well as skin protein. Allergy to urinary protein from small mammals is a major cause of morbidity among laboratory workers.

Industrial dust, vapours and fumes cause occupationally related perennial rhinitis more often than asthma.

The presence of perennial rhinitis makes the nose more reactive to nonspecific stimuli such as cigarette smoke, washing powders, household detergents, strong perfumes and traffic fumes. Although patients often think they are allergic to these stimuli, these are irritant responses and do not involve antibodies.

Perennial non-allergic rhinitis with eosinophilia

No extrinsic allergic cause can be identified, either from the history or on skin testing, but eosinophilic granulocytes are present in nasal secretions. Most of these patients are intolerant of aspirin/NSAIDs.

Vasomotor rhinitis

These patients with perennial rhinitis have no demonstrable allergy or nasal eosinophilia. Watery secretions and nasal congestion are triggered by, for example, cold air, smoke, perfume, newsprint, possibly because of an imbalance of the autonomic nerves controlling the erectile tissue (sinusoids) in the nasal mucosa.

Nasal polyps

These are round, smooth, soft, semi-translucent, pale or yellow, glistening structures attached to the sinus mucosa by a relatively narrow stalk or pedicle, occurring in patients with allergic or vasomotor rhinitis. The mechanism(s) of their formation is not known. They contain mast cells, eosinophils and mononuclear cells in large numbers and cause nasal obstruction, loss of smell and taste, and mouth breathing, but rarely sneezing, since the mucosa of the polyp is largely denervated.

Immunotherapy

This is used for patients with seasonal allergic rhinitis who have not responded to the above. Both oral and injectable vaccines are available (p. 69). Other forms of desensitizing vaccines are under development.

Pharyngitis

The most common viruses causing pharyngitis are adenoviruses, of which there are about 32 serotypes. Endemic adenovirus infection causes the common sore throat, in which the oropharynx and soft palate are reddened and the tonsils are inflamed and swollen. Within 1–2 days the tonsillar lymph nodes enlarge. Occasionally, localized epidemics due to adenovirus serotype 8 occur, particularly in schools during summer, with episodes of fever, conjunctivitis, pharyngitis and lymphadenitis of the neck glands. The disease is self-limiting and only requires symptomatic treatment without antibiotics.

Over several decades, the proportion of sore throats due to bacterial infections, e.g. haemolytic streptococcus, has fallen. Many different pathogens have been implicated in pharyngitis but most do not require specific treatment. Persistent and severe tonsillitis should be treated with phenoxymethylpenicillin 500 mg four times a day or cefaclor 250 mg three times daily. Amoxicillin and ampicillin should be avoided if there is a possibility of infectious mononucleosis (p. 100).

Acute laryngotracheobronchitis

Acute laryngitis is an occasional but striking complication of upper respiratory tract infections, particularly those caused by parainfluenza viruses and measles. The condition is most severe in children under the age of 3 years. Inflammatory oedema extends to the vocal cords and the epiglottis, causing narrowing of the airway; there may be associated tracheitis or tracheobronchitis. The voice becomes hoarse, with a barking cough (croup) and there is audible stridor. Progressive airways obstruction may occur, with recession of the soft tissue of the neck and abdomen during inspiration and, in severe cases, central cyanosis. Steam inhalations are not helpful. Nebulized adrenaline (epinephrine) gives short-term relief. Oral or i.m. corticosteroids (e.g. dexamethasone) should be given with oxygen and adequate fluids. If steroids are used, endotracheal intubation is rarely necessary. Rarely, a tracheostomy is required.

Acute epiglottitis

H. influenzae type b (Hib) can cause life-threatening infection of the epiglottis, usually in children under 5 years of age. The child becomes extremely ill with a high fever, and severe airflow obstruction may rapidly occur. This is a life-threatening emergency and requires urgent endotracheal intubation and intravenous antibiotics (e.g. ceftazidime 25–150 mg/kg). Chloramphenicol (50–100 mg/kg) can also be used. The epiglottis, which is red and swollen, should not be inspected until facilities to maintain the airways are available.

