Respiratory disease
Anthony J Frew, Sarah R Doffman, Katharine Hurt, Rachel Buxton-Thomas
Introduction
The main role of the respiratory system is to extract oxygen from the external environment and to dispose of waste gases, principally carbon dioxide. This requires the lungs to function as efficient bellows, bringing in fresh air and delivering it to the alveoli, and expelling used air at an appropriate rate. Gas exchange is achieved by exposing thin-walled capillaries to the alveolar gas and matching ventilation to blood flow through the pulmonary capillary bed. In doing this, the lungs expose a large area of tissue, which can be damaged by dusts, gases and infective agents. Host defence is therefore a key priority for the lung and is achieved by a combination of structural and immunological defences.
Anatomy of the Respiratory System
The nose, pharynx and larynx
See pages 1317 and 1319.
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 sub-segmental bronchi. There are about 25 divisions in all between the trachea and the alveoli.
The first seven divisions are bronchi that have:
• walls consisting of cartilage and smooth muscle
• an epithelial lining with cilia and goblet cells
• submucosal mucus-secreting glands
• endocrine cells – Kulchitsky or amine precursor and uptake decarboxylation (APUD) cells containing 5-hydroxytryptamine (5-HT, serotonin).
The next 16–18 divisions are bronchioles that have:
• no cartilage and a muscular layer that progressively becomes thinner
• a single layer of ciliated cells but very few goblet cells
• granulated Clara cells that produce a surfactant-like substance.
The ciliated epithelium is a key defence mechanism. Each cell bears approximately 200 cilia beating at 1000 beats per minute (b.p.m.) in organized waves of contraction. Each cilium consists of nine peripheral parts and two inner longitudinal fibrils in a cytoplasmic matrix (Fig. 24.1). Nexin links join the peripheral pairs. Dynein arms consisting of adenosine triphosphatase (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 pp. 92–93). 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).
The bronchioles finally divide within the acinus into smaller respiratory bronchioles that have alveoli arising from the surface (Fig. 24.2). 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.
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. 24.3). 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).
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 24.4. 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.
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; 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 veins, 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 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.
Physiology of the Respiratory System
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 >10 microns (µm) in 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 immunoglobulin A (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:
• the mechanical process of inspiration and expiration
• the control of respiration to a level appropriate for metabolic needs.
The 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.
Ventilation is controlled by a combination of neurogenic and chemical factors (Fig. 24.5). 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 that triggers respiratory drive. Typical normal values are shown in Box 24.1.
Box 24.1
Normal values for respiratory physiology
In a typical normal adult at rest:
• Pulmonary blood flow is about 5 L/min
• This carries 11 mmol/min (250 mL/min) of O2 to tissues
• Ventilation is about 6 L/min
• This removes 9 mmol/min (200 mL/min) of CO2 from the body
• Normal pressure of oxygen in arterial blood (PaO2) is 11–13 kPa
• Normal pressure of carbon dioxide in arterial blood (PaCO2) is 4.8–6.0 kPa
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:
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 (PALV) is equal to the pleural pressure (PPL) plus the elastic recoil pressure (PEL) 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. 24.6A).
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. 24.6B) 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. 24.6C). Where there is pathological loss of recoil pressure (as in 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. 24.7A).
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. 24.7B). 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 <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 is >1. This phenomenon, and the characteristic flow–volume loop, is diagnostic of extrathoracic airways obstruction (Fig. 24.7C).
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. 24.8). 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 under-perfusion during acceleration and deceleration, e.g. in aircraft and high-performance cars).
An increased physiological shunt results in arterial hypoxaemia since it is not possible to compensate for some of the blood being under-oxygenated 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 (PaCO2), together with hypoxaemia, which cannot be compensated for 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 is carried in three forms (in bicarbonate, in carbamino compounds and in simple solution), but the volume carried is proportional to the partial pressure of CO2. 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 (see Fig. 24.5). Alveolar hyperventilation reduces the alveolar PCO2 (PACO2) and diffusion leads to a proportional fall in the carbon dioxide content of the blood (PaCO2). However, as the haemoglobin is already saturated with oxygen, increasing the alveolar PO2 through hyperventilation will not increase blood oxygen content. This means that hypoxaemia due to physiological shunting cannot be compensated for by hyperventilation.
