Breathlessness on lying flat occurs in, for example, pulmonary oedema (p. 425). Breathlessness with a wheeze occurring on exposure to an allergen is seen in asthma (e.g. horse riding). It can occur many hours after exposure to an allergen (p. 520) in, for example, hypersensitivity pneumonitis.

Inhalation of foreign bodies can cause choking and acute shortage of breath. Treatment is with the Heimlich manoeuvre. See Emergencies in Medicine p. 714.

Chest pain

Chest pain in respiratory disease is usually pleuritic. Pain can be due to other causes, e.g. localized pain in costochondritis. Shoulder tip pain suggests irritation of the diaphragmatic pleura. Retrosternal soreness occurs with tracheitis but also in other conditions, e.g. oesophagitis, when it is usually burning. Chest pain should always be differentiated from cardiac pain, which is usually a central crushing chest pain radiating to the jaw, neck and left arm (p. 431).

Respiratory investigations

These are discussed under specific diseases.

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a slowly progressive condition predominantly caused by smoking and is the sixth commonest cause of death worldwide; its incidence is increasing. It is characterized by airflow limitation, which is not fully reversible. The lungs have an abnormal inflammatory response to inhaled particles or gases, resulting in airflow limitation. The GOLD (Global Initiative for Chronic Obstructive Lung Disease, WHO) criteria for the diagnosis of lung disease are shown in Table 13.1.

Table 13.1 COPD — Global Initiative in Obstructive Lung Disease (GOLD) criteria

Causes

Tobacco smoking, indoor air pollution from biomass fuel and environmental pollution are the major causes for COPD in the world, although only 10–20% of heavy smokers develop COPD.

Pathogenesis

• Inflammation, infection, scarring, loss of elasticity and increased secretion of mucus (which blocks airways) all play a role. There is also an imbalance of protease and antiprotease activity (α₁-antitrypsin being the major antiprotease).

• Small airways are particularly affected early in the process (obstructive bronchiolitis).

• If airway narrowing is combined with emphysema (loss of elastic recoil of the lung with collapse of small airways during expiration), airflow limitation is even more severe.

• Microscopically, there is infiltration of the walls of bronchi and bronchioles by acute and chronic inflammatory cells, with ulceration of epithelial layers leading to squamous metaplasia, scarring and thickening of walls.

• Systemic sequelae including skeletal muscle dysfunction (see below).

Thus, the characteristic physiological effects include airflow limitation and abnormal alveolar gas exchange, leading to cor pulmonale (pulmonary vascular disease).

Clinical features

COPD is suspected on the basis of chronic progressive symptoms, usually with a smoking history of more than 20 pack years (1 pack year = 20 cigarettes per day for 1 year). It is supported by objective evidence of airflow limitation (or obstruction), usually with spirometry, which does not return to normal with treatment.

• Patients are usually over the age of 35, have a risk factor and present with one or more of exertional breathlessness, chronic cough, regular sputum production, frequent winter ‘exacerbations/bronchitis’ or wheeze.

• Effort intolerance, ankle swelling and fatigue also occur.

• Chest pain and haemoptysis are uncommon and an alternative diagnosis should be looked for.

• Extrapulmonary features occur, e.g. osteoporosis, depression and metabolic problems leading to weight loss, loss of muscle mass and weakness.

Signs

• In mild COPD, signs are absent, except for a wheeze.

• In more severe COPD, tachypnoea, prolonged expiration, pursed lip breathing, use of accessory muscles and intercostal in-drawing on inspiration are seen. Hypercapnic patients will be vasodilated with a bounding pulse and a coarse flapping tremor of the outstretched hands. Severe hypercapnia causes confusion and progressive drowsiness. Clubbing is not a sign of COPD and should alert the physician to the possibility of bronchiectasis or lung cancer.

• In advanced COPD, patients develop cor pulmonale.

Pulmonary hypertension/cor pulmonale

Pulmonary hypertension/cor pulmonale (p. 520) is defined as heart disease secondary to disease of the lung. It occurs in hypoxic patients with COPD. Pulmonary hypertension can be present for years without causing symptoms.

Cor pulmonale is enlargement of the right ventricle secondary to increased afterload due to primary lung disease in patients who have no other cause of ventricular dysfunction. Symptoms include worsening exertional dyspnoea, fatigue and chest pain. On examination JVP is raised and there is a right ventricular parasternal heave, a loud pulmonary component of the second heart sound, fluid retention and peripheral oedema.

Diagnosis and investigations

The diagnosis of COPD is usually clinical, supported by the presence of airflow obstruction on spirometry.

Lung function tests

• Spirometry shows evidence of airflow obstruction, with a reduced forced expiratory volume in 1 second (FEV₁) of < 80%, a reduced FEV₁ to forced vital capacity (FVC) ratio of < 70% and a reduced peak expiratory flow rate (PEFR). In COPD reversibility is less than in asthmatic patients (usually a change in FEV₁ of < 15%). Clinically significant COPD is not present if the FEV₁ and FEV₁/FVC ratio return to normal following treatment. FEV₁ determines severity (Table 13.1) and can also be used to monitor the course of the disease and response to therapy. In addition, FEV₁ can be used to test reversibility and is a predictor of mortality. Five-year survival is about 50% when FEV₁ falls to < 1 L.

• Serial home PEF measurements can be useful to exclude asthma. Reversibility to bronchodilators is also helpful in distinguishing patients who have asthma and to aid further management.