Other manifestations of Hib infection are meningitis, septic arthritis and osteomyelitis. A highly effective vaccine is now available, which is given to infants at 2, 3 and 4 months, with their primary immunizations against diphtheria, tetanus and pertussis (DTP). This programme has reduced death rates from Hib infections virtually to zero in many countries.

Influenza (see also p. 108)

The influenza virus belongs to the orthomyxovirus group and exists in two main forms, A and B. Influenza B is associated with localized outbreaks of mild disease, whereas influenza A causes worldwide pandemics (see p. 108).

Inhalation of foreign bodies

Children inhale foreign bodies, e.g. peanuts, more commonly than do adults. In adults, inhalation may occur after excess alcohol or under general anaesthesia (loose teeth or dentures).

When the foreign body is large it may impact in the trachea. The person chokes and then becomes silent; death ensues unless the material is quickly removed (see Emergency Box 15.1).

More often, impaction occurs in the right main bronchus and produces:

Acute bronchitis

Acute bronchitis in previously healthy subjects is often viral. Bacterial infection with Strep. pneumoniae or H. influenzae is a common sequel to viral infections, and is more likely to occur in cigarette smokers or people with chronic obstructive pulmonary disease (COPD).

The illness begins with an irritating, non-productive cough, together with discomfort behind the sternum. There may be associated chest tightness, wheezing and shortness of breath. Later the cough becomes productive, with yellow or green sputum. There is a mild fever and a neutrophil leucocytosis; wheeze with occasional crackles can be heard on auscultation. In otherwise healthy adults the disease improves spontaneously in 4–8 days without the patient becoming seriously ill.

Antibiotics are often given (e.g. amoxicillin 250 mg three times daily), but it is not known whether this hastens recovery in otherwise healthy individuals.

Chronic obstructive pulmonary disease (COPD)

COPD is predicted to become the third most common cause of death and fifth most common cause of disability worldwide by 2020.

The term COPD was introduced to bring together a variety of clinical syndromes associated with airflow obstruction and destruction of the lung parenchyma. The older terms ‘chronic obstructive airways disease’ and ‘chronic obstructive lung disease’ are synonymous with COPD. Prior to 1979, patients with COPD were often classified by symptoms (chronic bronchitis, chronic asthma), by pathological changes (emphysema) or by physiological correlates (pink puffers, blue bloaters). Recognition that these entities overlapped and often co-existed led to introduction of the term COPD.

COPD is associated with a number of co-morbidities, e.g. ischaemic heart disease, hypertension, diabetes, heart failure and cancer, suggesting that it may be part of a generalized systemic inflammatory process.

Pathophysiology

The most consistent pathological finding in COPD is increased numbers of mucus-secreting goblet cells in the bronchial mucosa, especially in the larger bronchi (Fig. 15.19). In more advanced cases, the bronchi become overtly inflamed and pus is seen in the lumen.

Figure 15.19 COPD. Section of bronchial mucosa stained for mucus glands by PAS showing increase in mucus-secreting goblet cells.

(Courtesy of Dr J Wilson and Dr S Wilson, University of Southampton.)

Microscopically, there is infiltration of the walls of the bronchi and bronchioles with acute and chronic inflammatory cells; lymphoid follicles may develop in severe disease. In contrast to asthma, the lymphocytic infiltrate is predominantly CD8⁺. The epithelial layer may become ulcerated and, with time, squamous epithelium replaces the columnar cells. The inflammation is followed by scarring and thickening of the walls which narrows the small airways (Fig. 15.20).

Figure 15.20 Pathological changes in the airways in COPD.

The small airways are particularly affected early in the disease, initially without the development of any significant breathlessness. This initial inflammation of the small airways is reversible and accounts for the improvement in airway function if smoking is stopped early. In later stages the inflammation continues, even if smoking is stopped.