In individuals who have mild degrees of 
mismatch, the PaO2 and PaCO2 will still be normal at rest. Increasing the requirements for gas exchange by exercise will widen the 
mismatch and the PaO2 will fall. 
mismatch is by far the most common cause of arterial hypoxaemia.
Alveolar stability
Pulmonary alveoli are polygonal spaces within a sponge-like matrix. Surface tension acting at the curved internal surface tends to cause the alveoli 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, such as in patients with fractured ribs, gives rise to patchy basal lung collapse. Surfactant levels may be reduced in a number of lung diseases (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.
Defence mechanisms of the respiratory tract
Pulmonary disease often results from a failure of the normal host defence mechanisms of the healthy lung (Fig. 24.9). These can be divided into physical, physiological, humoral and cellular mechanisms.
Physical and physiological mechanisms
This prevents dehydration of the epithelium.
Particle removal
Over 90% of particles >10 µm in diameter are removed in the nostril or nasopharynx. This includes most pollen grains, which are typically >20 µm in diameter. Particles between 5 and 10 µm become impacted at the carina. Particles of <1 µm tend to remain airborne, thus the particles capable of reaching the deep lung are those in the 1–5 µm range.
Particle expulsion
This is effected by coughing, sneezing or gagging.
Respiratory tract secretions
The mucus of the respiratory tract is a gelatinous substance consisting of water and highly glycosylated proteins (mucins). The mucus forms a thick gel that is relatively impermeable to water and floats on a liquid or sol layer found around the cilia of the epithelial cells (Fig. 24.9). The gel layer is secreted from goblet cells and mucous glands as distinct globules that coalesce increasingly in the central airways to form a more or less continuous mucus blanket. In addition to the mucins, the gel contains various antimicrobial molecules (lysozyme, defensins), specific antibodies (IgA) and cytokines, which are secreted by cells in airways and are incorporated into the mucus gel. Bacteria, viruses and other particles become trapped in the mucus and are either inactivated or simply expelled before they can do any damage. Under normal conditions, the tips of the cilia engage with the undersurface of the gel phase and by coordinated movement they push the mucus blanket upwards and outwards to the pharynx, where it is either swallowed or coughed up. While it only takes 30–60 minutes for mucus to be cleared from the large bronchi, it can be several days before mucus is cleared from respiratory bronchioles. One of the major long-term effects of cigarette smoking is a reduction in mucociliary transport. This contributes to recurrent infection and prolongs contact with carcinogenic material. Air pollutants, local and general anaesthetics, and products of bacterial and viral infection also reduce mucociliary clearance.
Congenital defects in mucociliary transport lead to recurrent infections and eventually to bronchiectasis. For example, in the ‘immotile cilia’ syndrome there is an absence of the dynein arms in the cilia themselves, while in cystic fibrosis there is ciliary dyskinesia and abnormally thick mucus.
The respiratory microbiome
It has always been thought that the lower respiratory tract is sterile. Recent evidence has shown that there is a resident bacterial flora that is very similar to that of the mouth. The composition of the respiratory microbiome is determined by three factors:
• microbial immigration, e.g. by inhalation, or microaspiration from the gastrointestinal tract
• the local growth conditions for the bacteria, e.g. temperature, pH, nutrients, concentration and activation of local inflammatory cells, and epithelial cell interactions
• microbial elimination by the usual mechanisms, i.e. the mucociliary escalator, coughing, and the innate and adaptive humoral mechanisms.
All of these factors will change in both acute and chronic lung conditions when there is an increase in pathological bacteria. This respiratory tract dysbiosis causes a disregulation of the local immune response and favours the growth of bacteria: for example, in the exacerbation of chronic diseases in which inflammation is perpetuated. The background composition of the bacterial microbiome in different conditions might favour exacerbations.
Humoral and cellular mechanisms
• α-Antitrypsin (α1-antiprotease; see p. 479) in lung secretions is derived from plasma. It inhibits chymotrypsin and trypsin, and neutralizes proteases including neutrophil elastase.
