COMMON CLINICAL PROBLEMS FROM RESPIRATORY TRACT DISEASE

Pathological basis of respiratory signs and symptoms

CoughPhysiological refl ex response to presence of mucus, exudate, tumour or foreign materialWheezing

DyspnoeaDecreased oxygen in the blood from impaired alveolar gas exchange, left heart failure or anaemiaCyanosisIncreased non-oxygenated haemoglobin, e.g. circulatory bypassing of lungs in congenital heart diseases or impaired alveolar gas exchangePleuritic painIrritation of the pleura due to pulmonary infl ammation, infarction or tumourPleural effusion

ClubbingOften accompanies carcinoma of lung and pulmonary fi brosis, as well as, less commonly, cirrhosis and chronic infl ammatory bowel diseaseWeight lossProtein catabolic state induced by chronic infl ammatory disease (e.g. tuberculosis) or tumoursAuscultation signs

Percussion signs

Globally respiratory diseases, particularly lung infections, together with gastrointestinal infection, account for most deaths in the developing world. Respiratory disease is also a common cause of death in the industrialised nations, accounting for about 14% of deaths in each sex. Out of a global total of 55.69 million deaths in 2000, 3.86 million were due to acute lower respiratory tract infections, 1.66 million to tuberculosis, 2.94 million to HIV/AIDS, 1.21 million to lung cancer and 3.54 million to a variety of other respiratory diseases, mainly chronic obstructive pulmonary disease (2.52 million). There is also considerable morbidity due to respiratory diseases: it is estimated that, in the UK, about 40% of absence from work is the result of such diseases, approximately 85% of which are transient infections of the upper respiratory tract (Table 14.1).

Table 14.1 Major aetiological factors in respiratory disease

NORMAL STRUCTURE AND FUNCTION

The respiratory system extends from the nasal orifices to the periphery of the lung and the surrounding pleural cavity. From the nose to the distal bronchi, the mucosa is lined by mainly pseudostratified ciliated columnar epithelium with mucus-secreting goblet cells; this is respiratory mucosa (Fig. 14.1). A portion of the larynx is covered with stratified squamous epithelium.

Fig. 14.1 The respiratory system. Anatomy of the respiratory tract. Histology of respiratory epithelium. With the exception of the pharynx, epiglottis and vocal cords, the respiratory tract is lined by specialised epithelium compring ciliated columnar epithelia cells with admixed mucus-secreting goblet cells and scattered neuroendocrine cells.

Nasal passages and sinuses

These constitute the upper respiratory tract. The nasal passages and sinuses are in continuity and are lined with respiratory mucosa. The hairs in the nose trap large particles of foreign material, thereby filtering the air. The air is also warmed and humidified as it passes through the nasal cavity. The middle ear, also lined with respiratory epithelium, connects with the nasal cavity via the Eustachian tube.

Larynx

The larynx connects the trachea to the pharynx. Consisting of a complicated system of cartilages and muscles, it allows air into the trachea, with the epiglottis preventing the passage of food into the lungs, and also produces sound for speaking. Part of the larynx, including the vocal cords and epiglottis, is covered with non-keratinising squamous epithelium similar to that lining the oral cavity, pharynx and oesophagus.

Lungs

The lower respiratory tract consists of the trachea, bronchi, bronchioles, alveolar ducts and alveoli (Fig. 14.2). (Table 14.2).

Fig. 14.2 Structure and nomenclature of the lower respiratory tract.

Table 14.2 Structure of the respiratory tree

Part of respiratory tract	Structure
Trachea	Anterior C-shaped plates of cartilage with posterior smooth muscle. Mucous glands
Bronchi	Discontinuous foci of cartilage with smooth muscle. Mucous glands
Bronchioles	No cartilage or submucosal mucous glands. Clara cells secreting proteinaceous fluid. Ciliated epithelium
Alveolar duct	Flat epithelium. No glands. No cilia
Alveoli	Type I and II pneumocytes

The lungs develop from an outpouching of the anterior wall of the primitive foregut at about the fifth week of development. From this tube, two lateral outgrowths appear which eventually form the right and left lungs. These outgrowths are surrounded by mesenchyme from which forms the connective tissue of the respiratory tree. Thus the lungs, like the gastrointestinal tract, develop from endoderm, and developmental abnormalities such as cysts can therefore be lined by either respiratory or gastrointestinal mucosa.