Further progression of the airways disease leads to progressive squamous cell metaplasia, and fibrosis of the bronchial walls. The physiological consequence of these changes is the development of airflow limitation. If the airway narrowing is combined with emphysema (causing loss of the elastic recoil of the lung with collapse of small airways during expiration) the resulting airflow limitation is even more severe.

Emphysema is defined as abnormal, permanent enlargement of air spaces distal to the terminal bronchiole, accompanied by destruction of their walls and without obvious fibrosis. Recent evidence suggests that the enlargement of the distal air spaces (i.e. emphysema) is a secondary result of small airway inflammation and destruction. It is classified according to the site of damage:

Centri-acinar emphysema. Distension and damage of lung tissue is concentrated around the respiratory bronchioles, whilst the more distal alveolar ducts and alveoli tend to be well preserved. This form of emphysema is extremely common; when of modest extent, it is not necessarily associated with disability. Severe centri-acinar emphysema is associated with substantial airflow limitation.

Pan-acinar emphysema. This is less common. Distension and destruction affect the whole acinus, and in severe cases the lung is just a collection of bullae. Severe airflow limitation and mismatch occur. α₁-Antitrypsin deficiency is associated with this type of emphysema (see p. 341).

Irregular emphysema. There is scarring and damage affecting the lung parenchyma patchily independent of acinar structure.

Emphysema leads to expiratory airflow limitation and air trapping. The loss of lung elastic recoil results in an increase in TLC. Premature closure of airways limits expiratory flow while the loss of alveoli decreases capacity for gas transfer.

mismatch is partly due to damage and mucus plugging of smaller airways from chronic inflammation, and partly due to rapid closure of smaller airways in expiration owing to loss of elastic support. The mismatch leads to a fall in P_aO₂ and increased work of respiration.

CO₂ excretion is less affected by mismatch and many patients have low normal P_aCO₂ values due to increasing alveolar ventilation in an attempt to correct their hypoxia. Other patients fail to maintain their respiratory effort and then their P_aCO₂ levels increase. In the short term, this rise in CO₂ leads to stimulation of respiration but in the longer term, these patients often become insensitive to CO₂ and come to depend on hypoxaemia to drive their ventilation. Such patients appear less breathless and because of renal hypoxia they start to retain fluid and increase erythrocyte production (leading eventually to polycythaemia). In consequence they become bloated, plethoric and cyanosed, the typical appearance of the ‘blue bloater’. Attempts to abolish hypoxaemia by administering oxygen can make the situation much worse by decreasing respiratory drive in these patients who depend on hypoxia to drive their ventilation.

The classic Fletcher and Peto studies (Fig. 15.21) show that there is a loss of 50 mL per year in FEV₁ in patients with COPD compared with 20 mL per year in healthy people. A recent study has shown a 40 mL loss per year but only in 38% of the patients studied. Biomarkers to indicate the rate of decline have been unhelpful although CC16 (Clare cell secretory protein 16) was shown to be a reasonable indicator in a study.

Figure 15.21 Influence of smoking on airflow limitation.

(From Fletcher CM, Peto R. The natural history of chronic airflow abstruction. British Medical Journal 1977; 1:1645.)

In summary, three mechanisms have been suggested for this limitation of airflow in small airways (<2 mm in diameter).

Loss of elasticity and alveolar attachments of airways due to emphysema. This reduces the elastic recoil and the airways collapse during expiration.

Inflammation and scarring cause the small airways to narrow.

Mucus secretion, which blocks the airways.

Each of these narrows the small airways and causes air trapping leading to hyperinflation of the lungs, mismatch, increased work of breathing and breathlessness.

Management

See Figure 15.22 for management strategies.

Figure 15.22 Algorithm for the treatment of COPD. The various components of management are shown as the FEV₁ decreases and the symptoms become more severe.

(After Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. New England Journal of Medicine 2004; 350:2689–2697.