• Antioxidant defences include enzymes such as superoxide dismutase and low-molecular-weight antioxidant molecules (ascorbate, urate) in the epithelial lining fluid. In addition, lung cells are protected by an extensive range of intracellular defences, especially members of the glutathione S-transferase superfamily.
• Lysozyme is an enzyme found in granulocytes that has bactericidal properties.
• Lactoferrin is synthesized from epithelial cells and neutrophil granulocytes, and has bactericidal properties.
• Interferons are produced by most cells in response to viral infection and are potent modulators of lymphocyte function.
• Complement in secretions is also derived from plasma. In association with antibodies, it plays a major role in cytotoxicity.
• Surfactant protein A (SPA) is one of four species of surfactant proteins that opsonize bacteria/particles, enhancing phagocytosis by macrophages.
• Defensins are bactericidal peptides present in the azurophil granules of neutrophils.
• Dimeric secretory IgA targets specific antigens (see p. 392).
Innate and adaptive immunity
These mechanisms act as a defence against microbes, inorganic substances such as asbestos, particulate matter such as dust, and other antigens. They act by aiding opsonization so that macrophages can better ingest foreign material.
With infection, neutrophils migrate out of pulmonary capillaries into the air spaces and phagocytose and kill microbes with, for example, antimicrobial proteins (lactoferrin), degradative enzymes (elastase) and oxidant radicals. In addition, neutrophil extracellular traps ensnare and kill extracellular bacteria. Neutrophils also generate a variety of mediators, e.g. tumour necrosis factor alpha (TNF-α), interleukin 1 (IL-1), and chemokines that activate dendritic cells and B cells, and produce the T-cell-activating cytokine IL-12, which enhances neutrophil-mediated defence during pneumonia. Dendritic cells are antigen-presenting cells and are key to the adaptive immune response (see pp. 128–132).
Microbes are detected by host cells by pattern recognition receptors, such as toll-like receptors. These act via nuclear factor kappa B (NF-κB) transcription factors in the epithelial cells to produce adhesion molecules, chemokines and colony stimulating factors to initiate inflammation. Inflammation is necessary for innate immunity and host defence but can lead to lung damage; there is a fine line between defence and injury.
Clinical Approach to the Patient with Respiratory Disease
Clinical features of respiratory disease
Runny, blocked nose and sneezing
Nasal symptoms are extremely common; ‘runny nose’ (rhinorrhoea), nasal blockage and attacks of sneezing can be caused by allergic rhinitis (see p. 1075) and by common colds (pp. 1075–1076).
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 (see p. 1318). Nasal polyps typically present with nasal blockage and loss of smell.
Cough
Cough (see also pp. 1089–1090) is the most common 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 or acid reflux. Cough also occurs in asthmatics after mild exertion or following forced expiration. Cough can occur without any definable pathology; psychological causes may be blamed but there is only limited evidence.
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 in 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 most common 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.
• The most common cause of mild haemoptysis is acute infection, particularly in exacerbations of COPD, but it should not be attributed to this without investigation.
• Other common causes are pulmonary infarction, bronchial carcinoma and tuberculosis.
• In lobar pneumonia, the sputum is usually rusty in appearance rather than frankly blood-stained.
• Pink, frothy sputum is seen in pulmonary oedema.
• In bronchiectasis, the blood is often mixed with purulent sputum.
• Massive haemoptysis (>200 mL of blood in 24 h) is usually due to bronchiectasis or tuberculosis.
• Uncommon causes of haemoptysis include idiopathic pulmonary haemosiderosis, Goodpasture syndrome, microscopic polyangiitis, trauma, blood disorders and benign tumours.
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 diagnostic in only 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. 939) 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. 916).
Paroxysmal nocturnal dyspnoea (see p. 939) 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 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.
Examination of the respiratory system
The nose
See page 1318.
The chest
Assessment should be made of 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. 940) is a dusky colour of the skin and mucous membranes, due to the presence of >50 g/L of desaturated haemoglobin. When it has a central cause, 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 Box 24.2. Clubbing is not a feature of uncomplicated COPD.