Other tests

• Haemoglobin level and packed cell volume (PCV) can be elevated as a result of persistent hypoxaemia causing secondary polycythaemia.

• Arterial blood gases (ABGs) determine the degree of hypoxia and hypercapnia. A baseline should always be taken for assessment of patients in acute exacerbations and will help in assessing the need for long-term oxygen therapy (LTOT).

• Pulse oximetry measures oxyhaemoglobin concentration but remember that it does not give information about the CO₂ (PaCO₂ or arterial carbon dioxide tension) and hence alveolar ventilation.

• CXR can be normal or show hyper-expanded lung fields with low flattened diaphragms and the presence of bullae.

• Sputum culture is usually unnecessary.

• ECG is not necessary in routine assessment of COPD but can show advanced cor pulmonale; it is insensitive.

• Alpha₁-antitrypsin level and phenotype may be helpful (young non-smokers, lower lobe emphysema, a family history of chest problems). The normal range for α₁-antitrypsin is 2–4 g/L.

Management

With the exception of smoking cessation, the aims of COPD treatment are symptomatic relief and the prevention of exacerbations and complications. No existing medication has been shown to modify decline in lung function.

Smoking cessation

This is vital at any age or stage of the disease. An aggressive smoking cessation programme has been shown to reduce the age-related decline in FEV₁, significantly in middle-aged smokers with mild airways obstruction, and also lead to a decrease in cardiovascular and lung cancer mortality. Smokers should be told to stop and an agreed target date set. Nicotine replacement therapy (NRT) or bupropion is given, unless contraindicated, in addition to a support programme to improve the chances of success.

• NRT aims to replace nicotine and thus reduce the craving for a cigarette. Chewing gum 2 mg and 4 mg, transdermal patches 16-hour and 24-hour in varying doses, nasal spray 0.5 mg per spray, inhalational 10 mg inhalation cartridge, sublingual tablets 2 mg and lozenges 1, 2 and 4 mg are available. Nicotine patches should be limited to 3 months’ usage. NRT should be stopped if the patient restarts smoking. Common side-effects are localized reactions, such as skin irritation with patches, and minor sleep disturbances. Contradictions include vascular disease and allergy to the drug; NRT should not be used in pregnancy or breast feeding.

• Bupropion sustained release is a weak, selective inhibitor of the neuronal re-uptake of dopamine and noradrenaline (norepinephrine). The exact mechanism by which it aids smoking cessation is unclear. The dose is 150 mg once a day for 1 week prior to stopping smoking and then 300 mg a day for a further 6–8 weeks, provided the patient abstains from further cigarettes. Side-effects include seizures in about 1 in 1000 patients. Avoid in patients with a previous history of seizures, or a concomitant administration of other medication that lowers the seizure threshold. Other side-effects include hypersensitivity reactions (0.1%), insomnia and dry mouth.

• Combination therapy with NRT or bupropion has so far shown no significant benefit.

• Varenicline is an oral partial agonist on the α₄β₂ subtype of nicotinic acetylcholine receptor. A 12-week course increases the chances of stopping smoking four-fold; its main side-effect is nausea but severe depression has been recorded.

Drug therapy

This is used both for the short-term management of exacerbations and for the long-term relief of symptoms in patients with an FEV₁ < 80% predicted.

Bronchodilator therapy

Inhaler therapy remains the mainstay of treatment, despite the fact that COPD is characterized by irreversible airway obstruction. It causes relaxation of the smooth muscle and thus decreases airway resistance. Patients with mild COPD feel less breathless.

• Inhaler technique. Patients should be taught a good technique for using inhalers; this should be rechecked regularly. COPD patients may have problems in effective coordination and find it hard to use simple metered-dose inhalers (MDIs). This can be improved by offering different types of inhaler and/or a spacer.

• Beta₂-adrenoceptor agonists act directly on the smooth muscle, have a relatively rapid onset of action and can therefore be used for symptomatic relief and prior to exercise. They can be used on an ‘as required’ or a ‘regular’ basis.

• Short-acting β₂-adrenoceptor agonists. Salbutamol is usually given by pressurized aerosol inhalation 100–200 mcg (1–2 puffs) up to 4–6 times a day. Terbutaline is prescribed at a dose of 250–500 mcg (1–2 puffs) up to 3–4 times a day.

• Long-acting β₂-adrenoceptor agonists. These are used in more severe airway limitation (moderate and severe COPD). They include salmeterol 50–100 mcg (2–4 puffs) twice a day and formoterol 12 mcg inhaled twice a day (depending on formulation and severity).

Side-effects include fine tremor, nervous tension, tachycardia, arrhythmias and hypokalaemia.

• Antimuscarinic agents are used for achieving greater and more prolonged bronchodilatation.

• Short-acting antimuscarinics. These cause bronchodilatation by blocking the bronchoconstrictor effects of cholinergic nerves. They have a longer onset of action and a more prolonged and greater bronchodilatory effect than β₂ agonists, and are associated with less toxicity. Ipratropium bromide is given by aerosol inhalation at a dose of 20–40 mcg 3–4 times a day or by nebulized solution 250–500 mcg 3–4 times a day.

• Long-acting antimuscarinics. Inhaled tiotropium 18 mcg once daily improves the duration of bronchodilatation and the frequency of acute exacerbations in patients with moderate to severe COPD.