Smoking cessation

The single most useful measure is to persuade the patient to stop smoking. Even in advanced disease this may slow down the rate of deterioration and prolong the time before disability and death occur (see Fig. 15.22). Smoke from burning biomass fuels in poorly ventilated homes should also be reduced or get to non-smoking facilities if possible.

Drug therapy

This is used both for the short-term management of exacerbations and for the long-term relief of symptoms. Many of the drugs used are similar to those used in asthma (see p. 829).

Bronchodilators

β-Adrenergic agonists. Many patients with mild COPD feel less breathless after inhaling a β-adrenergic agonist such as salbutamol (200 µg every 4–6 hours). In more severe airway limitation (moderate and severe COPD), a long-acting β₂ agonist should be used, e.g. formoterol 12 µg powder inhaled twice daily or salmeterol 50 µg twice daily. Indacaterol 150–300 µg daily is also effective.

Antimuscarinic drugs. More prolonged and greater bronchodilatation is achieved with antimuscarinic agents: tiotropium (long-acting) (18 µg daily), ipratropium (40 µg four times daily) or oxitropium (200 µg twice daily). Tiotropium improves function and quality of life but does not affect the decline in FEV₁. Compound bronchodilators, a selective β₂ agonist and an antimuscarinic agent, are used. If patients find inhalers difficult to use, spacer devices improve delivery. Objective evidence of improvement in peak flow rate or FEV₁ may be small and decisions to continue or stop therapy are based mainly on the patient’s reported symptoms.

Theophyllines. Long-acting preparations of theophylline are of little benefit in COPD.

Phosphodiesterase type 4 inhibitors

Roflumilast is an inhibitor with anti-inflammatory properties. It is used as an adjunct to bronchodilators for the maintenance treatment of COPD patients.

Corticosteroids

In symptomatic patients with moderate/severe COPD, a trial of corticosteroids is always indicated, since a proportion of patients have a large, unsuspected, reversible element to their disease and airway function may improve considerably. Prednisolone 30 mg daily should be given for 2 weeks, with measurements of lung function before and after the treatment period. If there is objective evidence of a substantial degree of improvement in airflow limitation (FEV₁ increase >15%), prednisolone should be discontinued and replaced by inhaled corticosteroids (beclometasone 40 µg twice daily in the first instance, adjusted according to response). The long-term value of regular inhaled corticosteroids in all patients with COPD has not been proven.

Combination of a corticosteroid with a long-acting β₂ agonist may protect against lung function decline but does not improve overall mortality. High-dose inhaled steroids are not advised as they cause increased rates of respiratory infection

Antibiotics

Prompt antibiotic treatment shortens exacerbations and should always be given in acute episodes as it may prevent hospital admission and further lung damage. Patients can be given antibiotics to keep at home to start as soon as their sputum turns yellow or green. Although amoxicillin-resistant H. influenzae is increasing worldwide (occurring in about 20% of isolates from sputum) it is not a serious clinical problem. Resistance to cefaclor (500 mg 8-hourly) or cefixime (400 mg once daily) is significantly less frequent; co-amoxiclav is a useful alternative.

Long-term treatment with antibiotics remains controversial. They were once thought to be of no value, but eradication of infection and keeping the lower respiratory tract free of bacteria may help to prevent deterioration in lung function.

Antimucolytic agents

These reduce sputum viscosity and can reduce the number of acute exacerbations. A 4-week trial of carbocysteine 2.25 g daily can be tried.

Diuretic therapy (see p. 644)

This is necessary for all oedematous patients. Daily weights should be recorded during acute inpatient episodes.

Oxygen therapy

Two controlled trials (chiefly in males) have shown improved survival with the continuous administration of oxygen at 2 L/min via nasal prongs to achieve an oxygen saturation of greater than 90% for large proportions of the day and night. Survival curves from these two studies are shown in Figure 15.23.

Figure 15.23 Cumulative survival curves for patients receiving oxygen. Oxygen doses are in hours per day.