The lungs are divided into lobes: the right lung has three lobes (upper, middle, lower); the left lung has only two lobes (upper and lower). Each lung is formed of 10 anatomically defined bronchopulmonary segments. Each segment is supplied by a segmental branches of the pulmonary artery and bronchus (the bronchovascular bundle). The veins draining adjacent segments often anastomose before they reach the hilum and run principally in the fibrous septae of the lungs.

The respiratory tree is designed to transport clean, humidified air into distal airways and alveoli, where the waste product of metabolism (CO₂) is exchanged for O₂.

Bronchioles branch until they form terminal bronchioles less than 2 mm in diameter. The respiratory system distal to the terminal bronchiole is called the acinus or terminal respiratory unit, where gas exchange occurs. Small airways, defined as having an internal diameter of less than 2 mm, consist of terminal and respiratory bronchioles. Respiratory bronchioles are involved with gas exchange, having alveoli in their walls. A group of three to five respiratory acini is called a lobule.

The alveoli are lined by flattened type I pneumocytes with occasional type II pneumocytes; the latter are rounded cells with surface microvilli and are believed to be the stem cell population for the alveolus. Type II cells secrete surfactant, and replicate quickly after injury to alveolar walls. Beneath the alveolar cells lie a basement membrane which is shared by the alveolar capillary epithelial cells and some interstitial matrix, including elastin fibres. The structure of the alveolar–capillary membrane permits rapid and efficient diffusion of oxygen and carbon dioxide.

The lung is encased by the visceral pleura which is a thin layer of fibroconnective tissue and elastin with overlying mesothelial cells. The lungs sit within the chest cavity surrounded by the parietal pleura, by the diaphragm, ribs and intercostal muscles, vertebral column and sternum.

Blood supply and lymphatic drainage

The lungs are perfused by a dual arterial blood supply. The trunk of the pulmonary artery arises from the right ventricle, splits into main right and left pulmonary arteries and thence follows the airways, forming the bronchovascular bundles. The bronchial arteries arise from the descending thoracic aorta and supply oxygenated blood to lung parenchyma around the hilum. Pulmonary veins take all the blood from the lungs back to the left atrium.

Pulmonary veins course along the interlobular septa with lymphatics.These lymphatic channels and those in the pleura drain into the thoracic duct.

Acid–base balance

Normal acid–base balance in blood is dependent on both efficient alveolar ventilation and perfusion, with consequent successful gas exchange. This leads to the normal partial pressures of O₂ and CO₂ in arterial blood (Pao₂ and Paco₂), and a normal blood pH. Various metabolic disease states lead to disturbances in acid–base balance (Fig. 14.3). If the disease becomes chronic, compensatory mechanisms by both the lungs and kidneys operate in an attempt to restore blood pH.

Fig. 14.3 Acid–base imbalance. Changes in blood pH can occur as a result of alterations in hydrogen ion and carbon dioxide concentrations. These lead to different states of acidosis and alkalosis.

PULMONARY FUNCTION TESTS

In normal quiet respiration only a relatively small proportion of the total lung capacity (TLC) is inhaled and exhaled; this is the tidal volume (TV). TLC is made up of the amount of air totally exhaled after maximum inspiration (the vital capacity or VC) and the residual volume (RV). TLC, RV, TV and VC are all easily measured in the laboratory using helium dilution techniques.

In addition to calculating volume parameters, some techniques also assess actual pulmonary function. Spiro-metry measures the amount of exhaled air per second. The maximum volume of air blown from the lungs within the first second after a previous maximum inspiration is called the forced expiratory volume (FEV₁). This figure, highly reproducible in each individual, is a measure of small airway resistance. It is also dependent on the patient’s age, sex and size; for example, the small lungs of a child obviously cannot expel as much air as those of an adult. The ratio FEV₁:VC compensates to a degree for the variability of lung size. It is possible to inhale more rapidly than exhale because, during inspiration, forces on the airways tend to open them further; during expiration, opposite forces tend to close the airways and thus restrict airflow. For a given lung volume, the expiratory flow rate reaches a peak (PEFR), which is again a measure of airways resistance.