Side-effects include dry mouth, nausea, constipation, bladder outlet obstruction, exacerbation of acute-angle glaucoma and headache.

In mild disease short-acting β₂ agonists or short-acting antimuscarinic bronchodilators should be prescribed as required. Their effects are additive and once airflow becomes more severe a regular antimuscarinic can be added to a β agonist. Some patients prefer to use just one combined inhaler ipratropium bromide 20 mcg and salbutamol 100 mcg/metered dose 2 puffs 4 times a day.

Patients who remain symptomatic despite being treated with a combination of two short-acting bronchodilators or patients who have two or more exacerbations a year should be prescribed a long-acting bronchodilator and an inhaled corticosteroid should be added (see below).

Objective evidence of improvement in peak flow or FEV₁ may be small and the decision on whether to continue or stop therapy should be based on the patient’s reported symptoms.

Corticosteroids

Corticosteroids are given to patients in the community with increasing shortness of breath that interferes with daily activities. Inhaled corticosteroids are usually reserved for stable COPD, but if already prescribed, should be continued throughout exacerbations.

• Oral corticosteroids The use of corticosteroids in patients with COPD remains contentious but a subgroup of patients respond to these drugs with improvement of lung function. Therefore in symptomatic patients a trial of prednisolone of 30 mg a day for 2 weeks can be given, with spirometry measurements before and after the treatment period. If patients show a response (FEV₁ increases > 15%), prednisolone should be stopped and an inhaled steroid such as beclometasone 400 mcg twice daily started. Regular oral corticosteroids are not recommended, but in advanced COPD, patients may require a maintenance dose when steroids cannot be withdrawn after an exacerbation.

• Inhaled corticosteroids. An inhaled corticosteroid should be given, in addition to a bronchodilator, in patients with an FEV₁ < 50% or with two or more exacerbations a year requiring treatment with antibiotics or oral corticosteroids. In addition, a trial of high-dose inhaled corticosteroid for 3 weeks in patients with moderate airflow obstruction can distinguish those patients who actually have a diagnosis of asthma and not COPD. There are a number of different formulations and inhalers available. The dose varies from 200 mcg to 800 mcg a day.

There are many side-effects associated with corticosteroids (see Box 15.2, p. 585). Inhaled steroids cause considerably fewer systemic side-effects, although at high doses adverse effects have been reported.

Box 13.2 Guidelines for domiciliary oxygen (Royal College of Physicians, 1999)

• Chronic obstructive pulmonary disease with PaO₂ < 7.3 kPa when breathing air during a period of clinical stability

• Chronic obstructive pulmonary disease with PaO₂ 7.3–8 kPa in the presence of secondary polycythaemia, nocturnal hypoxaemia, peripheral oedema or evidence of pulmonary hypertension

• Severe chronic asthma with PaCO₂ < 7.3 kPa or persistent disabling breathlessness

• Diffuse lung disease with PaO₂ < 8 kPa and in patients with PaO₂ > 8 kPa with disabling dyspnoea

• Cystic fibrosis when PaO₂ < 7.3 kPa or if PaO₂ 7.3–8 kPa in the presence of secondary polycythaemia, nocturnal hypoxaemia, pulmonary hypertension or peripheral oedema

• Pulmonary hypertension without parenchymal lung involvement when PaO₂ < 8 kPa

• Neuromuscular or skeletal disorders, after specialist assessment

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

• Pulmonary malignancy or other terminal disease with disabling dyspnoea

• Heart failure with daytime PaO₂ < 7.3 kPa (on air) or with nocturnal hypoxaemia

Patients requiring LTOT will need an oxygen concentrator and education regarding its use. They should use the oxygen for at least 15 hours per day or, if possible, 20 hours per day. Once established, they should be reviewed at least once a year by a practitioner familiar with LTOT. They should be warned about the risks of explosion and fire if they continue to smoke. Short-burst oxygen should be reserved for patients with episodes of severe breathlessness that is not relieved by other treatment.

An oxygen alert card stating the oxygen saturation should be given to all patients who have had hypercapnic respiratory failure.

Non-invasive ventilation (NIV)

This is mainly used for exacerbations of COPD — see p. 485. The ventilators are small and can be used at home. Patients should be considered for home NIV if, despite maximal treatment, they have hypercapnic respiratory failure and have required ventilatory support during an exacerbation, or are acidotic or hypercapnic on LTOT.

Diuretic therapy (p. 420)

This is necessary for all oedematous patients. Patients should be weighed daily.

Other agents

• Oral mucolytic drugs. Mucolytics increase the expectoration of sputum by reducing its viscosity. Regular use of mucolytics for at least 2 months can reduce the number of exacerbations of COPD and days of illness. They should be used in patients with a chronic productive cough but only continued if there is continual symptomatic improvement.

• Carbocisteine 2.25 g a day in divided doses, then 1.5 g daily in divided doses. Erdosteine 300 mg twice daily is also used.

• Mecysteine hydrochloride 200 mg 4 times a day for 2 days, followed by 200 mg 3 times a day for 6 weeks, then 200 mg twice daily.

• Anti-oxidants. N-acetylcysteine has both anti-oxidant and mucolytic properties, and has been shown to reduce frequency of exacerbations. However, it and other anti-oxidants, such as α-tocopherol and β-carotene supplements, are currently not recommended.