Only 30% of those not receiving long-term oxygen therapy survived for more than 5 years. A fall in pulmonary artery pressure was achieved if oxygen was given for 15 hours daily, but substantial improvement in mortality was only achieved by the administration of oxygen for 19 hours daily. These results suggest that long-term continuous domiciliary oxygen therapy will benefit patients who have:

P_aO₂ of <7.3 kPa (55 mmHg) when breathing air. Measurements should be taken on two occasions at least 3 weeks apart after appropriate bronchodilator therapy (Box 15.1).

P_aO₂ 7.3–8 kPa with secondary polycythaemia, nocturnal hypoxaemia, peripheral oedema or evidence of pulmonary hypertension.

Carboxyhaemoglobin of <3% (i.e. patients who have stopped smoking).

 Box 15.1

Guidelines for domiciliary oxygen (Royal College of Physicians, 1999)

Chronic obstructive pulmonary disease with P_aO₂ <7.3 kPa when breathing air during a period of clinical stability

Chronic obstructive pulmonary disease with P_aO₂ 7.3–8 kPa in the presence of secondary polycythaemia, nocturnal hypoxaemia, peripheral oedema or evidence of pulmonary hypertension

Severe chronic asthma with a P_aCO₂ <7.3 kPa or persistent disabling breathlessness

Diffuse lung disease with P_aO₂ <8 kPa and in patients with P_aO₂ >8 kPa with disabling dyspnoea

Cystic fibrosis when P_aO₂ <7.3 kPa or if P_aO₂ 7.3–8 kPa in the presence of secondary polycythaemia, nocturnal hypoxaemia, pulmonary hypertension or peripheral oedema

Pulmonary hypertension without parenchymal lung involvement when P_aO₂ <8 kPa

Neuromuscular or skeletal disorders, after specialist assessment

Obstructive sleep apnoea despite continuous positive airways pressure therapy, after specialist assessment

Pulmonary malignancy or other terminal disease with disabling dyspnoea

Heart failure with daytime P_aO₂ <7.3 kPa (on air) or with nocturnal hypoxaemia

Domiciliary oxygen is best provided by using an oxygen concentrator, which is considerably cheaper than using oxygen cylinders.

FURTHER READING

Martinez FJ et al. The future of COPD treatment – difficulties of and basics to drug development. Lancet 2011; 378:1027–1037.

Rabe KF, Wedzicha JA. Controversies in the treatment of chronic obstructive pulmonary disease. Lancet 2011; 378:1038–1047.

Nocturnal hypoxia

COPD patients with severe arterial hypoxaemia may experience profound nocturnal hypoxaemia which may drop the P_aO₂ as low as 2.5 kPa (19 mmHg), particularly during the rapid eye movement (REM) phase of sleep.

Because patients with COPD are already hypoxic, the fall in P_aO₂ produces a much larger fall in oxygen saturation (owing to the shape of the oxygen-haemoglobin dissociation curve) and desaturation of up to 50% occurs. The mechanism is alveolar hypoventilation due to:

These nocturnal hypoxaemic episodes are associated with a further rise in pulmonary arterial pressure owing to vasoconstriction. Most deaths in patients with COPD occur at night, possibly from cardiac arrhythmias due to hypoxaemia. Secondary polycythaemia may be exacerbated by the severe nocturnal hypoxaemia.

Each episode of desaturation is usually terminated by arousal from sleep, so the amount of normal sleep is reduced and patients suffer from daytime sleepiness.

Treatment. Patients with arterial hypoxaemia should not be given sleeping tablets, as these will further depress respiratory drive. Treatment is with nocturnal administration of oxygen and ventilatory support.

Non-invasive positive-pressure ventilation can be administered with a tightly fitting nasal mask and bilevel positive airway pressure (BiPAP) – inspiratory to provide inspiratory assistance and expiratory to prevent alveolar closure, each adjusted independently. This improves ventilation during sleep and allows respiratory muscles to rest at night. BiPAP helps prevent hypoxaemic damage at night in COPD but it does not improve daytime respiratory function, respiratory muscle strength, exercise tolerance or breathlessness.