An assessment of the ability of the lungs to exchange gas efficiently can be made by measuring the transfer factor for carbon monoxide (T_CO). Air containing a known concentration of carbon monoxide is inhaled; the breath is held for 15 seconds and then exhaled. The amount of carbon monoxide absorbed is a measure of pulmonary gas exchange. T_CO is dependent on the concentration of blood haemoglobin, which has a strong affinity for carbon monoxide. Diseases that diffusely affect the alveolar–capillary membrane (such as diffuse pulmonary fibrosis or emphysema where there is loss of alveolar surface area) will result in a low T_CO.

Recently the level of nitric oxide (NO) in exhaled air has been added as a useful test; increased levels have been associated with asthma and other causes of bronchial irritation, while decreased levels have been found in cigarette smokers, patients with pulmonary hypertension and during treatment with corticosteroids.

Carbon monoxidetransfer (T_CO)Reduced in pulmonary fibrosis, emphysema, oedema, embolism and anaemiaExhaled nitric oxide (NO)Increased in asthma, bronchiectasis and infections Decreased in pulmonary hypertension, cigarette smokers and after treatment with corticosteroids

In obstructive airways disease, RV and TLC are mildly increased due to hyperinflation of the lung while FEV₁, FVC and the FEV₁: VC ratio is decreased. Clearly, in conditions such as asthma, the results of pulmonary function tests will depend on the clinical state of the patient, whether in an acute attack of asthma or in remission. Restrictive diseases are those that restrict normal lung movement during respiration and are associated with reduced RV and TLC. The FEV₁ and VC may be reduced but their ratio remains normal.

These tests are of most value in the follow-up of patients. They can also give an indication as to the possible benefits of treatment; for example, observing the improved FEV₁:VC and PEFR after treatment with a bronchodilator would be a measure of the reversibility of the airways obstruction.

RESPIRATORY FAILURE

Respiratory failure can occur as a result of:

The effects of respiratory failure include impaired clearance of CO₂ from the lungs, resulting in hypercapnia, and impaired absorption of O₂ from the air, resulting in hypoxaemia. The patient is typically dyspnoeic, cyanosed and lapsing into coma. Hypercapnia (high blood CO₂ concentration) is associated with a bounding pulse and warm, moist extremities.

DISEASES OF INFANCY AND CHILDHOOD

Respiratory diseases of infancy and childhood are predominantly infectious; such diseases, together with diarrhoea, are the primary cause of death in childhood in the developing world. Rarely disease may arise as a result of either developmental abnormalities or immaturity.

lmmaturity

Diseases due to immaturity include:

• hyaline membrane disease or idiopathic respiratory distress syndrome

• bronchopulmonary dysplasia.

Hyaline membrane disease or idiopathic respiratory distress syndrome

Complication of prematurity (less than 36 weeks’ gestation)

Due to deficiency of pulmonary surfactant

Tachypnoea, dyspnoea, expiratory grunting, cyanosis

Diffuse alveolar damage with hyaline membranes

Associated with maternal diabetes, multiple pregnancy, caesarean section, amniotic fluid aspiration

Many similarities to adult respiratory distress syndrome (ARDS)

 

Hyaline membrane disease (HMD) is almost always seen in premature infants of birth weight less than 2.5 kg. Infants are usually of less than 36 weeks’ gestation, and the incidence of HMD rises as the gestational age decreases. The risk of developing HMD may be decreased by giving mothers oral corticosteroids prior to delivery of the baby as this appears to stimulate surfactant production in the lungs.

Clinical features

After a few hours of relatively normal respiration, symptoms of tachypnoea and dyspnoea with expiratory grunting appear. Cyanosis quickly follows, with worsening respiratory distress. Hypoxaemia refractory to high concentration of inhaled oxygen is one hallmark of the disease, a finding also characteristic of adult respiratory distress syndrome (ARDS).

Pathogenesis

The pathogenesis is thought to be due to a deficiency of surfactant. This is secreted by type II pneumocytes, and normally lines distal airways; it reduces surface tension, thereby allowing airway opening during inspiration. Without normal quantities of surfactant, airways need greater effort to open, leading to respiratory distress.