• Anti-tussives. Regular use of anti-tussive medication is not recommended in COPD, as there is insufficient evidence for its benefit, and although cough is a problematic symptom, it has a protective role.

• Antibiotics

• There is no evidence for the use of prophylactic antibiotics.

• Give antibiotics in acute exacerbations, as they shorten exacerbations and may prevent hospital admission.

• Give the patient a supply of antibiotics to keep at home, to start when sputum turns yellow or green.

• Amoxicillin 500 mg 3 times daily is still effective, although resistance to H. influenzae occurs in 10–20%. Resistance is less frequent to cefaclor 500 mg 8-hourly or cefixime 400 mg once daily; co-amoxiclav is an alternative.

Long-term treatment with antibiotics was thought to be of little value but eradication of infection and keeping the lower respiratory tract free of bacteria may help prevent deterioration in lung function.

• Vaccination/antiviral therapy

• Polyvalent pneumococcal polysaccharide vaccine usually provides lifelong immunity after a single dose.

• Annual influenza vaccination should be given, unless patients have a hypersensitivity to eggs.

• Antiviral agents include zanamivir inhalation of 10 mg twice daily for 5 days and oseltamivir 75 mg 12-hourly for 5 days. They are recommended for the treatment of ‘at-risk’ adults who can start therapy within 48 hours of presenting with an influenza-like illness. For side-effects, see p. 91.

• Antidepressants. These may be helpful in COPD, as mood disturbances such as anxiety and depression are common.

• Alpha₁-protease inhibitor augmentation therapy. Young patients with severe hereditary α₁-antitrypsin deficiency with serum levels < 0.31 g/L and abnormal lung function are candidates for α₁-antitrypsin replacement therapy. There is limited evidence for its benefit in modifying the disease in the long term.

Non-pharmacological interventions

• Physiotherapy. Physiotherapy is helpful for patients with excessive sputum. Patients should be encouraged to cough to remove sputum and taught the active cycle of breathing techniques and how to use positive expiratory pressure masks.

• Nutrition. Weight loss is common in patients with COPD and there is an association between low BMI and increased mortality. Patients with a low BMI should be referred for dietary advice and nutritional supplements. Overweight patients should also be offered dietary advice, as obesity puts additional strain on the cardio-respiratory system.

• Pulmonary rehabilitation. Patients with moderate to severe COPD on optimal medical treatment should be put on a pulmonary rehabilitation programme. The aim is to prevent or reverse the deconditioning that occurs in patients with COPD due to lack of exercise and immobility caused by symptoms. The rehabilitation programme is provided by a multi-disciplinary team and includes physical training, disease education, nutritional advice, and psychological, social and behavioural intervention.

Surgery

Surgical treatment for COPD is associated with a high morbidity and mortality, and patients must be carefully selected and be receiving optimal medical management prior to surgery. Bullectomy, lung volume reduction surgery and lung transplantation are used in severe disease.

Acute exacerbations of COPD (type II respiratory failure)

An acute exacerbation is defined as ‘a sustained worsening of the patient’s symptoms from his or her usual stable state that is beyond normal day-to-day variations, and is acute in onset’.

Exacerbations of COPD are among the commonest acute respiratory problems presenting to primary or secondary care.

• They are usually caused by infection, although only 50% of patients will have a positive sputum culture. The commonest organisms are H. influenzae, Strep. pneumoniae and Moraxella catarrhalis.

• Viruses, including rhinovirus, influenza (including H1N1 swine flu variant), coronavirus, adenovirus and respiratory syncytial virus, account for up to 30% of cases.

• Pollutants may also precipitate an exacerbation.

• Some patients with mild exacerbations can be treated at home, but factors such as acute confusion, a decreased level of consciousness, significant co-morbidities, severe breathlessness and acidosis require hospital admission.

Investigations

• CXR for signs of infection or other pathologies, e.g. pneumothorax or pulmonary oedema.

• Baseline ABGs on room air (or a known inspired oxygen concentration) to look for hypoxia or hypercapnia.

• Purulent sputum for culture.

• ECG to look for a cardiac cause for the deterioration.

• Blood cultures if the patient is pyrexial.

• Routine bloods for FBC and U&E.

Treatment

The treatment of respiratory failure in COPD is shown in Fig. 13.1. General care includes prophylaxis against deep vein thrombosis, optimizing fluid status and ensuring adequate nutrition.

• Controlled oxygen. A fixed performance mask can deliver 24%, 28% and 35% oxygen. It is given to correct hypoxia and maintain oxygen saturations > 90%. In a minority of patients respiratory drive is hypoxic and high oxygen concentrations can result in increasing levels of carbon dioxide, decreasing consciousness, and respiratory acidosis and arrest. Pulse oximetry should always be available to measure oxygen saturations. An ABG is performed on arrival in hospital to monitor CO₂ levels. Oxygen concentrations should never be reduced in patients who are hypoxic, even if CO₂ levels are high.

• Bronchodilators (p. 478). There is no benefit in delivering bronchodilators via a nebulizer over an inhaler in acute exacerbations of COPD. Bronchodilators are, however, given via a nebulizer with a face mask or mouth piece delivering higher doses if patients are too breathless to coordinate the use of an inhaler/spacer. If the patient is hypercapnic, the nebulizer should be driven with air and not oxygen. Oxygen can be given at the same time via nasal cannulae.