Box 24.2
Some causes of finger clubbing
Palpation and percussion
The position of the trachea and apex beat should be checked. The supraclavicular fossa is examined for enlarged lymph nodes. The distance between the sternal notch and the cricoid cartilage (3–4 finger-breadths in full expiration) is reduced in patients with severe airflow limitation. Chest expansion should be checked; a tape measure may be used if precise or serial measurements are needed, such as 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 the lungs are over-inflated (Box 24.3).
Box 24.3
Physical signs of respiratory disease
| Pathological process | Mediastinal displacement | Percussion note | Breath sounds | Vocal resonance | Added sounds |
| Consolidation (i.e. lobar pneumonia) | None | Dull | Bronchial | Increased | Fine crackles |
| Collapse | |||||
| Major bronchus | Towards lesion | Dull | Diminished or absent | Reduced or absent | None |
| Peripheral bronchus | Towards lesion | Dull | Bronchial | Increased | Fine crackles |
| Fibrosis | |||||
| Localized | Towards lesion | Dull | Bronchial | Increased | Coarse crackles |
| Generalized (e.g. idiopathic lung fibrosis) | None | Normal | Vesicular | Increased | Fine crackles |
| Pleural effusion (>500 mL) | Away from lesion (in massive effusion) | Stony dull | Vesicular reduced or absent | Reduced or absent | None |
| Large pneumothorax | Away from lesion | Normal or hyper-resonant | Reduced or absent | Reduced or absent | None |
| Asthma | None | Normal | Vesicular Prolonged expiration | Normal | Expiratory polyphonic wheeze |
| Chronic obstructive pulmonary disease | None | Normal | Vesicular Prolonged expiration | Normal | Expiratory polyphonic wheeze and coarse crackles |
Auscultation
The patient is asked 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).
Added sounds
Wheeze. Wheeze results from vibrations in the collapsible part of the airways when apposition occurs as a result of the flow-limiting mechanisms. Wheeze is usually heard during expiration and is commonly but not invariably present in asthma and COPD. In acute severe asthma, wheeze may not be heard, as airflow may be insufficient to generate the sound. Wheezes may be monophonic (single large airway obstruction) or polyphonic (narrowing of many small airways). An end-inspiratory wheeze or ‘squeak’ may be heard in obliterative bronchiolitis.
Crackles. These brief crackling sounds are probably produced by opening of previously closed bronchioles; early inspiratory crackles are associated with diffuse airflow limitation, while late inspiratory crackles are characteristically heard in pulmonary oedema, lung fibrosis and bronchiectasis.
Pleural rub. This creaking or groaning sound is usually well localized. It indicates inflammation and roughening of the pleural surfaces, which normally glide silently over one another.
Vocal resonance. Healthy lung attenuates high-frequency notes, as compared to the lower-pitched components of speech. Consolidated lung has the reverse effect, transmitting high frequencies well; the spoken word then takes on a bleating quality. Whispered (and therefore high-pitched) speech can be clearly heard over consolidated areas, as compared to healthy lung. Low-frequency sounds such as ‘ninety-nine’ are well transmitted across healthy lung to produce vibration that can be felt over the chest wall. Consolidated lung transmits these low-frequency noises less well, and pleural fluid severely dampens or obliterates the vibrations altogether. Tactile vocal fremitus is the palpation of this vibration, usually by placing the edge of the hand on the chest wall. For all practical purposes, this duplicates the assessment of vocal resonance and is not routinely performed as part of the chest examination.
Cardiovascular system examination
This gives additional information about the lungs (see pp. 940–943).
Additional bedside tests
Since so many patients with respiratory disease have airflow limitation, airflow should be routinely measured using a peak flow meter or spirometer. This is a much more useful assessment of airflow limitation than any physical sign.
Investigation of respiratory disease
Imaging
Imaging is essential in the investigation of 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 obtain previous images for comparison.
Chest X-ray
See Box 24.4.
Box 24.4
The chest X-ray
Check
• Centring of the image. The distance between each clavicular head and the spinal processes should be equal.
• Penetration. Check the image is not too dark and adjust the contrast.
– Postero-anterior (PA) views are used for routine images; the X-ray source is behind the patient.