Morphology

At autopsy the lungs are heavy, purple and solid, and sink in water. Histology shows collapsed alveoli with hyaline membranes lining alveolar ducts. Pulmonary lymphatics are dilated. As in ARDS, if the infant survives, resolution follows within the next few days, although pulmonary fibrosis may occur. Treatment is with oxygen and artificial ventilation.

Bronchopulmonary dysplasia

Bronchopulmonary dysplasia is the term used to describe the picture of lung organisation after HMD. Often, infants have been previously treated with high levels of oxygen, and it is not clear whether bronchopulmonary dysplasia is a separate disorder, solely related to oxygen toxicity, or merely a result of organisation after HMD. Certainly, the features are almost identical to those seen with organisation of ARDS; there is interstitial fibrosis, peribronchial fibrosis, and features of pulmonary hypertension. The airways may show extensive squamous metaplasia.

NASAL PASSAGES, MIDDLE EAR AND SINUSES

Inflammatory diseases, e.g. rhinitis, are very common

Nasal polyps are either inflammatory or allergic

Malignant tumours are rare

INFLAMMATORY DISORDERS

Rhinitis (the common cold) is caused by many different viruses, especially rhinoviruses, although respiratory syncytial virus (RSV), para-influenza viruses, coronaviruses, coxsackieviruses, echoviruses and bacteria, such as Haemophilus influenzae, may also be implicated. Rhinitis may also be caused by inhaled allergens as in ‘hay fever’ where the inflammatory reaction is mediated via type I and type III hypersensitivity reactions (Chs 9 and 10).

Nasal polyps may result from either chronic infective inflammation or chronic allergic inflammation. They consist of polypoid oedematous masses of mucosal tissue infiltrated with chronic inflammatory cells, especially plasma cells; eosinophils may be numerous if allergy is the cause.

Sinusitis is inflammation of the paranasal sinuses; it may be acute or chronic. If the drainage orifice is blocked by inflamed swollen mucosa, an abscess may follow. Cranial osteomyelitis, meningitis or cerebral abscess may then result from sinusitis by direct extension.

Wegener’s granulomatosis, a granulomatous form of vasculitis may involve the nose and upper respiratory tract and present with septal perforation or collapse of the nasal cartilages.

Otitis media is infection of the middle ear, often associated with generalised upper respiratory tract infection (URTI). The Eustachian tube may become swollen and blocked, leading to trapping of exudate in the middle ear. Eardrum perforation may ensue, followed by drainage of the effusion. More serious complications include mastoiditis, meningitis and brain abscess.

TUMOURS

Tumours of the nasal passages and sinuses are uncommon. They may be:

Haemangioma and squamous papilloma are benign lesions, the former often presenting with troublesome epistaxis (nosebleeds). Some squamous papillomas may be caused by human papillomavirus.

Juvenile angiofibromas are rare and occur exclusively in males, usually during adolescence. They are extremely vascular, and surgical removal can be difficult. These tumours contain androgen receptors, explaining the male preponderance.

Squamous cell carcinoma may be well differentiated, producing keratin, or very poorly differentiated. The latter may contain many lymphocytes and have been misnamed ‘lympho-epitheliomas’. Such tumours are most common in South-East Asia and account for 18% of all cancers in China; evidence suggests the Epstein–Barr virus is involved in the aetiology and pathogenesis of squamous cell carcinoma.

Adenocarcinoma of the nasal passages and sinuses occurs more frequently in people who have worked in woodwork and furniture industries. These tumours may present clinically up to 40 years after initial exposure.

Primary mucosal melanomas of the nose and sinuses are rare but have a very poor prognosis.

Primary extranodal lymphomas are almost always of non-Hodgkin’s type.

Plasmacytomas are tumours composed of plasma cells. They can occur as part of multiple myeloma or as isolated lesions without systemic disease.

LARYNX

Laryngitis may be infective, allergic or irritative

Polyps and papillomas are benign lesions

Squamous cell carcinoma, typically in male smokers

INFLAMMATORY DISORDERS

Laryngitis may occur in association with viral or bacterial inflammation of trachea and bronchi; this is laryngotracheo-bronchitis. Diphtheria was once a common, and serious, bacterial cause of laryngitis, leading to the formation of a fibrinopurulent membrane that could cause airway obstruction. Now, partly as a result of immunisation in infancy with diphtheria toxoid, the disease is rare.