• Inhaled β₂ short-acting adrenergic agonists (p. 478). The frequency and dose of inhaled β₂-agonists can be increased in an acute exacerbation. They reach peak activity between 10 and 30 mins, and remain effective for about 4–6 hours. Salbutamol (via inhaler or nebulizer) is the most commonly used. Nebulizers are given at a dose of 2.5–5 mg, usually 4 times daily, although this can be increased provided side-effects are tolerated. Currently, there is no evidence to support the use of IV β₂-agonists in acute exacerbations of COPD.

• Inhaled short-acting antimuscarinics. These agents are often used in combination with inhaled β₂-agonists in acute exacerbations of COPD and are associated with fewer side-effects. They have a less rapid onset of action but a longer duration of action. They can be delivered via an inhaler as ipratropium bromide 20–40 mcg, or via a nebulizer ipratropium bromide 500 mcg, salbutamol 2.5 mg/2.5 mL vial, 1 vial 4 times a day.

• Systemic corticosteroids. These drugs reduce the increased airway inflammation in patients with acute exacerbations of COPD. Short courses of corticosteroids have been shown to reduce FEV₁, improve hypoxia and shorten duration of hospital stay compared to placebo. All patients admitted to hospital with an acute exacerbation should receive a course of oral corticosteroids 30 mg for 7–14 days, in addition to other therapies, provided there are no contraindications. The first dose of corticosteroids can be given intravenously as hydrocortisone or methylprednisolone. If patients do receive a prolonged course of corticosteroids, the dose should be gradually tapered down.

• Antibiotics (p. 482). There is some evidence for a small but significant benefit with antibiotics in acute exacerbations of COPD, especially in those with more severe disease. The use of antibiotics is recommended in patients with a history of increased purulence or production of sputum or in those with consolidation on CXR or clinical signs of pneumonia. Initially, treatment is empirical, with an aminopenicillin, a macrolide or a tetracycline, and then changed when culture results and sensitivities become available. Antibiotic use should be guided by local policy. Commonly used antibiotics include amoxicillin 250–500 mg 3 times daily (15% of Haemophilus strains may be resistant), doxycycline 200 mg then 100 mg daily, or erythromycin 250–500 mg every 6 hours or 0.5–1 g every 12 hours. Ampicillin can be used instead of amoxicillin.

• Methylxanthines. The use of methylxanthines such as theophylline (p. 501) remains controversial, as there is currently no clear evidence of benefit in acute exacerbations of COPD. IV theophylline should only be used in patients refractory to nebulized bronchodilators, and levels should be monitored within 24 hours of treatment and regularly after this period. Patients already taking oral methylxanthines should continue on this medication during an exacerbation and should not receive additional IV methylxanthines. IV methylxanthines are usually prescribed as aminophylline loading dose 5 mg/kg (250–500 mg) over at least 20 mins, followed by 0.5 mg/kg/hour over 24 hours adjusted according to plasma levels. Patients should be closely monitored throughout.

• Respiratory stimulants. These (e.g. Doxapram 1.5–4.0 mg/min) are only recommended for use when NIV is unavailable or considered inappropriate.

Fig. 13.1 Algorithm for the treatment of respiratory failure in chronic obstructive pulmonary disease. BiPAP, bilevel positive airways pressure; CPAP, continuous positive airways pressure; LVF, left ventricular failure; NIV, non-invasive ventilation

(Calvaley & Walter 2008, with permission).

• Non-invasive ventilation (NIV)

This is the treatment of choice in patients with exacerbations of COPD who, despite maximal medical therapy and controlled oxygen therapy, have a persistent respiratory acidosis (pH 7.25–7.35, [H+] 45–56 nmol/L).

A tight-fitting facial mask delivers bi-level positive airway pressure ventilatory support (BiPAP). Continuous positive airway pressure (CPAP, p. 542) is also used. NIV can avoid the need for endotracheal intubation.

• Patients with pH < 7.25 respond less well to NIV and should be referred directly for tracheal intubation or a trial of NIV in an intensive care setting.

• NIV results in a reduced need for endotracheal intubation and thus the associated complications. There is improved acidaemia, a reduction in mortality and a shortening of hospital stay. NIV allows better communication, and nutrition and physiotherapy to continue as normal.

• Contraindications to NIV include impaired consciousness, recent facial or upper airway surgery, facial abnormalities such as burns or trauma, undrained pneumothorax, hypoxaemia, cardiovascular instability, inability to protect the airway, recent gastrointestinal surgery, vomiting and copious respiratory secretions.

• Endotracheal intubation

Endotracheal intubation and mechanical ventilation are used in patients with acidaemia or with persistent or worsening hypoxia despite NIV, and when NIV is contraindicated.

• Mortality in patients with COPD who are intubated for an exacerbation is about 20%.

• Assessment for suitability for intubation and ventilation includes functional status, requirement for oxygen when stable, BMI, co-morbidities, previous admissions to the ICU, FEV₁ and age. Weaning from a ventilator can be difficult and NIV can be used post extubation to shorten weaning time.

• Other therapies

Although there is no proven benefit, chest physiotherapy, particularly with the use of positive expiratory pressure masks, can be helpful in patients with copious secretions. Currently, there is no evidence showing benefit for the use of heliox (helium and oxygen mixture) in patients with exacerbations of COPD.