– Anteroposterior (AP) views are used only in patients who are unable to stand or cannot be taken to the radiology department; the cardiac outline appears bigger and the scapulae cannot be moved out of the way.
– Lateral views were used to localize pathology but have been replaced by CT scans.
Collapse and consolidation
Simple pneumonia is easy to recognize (see Fig. 24.33) but a careful search should be made for any evidence of collapse (Fig. 24.10; Box 24.5). Loss of volume or crowding of the ribs is the best indicator 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; and the right upper lobe collapses upwards and inwards, giving the appearance of an arch over the remaining lung. The right middle lobe collapses anteriorly and inwards, 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.
Box 24.5
Causes of lung collapse
• Enlarged tracheobronchial lymph nodes due to malignant disease or 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. 24.45) 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 they are very large, the whole of one hemithorax may be opaque, with mediastinal shift away from the effusion.
Fibrosis
Localized fibrosis produces 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. 1115), seen as diffuse shadows containing multiple circular translucencies a few millimetres in diameter.
Round shadows
Lung cancer is the most common cause of large round shadows but many other causes are recognized (Box 24.6).
Miliary mottling
This term, derived from the Latin for millet, describes numerous minute opacities, 1–3 mm in size. The most common causes are tuberculosis, pneumoconiosis, sarcoidosis, idiopathic pulmonary fibrosis and pulmonary oedema (see Fig. 23.15), 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
Computed tomography (CT) provides excellent images of the lungs and mediastinal structures (Fig. 24.11). It 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. Mediastinal structures are shown more clearly after injecting intravenous contrast medium.
High-resolution CT (HRCT) samples lung parenchyma with 1–2 mm thickness scans at 10–20 mm intervals and is used to assess diffuse inflammatory and infective parenchymal processes. It is valuable in:
• evaluation of diffuse disease of the lung parenchyma, including sarcoidosis, hypersensitivity pneumonitis, occupational lung disease, and any other form of interstitial pulmonary fibrosis
• diagnosis of bronchiectasis; HRCT has a sensitivity and specificity of >90%
• distinction of emphysema from diffuse parenchymal lung disease or pulmonary vascular disease as a cause of a low gas transfer factor with otherwise normal lung function
• suspected opportunistic lung infection in immunocompromised patients
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, reducing the need for HRCT.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) with electrocardiography (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. MRI is less valuable than CT in assessing the lung parenchyma.
Positron emission tomography
Tumours take up labelled fluorodeoxyglucose (FDG), which emits positrons that can be imaged. In bronchial carcinoma, positron emission tomography (PET) scanning combined with CT is the investigation of choice for assessing lymph nodes and metastatic disease, and helps to differentiate benign from malignant tumours.
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 CT pulmonary angiography.
Perfusion scan
Macro-aggregated human albumin labelled with technetium-99m (99mTc) is injected intravenously. The particles impact in pulmonary capillaries, where they remain for a few hours. A gamma camera is then used to detect the deposition of the particles. The resultant pattern indicates the distribution of pulmonary blood flow; cold areas occur where there is defective blood flow (e.g. in pulmonary emboli).
Ventilation–perfusion scan
Xenon-133 gas is inhaled and its distribution is detected at the same time as the perfusion scan. Areas affected by pulmonary embolism will have reduced perfusion relative to ventilation (see pp. 1032–1033). Other lung diseases (e.g. asthma or pneumonia) impair both ventilation and perfusion. Unfortunately, a pulmonary embolus can affect the lung substance (e.g. atelectasis), leading to reduced ventilation. Nevertheless, this is a better technique than perfusion scanning alone.
Ultrasound
Ultrasound (USS) is useful for diagnosing and aspirating small pleural effusions, and for placing intercostal drains safely. USS-guided biopsy is used for lung masses that abut the pleura. Endobronchial USS is increasingly being used to assess mediastinal lymphadenopathy and to stage lung cancer.
Respiratory function tests
In clinical practice, airflow limitation can be assessed by relatively simple tests that have good intra-subject repeatability (Box 24.7). 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.