Epiglottitis is caused by capsulated forms of Haemophilus influenzae type B. The epiglottis becomes inflamed and greatly swollen, leading to airway obstruction (Fig. 14.4). Treatment is by intubation, although, rarely, tracheostomy may be necessary; antibiotics are also given to treat the infection.

Fig. 14.4 Acute epiglottitis. Gross swelling of the epiglottis (arrowed) leading to respiratory obstruction in a child.

Allergic laryngitis occurs after inhalation of an allergen. There may be gross oedema leading to airway obstruction. Irritative laryngitis may be due to cigarette smoke or mechanical factors, e.g. endotracheal intubation.

Laryngeal polyps often develop in singers and are thus sometimes referred to as ‘singer’s nodes’. Even when only a few millimetres in diameter they can alter the character of the voice. They consist of oedematous myxoid connective tissue covered with squamous mucosa with amyloid-like material in the stroma.

TUMOURS

Laryngeal tumours may be:

Papilloma may be caused by types of human papillomavirus. Papillomas consist of squamous epithelium covering fibrovascular cores of stroma. They may be multiple and recurrent, especially in children, but are usually single in adults. Such papillomas can extend into the trachea and bronchi.

Squamous cell carcinoma of the larynx typically affects males over 40 years of age and is associated with cigarette smoking. There may also be an increased risk in asbestos workers. As in squamous epithelium of the cervix, neoplasia is thought to be preceded by a phase of dysplasia. The dysplasia, especially if low grade, may be reversible on withdrawal of causative factors.

Most laryngeal carcinomas arise on the vocal cords (Fig. 14.5), although they may arise above, in the pyriform fossa, or below, as upper tracheal carcinomas. The lesions ulcerate, fungate and invade locally, later causing metastases in regional lymph nodes in the neck and beyond. Symptoms are hoarseness of voice and, later, pain, haemoptysis and dysphagia. Treatment is by chemo-radiotherapy and/or resection. These patients often have widespread mucosal abnormalities throughout the respiratory tract and are at high risk of developing further cancers, especially if they continueto smoke.

Fig. 14.5 Laryngeal carcinoma. The tumour is protruding into the larynx and invading the underlying tissues.

THE LUNGS

Bronchitis

Characterised by cough, dyspnoea, tachypnoea, sputum

Usually viral

In acute bronchitis, the trachea and larynx are involved as well as the lungs, and the disease is then known as acute laryngotracheobronchitis (or ‘croup’). The disease is most severe in children, with symptoms of cough, dyspnoea and tachypnoea. Viruses are usually the cause, especially respiratory syncytial virus (RSV), although Haemophilus influenzae and Streptococcus pneumoniae are frequent bacterial causes. Episodes of acute bronchitis are common in chronic obstructive airways disease, and cause a sudden deterioration in pulmonary function with cough and the production of purulent sputum. Acute bronchitis may be caused by direct chemical injury from air pollutants, such as smoke, sulphur dioxide and chlorine.

Chronic bronchitis is a clinical term defined as cough and sputum for 3 months in 2 consecutive years; it is discussed below under diffuse obstructive airways disease (p. 338).

Bronchiolitis

Usually a primary viral infection in infants (respiratory syncytial virus)

May be secondary to other inhaled irritants or part of a systemic disease process

Causes dyspnoea and tachypnoea

Primary bronchiolitis is an uncommon respiratory infection caused by viruses, especially RSV, in infants. Symptoms are of acute respiratory distress with dyspnoea and tachypnoea. Most cases resolve within a few days, although a minority may develop secondary pneumonia.

Follicular bronchiolitis with lymphoid aggregates and germinal centres, compressing the airway, can occur in rheumatoid disease.

Bronchiolitis obliterans is characterised by concentric fibrosis of the submucosa of small bronchioles resulting in obliteration of the lumen. It may occur in viral infections, especially RSV, after inhalation of toxic fumes, in lung transplant rejection, after aspiration, and with collagen vascular diseases.