Prognosis of COPD

The predictors of a poor prognosis are increasing age and worsening airflow limitation, i.e. a fall in FEV₁. A predictive index (BODE = body mass index, degree of airflow obstruction, dyspnoea and exercise capacity) has recently been modified, improving prediction of outcome, and is shown in Table 13.2. A patient with a BODE index of 0–2 has a mortality rate of 10% and with 7–10 it rises to 80% at 4 years. A simpler index using age, dyspnoea and airflow obstruction (ADO) gives a similar prognosis.

Table 13.2 Assignment of points for the updated BODE index

Discharge planning

• Prior to discharge patients should have adequate and stable gas exchange (oxygen saturations and ABGs) on optimal maintenance bronchodilator therapy.

• They should understand what medication to take, including oxygen therapy if required.

• Spirometry should be measured prior to discharge as a baseline for further measurements.

• A follow-up appointment should be made for 4–6 weeks, especially for those with respiratory failure who may require assessment for LTOT.

• Ensure that there is adequate support at home.

Obstructive sleep apnoea/hypopnoea syndrome

• Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) affects 1–2% of the population and is commonly seen in overweight, middle-aged men.

• It is a syndrome caused by abnormal size and/or collapsibility of the pharynx during sleep, which disrupts sleep and causes symptoms.

• During sleep, activity of the respiratory muscles is reduced and in OSAHS this results in collapse of the upper airways intermittently and repeatedly. If there is complete collapse, there is total obstruction of the airway and no respiratory flow (apnoea); partial collapse may cause snoring; and if there is critical collapse, there is reduced flow (hypopnoea).

• Apnoea results in hypoxia and increasingly strenuous respiratory efforts until the patient overcomes the resistance and there is termination of the apnoea and resumption of breathing.

• The patient wakes up as a result of the combination of this increased respiratory effort and central hypoxic stimulation. Patients may wake up hundreds of times per night, resulting in reduced rapid eye movement (REM) sleep and sleep deprivation. Patients are usually unaware of these night-time awakenings.

Factors predisposing to OSAH include increasing age, male gender, obesity, sedative drugs, smoking and alcohol consumption.

• Differential diagnosis. Central sleep apnoea is due to impairment of central ventilatory control secondary to brainstem pathology. It occurs at the onset of sleep and is seen in non-obese patients with no history of snoring.

Diagnosis

Symptoms

These include excessive daytime somnolence (90%), impaired concentration and loud snoring (95%). Patients may fall asleep at work, whilst driving or in mid-conversation.

If patients present with typical symptoms, they should be asked to complete an Epworth Sleepiness Scale (ESS). The maximum score is 24, normal range is < 11, mild daytime sleepiness 11–14, moderate subjective daytime sleepiness 15–18 and severe daytime sleepiness > 18. Patients and their partners should fill out the Epworth Sleepiness Scale independently, as patients often under-estimate the severity of their symptoms because onset is often gradual and there may be concerns over driving.

Examination

Examination includes a recording of weight, height, neck circumference and BP. Mandible size should be noted. There should be a full examination of the nose, oral cavity and upper airways, and a complete respiratory, cardiovascular and neurological assessment.

Complications

OSAHS has been associated with hypertension, hypothyroidism, diabetes and lipid abnormalities, and there is increasing evidence of an association with increased cerebrovascular events. Patients with OSAHS may decompensate with hypercapnic respiratory failure or cor pulmonale, especially if there is co-existent COPD.

Referrals

Patients with an abnormal Epworth Sleepiness Scale; those with symptoms suggestive of OSAHS with sleepiness in dangerous situations, such as driving or operating hazardous equipment, even if the ESS is normal; and those with likely OSAHS and COPD should be referred to a specialist sleep centre.

Investigations

Sleep studies

The primary aims of sleep studies are to assess sleep fragmentation, to establish whether a respiratory problem is responsible and to decide if upper airway obstruction is the primary cause.

• Oximetry is cheap and widely available. It can be used to measure the number of oxygen desaturations per hour or the time spent below an agreed SpO₂ level during the study. Oximetry has a role in initial assessment but limited sleep studies or polysomnography are usually required for diagnosis of OSAHS.

• Polysomnography records sleep and breathing patterns simultaneously. Full polysomnography monitors sleep stage, oxygen saturation, respiratory effort, airflow, thoraco-abdominal movement, snoring, ECG, body position and limb movements. This is an expensive technique, as the patient needs to spend the night in a sleep centre and a technician must be available throughout. Full polysomnography is not necessary for diagnosis in most cases.

• Limited sleep studies can measure thoraco-abdominal movement, oximetry, flow and heart rate. The limited sleep studies can be performed at home, although there is reduced sensitivity and specificity, compared to full polysomnography.

Treatment

Treatment depends on the severity of disease, underlying medical conditions and patient compliance. Management should consist firstly of correction of treatable and potentially reversible factors.

• Who to treat. Patients who have a sleep study showing a > 4% oxygen saturation dip more than 10 times an hour should be referred for treatment. Treatment is also necessary in those with mild OSAHS who are symptomatic or have complications.

Behavioural interventions

Weight loss can reduce symptoms, as can smoking cessation and avoidance of alcohol, sedatives and sleeping tablets. Some patients may benefit from sleeping on their side. Keeping the nose as clear as possible, with the use of nasal decongestants if required, may improve symptoms.

Treatment of underlying conditions such as hypothyroidism may greatly improve symptoms of OSAHS.