Box 24.7
Respiratory function and exercise tests
| Test | Use | Advantages | Disadvantages |
| PEFR | Monitoring changes in airflow limitation in asthma | Portable Can be used at the bedside | Effort-dependent Poor measure of chronic airflow limitation |
| FEV, FVC, FEV1/FVC | Assessment of airflow limitation The best single test | Reproducible Relatively effort-independent | Bulky equipment but smaller portable machines available |
| Flow–volume curves | Assessment of flow at lower lung volumes Detection of large-airway obstruction, both intra- and extrathoracic (e.g. tracheal stenosis, tumour) | Recognizes patterns of flow–volume curves for different diseases | Sophisticated equipment needed for full test but expiratory loop possible with compact spirometry |
| Airways resistance | Assessment of airflow limitation | Sensitive | Technique difficult to perform |
| Lung volumes | Differentiation between restrictive and obstructive lung disease | Effort-independent, complements FEV1 | Sophisticated equipment needed |
| Gas transfer | Assessment and monitoring of extent of interstitial lung disease and emphysema | Non-invasive (compared with lung biopsy or radiation from repeated chest X-rays and CT) | Sophisticated equipment needed |
| Blood gases | Assessment of respiratory failure | Can detect early lung disease when measured during exercise | Invasive |
| Pulse oximetry | Postoperative, sleep studies and respiratory failure | Continuous monitoring Non-invasive | Measures saturation only |
| Exercise tests (6-min walk) | Practical assessment for disability and effects of therapy | No equipment required | Time-consuming Learning effect At least two walks required |
| Cardiorespiratory assessment | Early detection of lung/heart disease Fitness assessment | Differentiates breathlessness due to lung or heart disease | Expensive and complicated equipment required |
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 1-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. 24.12).
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 because collapse of small airways causes 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
Peak expiratory flow rate (PEFR) 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. 24.13). The best of three attempts is recorded.
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. 24.14).
Other ventilatory function tests
Measurement of airways resistance in a body box (plethysmograph) is more sensitive but the equipment is expensive and the necessary manœuvres are too exhausting for many patients with chronic airflow limitation.
Flow–volume loops
Plotting flow rates against expired volume (flow–volume loops; see Fig. 24.7) 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 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: for example, tracheal narrowing due to tumour or retrosternal goitre.
Lung volumes
The subdivisions of lung volume are shown in Figure 24.15. 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.
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 (see above). 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 (DCO) 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 (KCO).
Gas transfer is reduced in patients with severe degrees of emphysema and fibrosis, but also in heart failure and anaemia. Although relatively non-specific, gas transfer is particularly useful in the detection and monitoring of diseases affecting the lung parenchyma (e.g. idiopathic pulmonary fibrosis, sarcoidosis and asbestosis).
Measurement of blood gases
This technique is described on pages 1161–1162.
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 (SpO2) can be continuously measured using an oximeter with either ear or finger probes. Pulse oximetry has become an essential part of the 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 (NO) 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:
• haemoglobin, to detect anaemia or polycythaemia
• packed cell volume (secondary polycythaemia occurs with chronic hypoxia)
• routine biochemistry (often disturbed in carcinoma and infection)
• D-dimer to detect intravascular coagulation; a negative test makes pulmonary embolism very unlikely.
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:
• Yellowish-green indicates inflammation (infection or allergy).
• Blood suggests a neoplasm or pulmonary infarct (see ‘Haemoptysis’, p. 1066).
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:
Sputum cytology
This is useful in the diagnosis of bronchial carcinoma and asthma. Its advantages are speed, cheapness and its non-invasive nature.
However, not everyone can produce sputum and a reliable cytologist is needed. Sputum can be induced by inhalation of nebulized hypertonic saline (5%). Better samples can be obtained by bronchoscopy and bronchial washings (see p. 1074).
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. These involve measurement of oxygen uptake (
), work performed, heart rate, blood pressure and serial ECGs.
Pleural aspiration
Diagnostic aspiration is necessary for all but very small effusions. Nowadays, this is usually done under ultrasound guidance, using full aseptic precautions. A needle is inserted under local anaesthesia through an intercostal space towards the top of the area identified on ultrasound. Fluid is withdrawn and the presence of any blood is noted. Samples are sent for cytology, protein estimation, lactate dehydrogenase (LDH) and bacteriological examination, including culture and Ziehl–Neelsen/auramine staining 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 (VATS).