Additional measures

Vaccines. Patients with COPD should receive a single dose of the polyvalent pneumococcal polysaccharide vaccine and yearly influenza vaccinations.

α₁-Antitrypsin replacement. Weekly or monthly infusions of α₁-antitrypsin have been recommended for patients with serum levels below 310 mg/L and abnormal lung function. Whether this modifies the long-term progression of the disease remains to be determined.

Heart failure should be treated (p. 718).

Secondary polycythaemia requires venesection if the PCV is >55%.

Pulmonary hypertension can be partially relieved by the use of oral β-adrenergic agonists such as salbutamol (4 mg three times daily), but the long-term value is unknown.

The sensation of breathlessness can be reduced by either promethazine 125 mg daily or dihydrocodeine 1 mg/kg by mouth. Although opiates are the most effective treatment for intractable breathlessness they depress ventilation and carry the risk of increasing respiratory failure.

Antileukotriene agents have been tried but are rarely effective (p. 831).

Air travel. Commercial aircraft are pressurized to the equivalent of 2000–2400 m altitude. In healthy people, this causes P_aO₂ to fall from 13.5 to 10 kPa, causing a trivial 3% drop in oxygen saturation, but patients with moderate COPD may desaturate significantly. The desaturation associated with air travel can be simulated by breathing 15% oxygen at sea level. Patients whose saturation drops below 85% within 15 minutes should be advised to contact their airline to request supplemental oxygen during flight.

Surgery. Some patients have large emphysematous bullae which reduce lung capacity. Surgical bullectomy can enable adjacent areas of collapsed lung to re-expand and start functioning again. In addition, carefully selected patients with severe COPD (FEV₁ <1 L) have been treated with lung volume reduction surgery. This increases elastic recoil, which reduces the expiratory collapse of the airway and decreases expiratory airflow limitation. It also enables the diaphragm to work at a better mechanical advantage. Initial studies suggested that ventilation was improved and patients felt less breathless, although mortality was unchanged. However, a controlled trial in severe emphysema found increased mortality and no improvement in the patients’ condition. Single lung transplantation (see p. 822) is used for end-stage emphysema, with 3-year survival rates of 75%. The principal benefit is improved quality of life but it does not extend survival.

Acute respiratory failure in COPD

Oxygen therapy. COPD is by far the commonest cause of respiratory failure (Fig. 15.24). In managing respiratory failure the main goal is to improve the P_aO₂ by continuous oxygen therapy. In type II respiratory failure the P_aCO₂ is elevated and the patient is dependent on hypoxic drive. In this setting, giving additional oxygen will nearly always cause a further rise in P_aCO₂. Small increases in P_aCO₂ can be tolerated but the pH should not be allowed to fall below 7.25; if it does, increased ventilation must be achieved either by artificial ventilation or by using a respiratory stimulant. In COPD exacerbations, a fixed-percentage mask (Venturi mask; Fig. 15.25) is used to deliver controlled concentrations of oxygen. Initially, 24% oxygen is given, and the concentration of inspired oxygen can be gradually increased provided the P_aCO₂ does not rise unacceptably.

Removal of retained secretions. Patients should be encouraged to cough up secretions. Physiotherapy is helpful. If this fails, secretions can be aspirated by bronchoscopy or via an endotracheal tube

Respiratory support (see p. 895). Non-invasive ventilatory techniques can be very helpful in avoiding the need for endotracheal intubation. The best current technique uses tight-fitting facial masks to deliver bilevel positive airway pressure ventilatory support (BiPAP). Assisted ventilation with an endotracheal tube is occasionally used for patients with COPD with severe respiratory failure but only when there is a clear precipitating factor and the overall prognosis is reasonable. Assessing the likelihood of reversibility in an acute setting can present a difficult ethical problem.

Respiratory stimulants. Respiratory stimulants such as doxapram were widely used in the past, but have fallen out of favour due to improvements in non-invasive ventilation.