Pneumonia

Alveolar inflammation

Protein-rich exudate

Polymorphs and later lymphocytes and macrophages

Lobar or bronchopneumonia

Pneumonia is usually due to infection affecting distal airways and alveoli, with the formation of an inflammatory exudate. It may be classified according to several criteria (Table 14.4, Fig. 14.6).

Table 14.4 Classifications of pneumonia

Criterion	Type	Example/comment
Clinical circumstances	Primary	In an otherwise healthy person
	Secondary	With local or systemic defects in defence
Aetiological agent	Bacterial	Streptococcuspneumoniae,Staphylococcus aureus,Mycobacteriumtuberculosis, etc.
	Viral	Influenza, measles, etc.
	Fungal	Cryptococcus, Candida,Aspergillus,etc.
	Other	Pneumocystis jiroveci, Mycoplasma, aspiration, lipid, eosinophilic
Host reaction	Fibrinous Suppurative

According to dominant component of exudateAnatomicalpattern

Bronchopneumonia

Lobar pneumonia

Most widely usedclassification before identifying aetiological agent

Fig. 14.6 Distribution of lesions in lobar and bronchopneumonia. Bronchopneumonia is characterised by focal inflammation centred on the airways; it is often bilateral. Lobar pneumonia is characterised by diffuse inflammation affecting the entire lobe. Pleural exudate is common.

Bronchopneumonia

Patchy consolidation—often several lobes or billateral

Centred on bronchioles or bronchi

Usually in infancy or old age

Usually secondary to pre-existing disease

Bronchopneumonia has a characteristic patchy distribution, centred on inflamed bronchioles and bronchi with subsequent spread to surrounding alveoli (Fig. 14.6). It occurs most commonly in old age, in infancy and in patients with debilitating diseases, such as cancer, cardiac failure, chronic renal failure or cerebrovascular accidents. Bronchopneumonia may also occur in patients with acute bronchitis, chronic obstructive airways disease or cystic fibrosis. Failure to clear respiratory secretions, such as is common in the post-operative period, also predisposes to the development of bronchopneumonia.

Typical organisms include staphylococci, streptococci and Haemophilus influenzae. Patients often become septicaemic and toxic, with fever and reduced consciousness.

Affected areas of the lung tend to be basal and bilateral, and appear focally grey or grey–red at postmortem (Fig. 14.7). The inflamed lung parenchyma can be demonstrated by gently pressing on an affected area; normal lung recoils like a sponge, whereas pneumonic lung offers little resistance. Histology shows typical acute inflammation with exudation. With antibiotics and physiotherapy, the areas of inflammation most commonly resolve but may heal by organisation with scarring.

Fig. 14.7 Bronchopneumonia. Note the patchy areas of consolidation and pus-filled bronchi (arrowed) in this lung which also shows upper lobe emphysema.

Lobar pneumonia

Affects anatomically delineated segment(s) or the entirety, of a lobe

Relatively uncommon in infancy and old age

Affects males more than females

90% due to Streptococcus pneumoniae (pneumococcus)

Cough and fever with purulent or ‘rusty’ sputum

Pneumococcal pneumonia typically affects otherwise healthy adults between 20 and 50 years of age; however, lobar pneumonia caused by Klebsiella typically affects the elderly, diabetics or alcoholics. Symptoms include a cough, fever and production of sputum. The sputum appears purulent and may contain flecks of blood, so-called ‘rusty’ sputum. Fever can be very high (over 40°C), with rigors. Acute pleuritic chest pain on deep inspiration reflects involvement of the pleura. As the lung becomes consolidated (Fig. 14.8), the chest signs are dullness to percussion with bronchial breathing. The dullness recedes with resolution of the exudate.

Fig. 14.8 Lobar pneumonia. An entire lobe, paler than the other, has become consolidated due to accumulation of acute inflammatory exudate within the alveoli. Note the abrupt demarcation at the interlobar fissure.

The pathology of lobar pneumonia is a classic example of acute inflammation, involving four stages:

1. Congestion. This first stage lasts for about 24 hours and represents the outpouring of a protein-rich exudate into alveolar spaces, with venous congestion. The lung is heavy, oedematous and red.

2. Red hepatisation.

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