Intercostal drainage
This is carried out when large effusions are present, producing severe breathlessness, or for drainage of an empyema (Box 24.8). Drains should be inserted with ultrasound guidance. Pleurodesis is performed for recurrent/malignant effusion. Occasionally, a long-term pleural drain may be needed for recurrent effusions.
Box 24.8
Intercostal drainage
Explain the nature of the procedure to the patient and obtain written consent.
Technique
1. Identify the site for aspiration (using ultrasound in most cases).
2. Carefully sterilize the skin over the aspiration site.
3. Anaesthetize the skin, muscle and pleura with 2% lidocaine.
4. Make a small incision and insert an 8–12 French gauge drain, using the Seldinger technique. A needle is used to enter the pleural space, and then withdrawn over a guide wire over which the catheter is then inserted. (A larger-calibre catheter is needed for drainage of empyema, or a 28 French gauge Argyle catheter.)
5. Attach to a three-way tap and 50 mL syringe, and aspirate up to 1000 mL. Stop aspiration if the patient becomes uncomfortable; shock may ensue if too much fluid is withdrawn too quickly.
6. If the drain is to stay in, secure it to skin with suture and sterile dressing.
7. Attach the drain to an underwater seal drainage bottle and allow fluid to drain. Clamp the drain and release periodically, especially if patient becomes uncomfortable (usually up to 1000 mL at a time before clamping for a few hours).
Mediastinoscopy
Mediastinoscopy is used in the diagnosis of mediastinal masses and in the staging of nodal disease in carcinoma of the bronchus. An incision is made just above the sternum and a mediastinoscope inserted by blunt dissection. Mediastinoscopy is needed much less often now, since the introduction of endobronchial ultrasound (EBUS).
Fibreoptic bronchoscopy
See Box 24.9 and Figure 24.16.
Box 24.9
Fibreoptic bronchoscopy
This enables the direct visualization of the bronchial tree as far as the sub-segmental bronchi under a local anaesthetic. Obtain informed written consent after explaining the nature of the procedure.
Indications
• Lesions requiring biopsy seen on chest X-ray
• Positive sputum cytology for malignant cells with no chest X-ray abnormality
• Collection of bronchial secretions for bacteriology, especially tuberculosis
• Recurrent laryngeal nerve paralysis of unknown aetiology
• Infiltrative lung disease (to obtain a transbronchial biopsy)
• Investigation of collapsed lobes or segments and aspiration of mucus plugs
Disadvantages
• All patients require sedation to tolerate the procedure
• Minor and transient cardiac dysrhythmias occur in up to 40% of patients on passage of the bronchoscope through the larynx. Monitoring is required
• Oxygen supplementation is required in patients with PaO2 <8 kPa
• Fibreoptic bronchoscopy should be performed with care in the very sick, and transbronchial biopsies avoided in ventilated patients owing to the increased risk of pneumothorax
• Massive bleeding may occur after biopsy of vascular lesions or carcinoid tumours. Rigid bronchoscopy may be required to allow adequate access to the bleeding point for haemostasis
Under local anaesthesia and sedation, the central airways can be visualized down to sub-segmental 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 rarely yield diagnostic samples so it may be preferable to perform open or thoracoscopic lung biopsy. EBUS enables direct sampling of lymph nodes for diagnostic staging of lung cancer.
Video-assisted thoracoscopic lung biopsy
Video-assisted thoracoscopic (VATS) lung biopsy has largely replaced open thoracotomy when a lung biopsy is required (see p. 1115).
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 weal develops. The weal diameter is measured after 10 minutes. A weal 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.
Smoking
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, about 21% of men and 19% of women aged 16 years and over smoke. The highest rates are in people aged 20–24 (28% of women and 30% of men in this age group smoke). The highest rates of cigarette consumption per capita are in Serbia, Bulgaria, Greece and Russia. In global terms, the USA ranks 51st and the UK ranks 73rd, close to the rates in Sweden, Canada and the Netherlands. 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. 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 (Box 24.10). 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.