Corticosteroids, antibiotics and bronchodilators should be administered in the acute phase of respiratory failure but decisions on long-term use should wait until the patient has recovered (see above).

Figure 15.24 Algorithm for the treatment of respiratory failure in COPD. LVF, left ventricular failure; CPAP, continuous positive airway pressure; BiPAP, bilevel positive airway pressure; CXR, chest X-ray.

Figure 15.25 ‘Fixed-performance’ device for administration of oxygen to spontaneously breathing patients (Venturi mask). Oxygen is delivered through the injector of the Venturi mask at a given flow rate. A fixed amount of air is entrapped and the inspired oxygen can be predicted accurately. Masks are available to deliver 24%, 28% and 35% oxygen.

Prognosis of COPD

Predictors of a poor prognosis are increasing age and worsening airflow limitation, i.e. decreasing FEV₁. A predictive index (BODE: Body mass index, degree of airflow Obstruction, Dyspnoea and Exercise capacity) is shown in Box 15.2.

 Box 15.2

BODE index (body mass index, degree of airflow obstruction, dyspnoea and exercise capacity)

Scores on the modified Medical Research Council (MMRC) dyspnoea scale range from 0 to 4, with a score of 4 indicating that the patient is breathless when dressing.

A patient with a BODE index of 0–2 has a 4-year mortality rate of 10%, compared with an 80% rate in one with a BODE index of 7–10.

Obstructive sleep apnoea

OSA affects 1–2% of the population and occurs most often in overweight middle-aged men. It can occur in children, particularly those with enlarged tonsils. The major symptoms and their frequency are listed in Table 15.10. During sleep, activity of the respiratory muscles is reduced, especially during REM sleep when the diaphragm is virtually the only active muscle. Apnoeas occur when the airway at the back of the throat is sucked closed when breathing in during sleep. When awake, this tendency is overcome by the action of opening muscles of the upper airway, the genioglossus and palatal muscles, but these become hypotonic during sleep (Fig. 15.26). Partial narrowing results in snoring, complete occlusion causes apnoea and critical narrowing causes hypopnoeas. Apnoea leads to hypoxia and increasingly strenuous respiratory efforts until the patient overcomes the resistance. The combination of the central hypoxic stimulation and the effort to overcome obstruction wakes the patient from sleep. These awakenings are so brief that the patient remains unaware of them but may be woken hundreds of times per night leading to sleep deprivation, especially a reduction in REM sleep, with consequent daytime sleepiness and impaired intellectual performance. Contributory factors are obesity, narrow pharyngeal opening and co-existent COPD.

Table 15.10 Symptoms of obstructive sleep apnoea

Figure 15.26 Section through head, showing pressure changes (in kPa) in (a) the normal situation and (b) obstructive sleep apnoea. There is a pressure drop during inspiration as air is sucked through the turbinates. In patients with obstructive sleep apnoea this is sufficient to collapse the pharynx, obstructing inspiration.

Correctable factors occur in about one-third of cases and include:

Bronchiectasis

This term describes abnormal and permanently dilated airways. Bronchial walls become inflamed, thickened and irreversibly damaged. The mucociliary transport mechanism is impaired and frequent bacterial infections ensue. Clinically, the disease is characterized by productive cough with large amounts of discoloured sputum, and dilated, thickened bronchi, detected on CT.

Investigations

Chest X-ray may show dilated bronchi with thickened bronchial walls and sometimes multiple cysts containing fluid, but can be normal.

High-resolution CT scanning (see p. 791) reveals thickened, dilated bronchi and cysts at the end of the bronchioles (Fig. 15.27). Characteristically the airways are larger than their associated blood vessels.

Sputum examination and culture are essential for adequate treatment. The major pathogens are Staph. aureus, Pseudomonas aeruginosa, H. influenzae and anaerobes. Other pathogens include Strep. pneumoniae and Klebsiella pneumoniae. Aspergillus fumigatus can be isolated from 10% of sputum specimens in cystic fibrosis, but the role of this organism in producing infection is uncertain. Mycobacterium avium-intracellulare complex (MAI) is being increasingly found.