The above measures may alleviate symptoms in patients who snore or have mild OSAHS. However, in those with more severe disease, additional treatment, as well as behavioural change, is likely to be required and should not be delayed.

Non-surgical interventions

• NIV

• CPAP. This involves wearing a tight-fitting mask during sleep, which delivers pressure via air tubing from a flow generator in the region of 5–10 mmHg. The pressure splints open the pharynx and prevents collapse, allowing unobstructed breathing and an undisturbed night. Nasal CPAP is currently the treatment of choice. There are machines available that automatically ‘hunt’ the pressure required to overcome the collapse of the airway. Supplemental oxygen can be delivered via the machine if oxygen saturations are low, such as in COPD patients. Treatment with CPAP improves symptoms and may improve BP. Once patients are established on CPAP, they are likely to require it for life. However, compliance is poor because of the discomfort and noise. Other side-effects include rhinitis, nasal congestion, nasal bridge abrasions, claustrophobia and abdominal bloating.

• Intra-oral devices. Mandibular advancement devices may be worn at night; by holding the lower jaw forward, they increase the space behind the tongue and thus pharyngeal volume. This improves airflow. Alternatives include tongue-retaining devices, which hold the tongue forward. These devices need to be made individually and are useful in patients with mild OSAHS and for snorers.

• Pharmacological treatment

• Supplementary oxygen may benefit a small subset of patients, especially those living at altitude.

• Modafinil 200–400 mg daily (100 mg in the elderly) in the morning is a wake-promoting drug that is a potential adjunctive therapy. There are, however, ongoing debates regarding its efficacy.

Surgery

The aims of surgery are to increase the calibre of the pharynx and thus reduce pharyngeal resistance during sleep.

• Uvulopalatopharyngoplasty involves resection of the uvula, redundant retro-lingual soft tissue and palatine tonsillar tissue if present. The outcome is difficult to predict and it is not uniformly successful. Side-effects include post-operative pain, changes in voice and nasal regurgitation of food. In addition, patients are more likely to have difficulty with CPAP following surgery.

• Tonsillectomy may help patients with large tonsils.

• Tracheostomy is only used in patients with life-threatening apnoea in whom all other treatments have failed. It works by bypassing the obstruction.

Mandibular advancement, suprahyoid tensing, weight reduction surgery and nasal surgery have been used but there is insufficient evidence to recommend these treatments.

Driving

It is the doctor’s responsibility to inform the patient of the risks associated with continued driving, even if the diagnosis is clinically suspected but not yet formally diagnosed. Once a diagnosis is made, patients must be told verbally and in writing that it is their responsibility to inform the authorities.

Cystic fibrosis

Cystic fibrosis (CF) is a common recessively inherited disease with an incidence of 1 in 2500 and a calculated carrier frequency of 1 in 25 in the UK. It is more common in the Caucasian population.

Genetics

• CF is caused by a genetic mutation in the cystic fibrosis gene, which codes for a protein known as the cystic fibrosis transmembrane regulator (CFTR) protein. The gene is situated on the long arm of chromosome 7 (7q21.3→7q22.1).

• The commonest mutation in the European population is δF508, which is found in about 70% of affected cases and causes defective synthesis, defective maturation, blocked activation or defective function of the CFTR protein.

Pathophysiology

• The CFTR protein is essential for regulation and transport of electrolytes across the epithelial cell and intracellular membranes. In the presence of a mutant CFTR protein, chloride channels in the epithelial cells fail to open in response to elevated cyclic adenosine monophosphate (cAMP), leading to a decreased excretion of chloride ions and an increased reabsorption of sodium. As a result, less water is secreted into the airways, making the secretions more tenacious and viscous, more difficult to expectorate, and prone to infection. There is a continuous cycle of infection and inflammation, resulting in severe airway damage, bronchiectasis and loss of respiratory function.

• In the sweat ducts a similar process results in increased concentrations of sweat sodium and chloride, which is useful for diagnosis. Other organs involved include the pancreas, liver, biliary tree and gut.

Clinical features

Respiratory

The commonest presentation is with recurrent respiratory infections. A cough productive of purulent sputum in childhood eventually results in bronchiectasis and chronic airway obstruction. Increased breathlessness occurs as the disease develops. Other pulmonary complications include haemoptysis, pneumothorax and allergic bronchopulmonary aspergillosis. Eventually, cor pulmonale and respiratory failure develop. Nasal polyps and purulent sinusitis occur. Physical signs include clubbing, cyanosis, wheeze and scattered coarse crackles.

• Infection is a major problem. The bacteria are described in the treatment section. Colonization with Burkholderia cepacia is an increasing problem. It is multi-resistant and is spread by patient-to-patient contact, resulting in clinic segregation and the end of ‘CF holidays’.

• Clinically, one-third of patients have no change in symptoms or lung function, in one-third there is deterioration of lung function, and in one-third there is rapid deterioration resulting in death, even in patients with previous mild disease. The latter is known as ‘cepacia syndrome’.

• Viral infections also occur.

Gastrointestinal

About 85% of patients have pancreatic insufficiency from birth, resulting in malabsorption of fat and protein, and causing steatorrhoea and malnutrition. Infants and children may present with failure to thrive, diarrhoea or acute pancreatitis. Bowel obstruction secondary to meconium ileus (10%) can occur soon after birth; if it occurs later in life, it is known as ‘meconium ileus equivalent’ or ‘distal intestinal obstructive syndrome’ (DIOS). These patients present with volvulus or rectal prolapse. Biliary obstruction may result in cholecystitis, while chronic liver disease and cirrhosis can lead to portal hypertension, varices and splenomegaly. There is an increased prevalence of gallstones (especially cholesterol), reflux oesophagitis, peptic ulceration and gastrointestinal malignancy in CF.