Box 24.10
The dangers of cigarette smoking
Significant dose–response relationships exist between cigarette consumption, airway inflammation and lung cancer mortality (Box 24.11). 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.
Box 24.11
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 disability-adjusted life years (DALYs).
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 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 more than 10 cigarettes/day. Both should be used only 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 quadruples the chance of stopping smoking; its main side-effects are nausea and sometimes severe depression. Cytisine, which has high affinity for the same receptor, also aids smoking cessation. Electronic cigarettes (battery-operated vaporizer) are a useful alternative for ex-smokers who miss the physical process of handling cigarettes and inhaling nicotine. While E-cigarettes are not harmless, they are much less harmful than ordinary cigarettes.
Diseases of the Upper Respiratory Tract
Rhinitis
The common cold (acute coryza)
This highly infectious illness (see p. 253) is due to a variety of respiratory viruses: for example, the rhinoviruses (most common), 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. 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 that may persist for up to a week. Secondary bacterial infection occurs in only a minority of cases.
Other forms of rhinitis
Rhinitis is defined clinically as sneezing attacks, nasal discharge or blockage occurring for more than an hour on most days:
• for a limited period of the year (seasonal or intermittent rhinitis)
• throughout the whole year (perennial or persistent rhinitis).
Seasonal rhinitis
This is the most common 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 second decade, and up to 30% of UK teenagers and young adults are affected each June and July.
Nasal irritation, sneezing and watery rhinorrhoea occur, 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 24.17.
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.
Perennial rhinitis
In about 50% of patients with perennial rhinitis, symptoms of sneezing and watery rhinorrhoea predominate, whilst the other half complain mostly of nasal blockage. The patient may lose the senses of smell and taste but rarely has eye or throat symptoms. Sinusitis occurs in about 50% of cases, due to mucosal swelling that obstructs drainage from the sinuses. Perennial rhinitis is most frequent in the second and third decades, decreasing with age, and can be divided into four main types.
Perennial allergic rhinitis
The most common 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. 24.18), 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. 24.18), and impact in the nose rather than the lungs, unless the patient breathes through the mouth.
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 non-specific 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/non-steroidal anti-inflammatory drugs (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 or 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.
Pathogenesis of rhinitis
Sneezing, increased secretion and changes in mucosal blood flow are mediated both by efferent nerve fibres and by released mediators (see p. 1094). Mucus production results largely from parasympathetic stimulation. Blood vessels are under both sympathetic and parasympathetic control. Sympathetic fibres maintain tonic contraction of blood vessels, keeping the sinusoids of the nose partially constricted and aiding nasal patency. Stimulation of the parasympathetic system dilates these blood vessels. This stimulation varies spontaneously in a cyclical fashion so that air intake alternates slowly over several hours from one nostril to the other. The erectile cavernous nasal sinusoids can be influenced by emotion and hence affect nasal patency.
B cells produce IgE antibody against allergens. IgE binds to mast cells via high-affinity cell surface receptors, whose crosslinking causes degranulation and release of histamine, proteases (tryptase, chymase), prostaglandins (PGDs), cysteinyl leukotrienes (LTC4, LTD4, LTE4) and cytokines. These mediators cause the acute symptoms of sneezing, itch, rhinorrhoea and nasal congestion. Sneezing results from stimulation of afferent nerve endings (mostly via histamine) and begins within minutes of an allergen entering the nose. This is followed by nasal exudation and secretion, and eventually nasal blockage, peaking 15–20 minutes after allergen exposure. These latter symptoms are driven by increased epithelial permeability, mostly due to histamine.
Additionally, allergens are presented to T cells via antigen-presenting cells (dendritic cells). This causes release of IL-4 and IL-13, which further stimulate the B cells, and also IL-5, IL-9 and granulocyte macrophage colony stimulating factor (GM-CSF), switching from a Th1 to a Th2 response to activate and recruit eosinophils, basophils, neutrophils and T lymphocytes. These cause chronic swelling and irritation, leading to nasal obstruction, hyper-reactivity and anosmia.