Sinus X-rays. 30% of bronchiectasis patients also have rhinosinusitis.

Serum immunoglobulins. Up to 10% of adults with bronchiectasis have antibody class or subclass deficiency (mainly IgA). Some have normal antibody class levels but fail to respond to respiratory pathogens. Responses to Hib and pneumococcal vaccines may be impaired.

Sweat electrolytes – if cystic fibrosis is suspected (see p. 821).

Mucociliary clearance (nasal clearance of saccharin). A 1 mm cube of saccharin is placed on the inferior turbinate and the time to taste measured (normally <30 minutes).

Figure 15.27 CT scan showing bronchiectasis. Note dilated bronchi with thickened wall, which are larger than adjacent arteries, giving a signet ring appearance.

Cystic fibrosis

In cystic fibrosis (CF) there is an alteration in the viscosity and tenacity of mucus produced at epithelial surfaces. The classical form of the syndrome includes bronchopulmonary infection and pancreatic insufficiency, with a high sweat sodium and chloride concentration. It is an autosomal recessive inherited disorder with a carrier frequency in Caucasians of 1 in 22 (see p. 43). There is a gene mutation on the long arm of chromosome 7 in the region of 7q31.2. The commonest abnormality is a specific deletion at position 508 in the amino acid sequence [ΔF₅₀₈] – which results in a defect in a transmembrane regulator protein (see p. 44). This is the cystic fibrosis transmembrane conductance regulator (CFTR), which is a critical chloride channel (Fig. 15.28). The mutation alters the secondary and tertiary structure of the protein, leading to a failure of opening of the chloride channel in response to elevated cyclic AMP in epithelial cells. This results in decreased excretion of chloride into the airway lumen and an increased reabsorption of sodium into the epithelial cells. With less excretion of salt there is less excretion of water and increased viscosity and tenacity of airway secretions. A possible reason for the high salt content of sweat is that there is a CFTR-independent mechanism of chloride secretion in the sweat gland with an impaired reabsorption of sodium chloride in the distal end of the duct. Many genetic variants are known. The frequency of λF₅₀₈ mutation in CF is 70% in the USA and UK, under 50% in southern Europe and 30% in Ashkenazi families. A further mutation G551D-CFTR reaches the cell surface but fails to open VX-770 allows it to open momentarily (see p. 811)

Figure 15.28 Cystic fibrosis. Abnormalities and possible therapies (see text). CFTR, cystic fibrosis transmembrane conductance regulator. Ph⁵⁰⁸ phenylalanine deletion in λ F₅₀₈. G551D, glycine replaced by aspartate.

Chronic cough (see p. 798)

Pathological coughing results from two mechanisms:

Sensitization of the cough reflex can be demonstrated by inhalation of capsaicin or saline solution and presents clinically as a persistent tickling sensation in the throat with paroxysms of coughing induced by changes in air temperature, aerosol sprays, perfumes and cigarette smoke. It is found in association with viral infections, oesophageal reflux, post-nasal drip, cough-variant asthma, and in 15% of patients taking angiotensin-converting enzyme (ACE) inhibitors. The association with ACE inhibitors implicates neuropeptides, prostaglandins E₂ and F₂ and bradykinin as causes of the cough. In some patients no cause can be found (idiopathic cough). In the absence of chest X-ray abnormalities, possible investigations include:

Symptomatic management of unexplained cough can be difficult. Morphine depresses the sensitized cough reflex but its unwanted effects limit its long-term use. Dihydrocodeine linctus may help some patients. Demulcent preparations and cough sweets only provide temporary relief. Patients who cough while taking ACE inhibitors should switch to an angiotensin-II receptor antagonist, e.g. losartan (see p. 719), which does not block bradykinin breakdown.

Lung and heart-lung transplantation