Endocrine

There is gradual loss of pancreatic islet cells with the development of diabetes mellitus in about 11% of adult patients with CF. Diabetic ketoacidosis is rare. Male patients are infertile as a result of failure of the vas deferens and epididymis to develop. Female patients are able to conceive but their fertility may be reduced secondary to thickened cervical mucus.

Other

Puberty and skeletal maturity are delayed in many CF patients. Growth retardation, demineralization and osteoarthropathy may occur. Patients on long-term steroids may develop osteoporosis (p. 585).

Diagnosis and investigations

• Positive family history.

• Sweat test. This is the gold standard test for diagnosis of CF and must be performed in an experienced laboratory. Sweat is collected with pilocarpine iontophoresis; chloride levels with CF are > 60 mmol/L. The test can be repeated the day after receiving fludrocortisone 3 mg/m² for 2 days, when the sweat electrolyte concentration fails to suppress into the normal range in CF patients.

• Nasal potential difference. Normal values are −10 to −30 mV; in CF they are −34 to −60 mV. The test is performed in specialist centres.

• Genotyping. The diagnosis can be confirmed if two abnormal mutations (see above) are found.

• Radiology. A CXR or CT showing enlarged lung volumes and evidence of bronchiectasis supports a diagnosis of CF.

• Pancreatic insufficiency. This is demonstrated by a low stool elastase, abnormal pancreatic stimulation tests or fat malabsorption.

Treatment

The main aims of therapy should be to reduce exacerbations and hospitalization, enhance quality of life, prevent complications (particularly those associated with treatment) and improve mortality.

• Management. Management requires a multi-disciplinary team and is best provided in centres that specialize in CF.

• Clinic visits. Spirometry, blood tests (including vitamins and Aspergillus precipitins), CXR and a physiotherapy and dietician review should be carried out.

• Respiratory management. The aim of respiratory therapy is to decrease the number and pathogenicity of the infecting organism and suppress the lung’s hyper-responsive immune system. This can be achieved with antibiotics, anti-inflammatory agents, bronchodilators and airway clearance techniques. There is no good clinical evidence for the use of oxygen. In hypoxic patients, oxygen may delay or prevent the complications of chronic hypoxia, as it does in COPD. Oxygen may also be used during exercise.

Antibiotics

Routine sputum cultures and sensitivities guide antibiotic therapy. There is no overall consensus on the use of prophylactic antibiotics and duration of treatment.

• Acute respiratory exacerbations. IV antibiotics may be required if there is bacterial resistance to all orally administered antibiotics and if oral antibiotics fail to resolve symptoms. FEV₁ and CRP can be used to monitor response to therapy.

• Staph. aureus. Antibiotics (p. 77) such as continuous twice-daily oral flucloxacillin are usually prescribed if there is evidence of chronic colonization. Continuous prophylactic antibiotics are used in patients with frequent recurrent exacerbations. Despite prophylaxis, isolates of Staph. aureus require high-dose flucloxacillin and an additional antibiotic such as sodium fusidate, azithromycin/erythromycin, clindamycin or rifampicin. Patients with severe exacerbations should receive a second-generation cephalosporin, an aminoglycoside or vancomycin for at least 10–14 days.

• H. influenzae. All isolates should be regarded as pathogenic. A 2-week course of a macrolide or ampicillin should usually treat H. influenzae, although resistance is common. Persistent infection can be treated with cefuroxime, cefotaxime or ceftazidime, which should be continued until there is a sustained improvement in symptoms. Patients with repeated isolates despite the above measures should receive continuous oral antibiotics chosen according to sensitivities.

• Pseudomonas aeruginosa. Once isolates are identified, aggressive treatment must be initiated to delay chronic colonization. Strategies for the first isolation of P. aeruginosa include:

a) oral ciprofloxacin 750 mg twice daily plus nebulized colomycin 1–2 MU twice daily or tobramycin/gentamicin for 3 weeks; a 2-week course of IV antipseudomonal antibiotics is given, delaying the introduction of continuous antibiotic inhalation until subsequent positive cultures or

b) combined use of nebulized colomycin plus gentamicin or tobramycin, followed by intensive oral or IV antibiotic therapy. The exact duration of therapy is controversial. Many prescribe a 3-month course.

Management of chronic infection varies and includes a regular IV antibiotic, irrespective of clinical state. Antimicrobial sensitivities should be checked regularly for appropriate therapy.

a) A β-lactam in combination with an aminoglycoside is recommended as first-line in patients colonized with P. aeruginosa. Treatments should be given for 10–14 days but may need to be continued for longer if the patient has persistent symptoms.

b) Combination therapy reduces antibiotic resistance and can produce synergistic effects.

c) Oral ciprofloxacin can be used to treat mild exacerbation but is not sufficient as monotherapy if there is concomitant Staph. aureus infection.

d) Nebulized antipseudomonal antibiotic treatment, such as tobramycin 300 mg nebulized 12-hourly for 28 days, alternating with 28 days off, decreases P. aeruginosa colonization.

Many patients receive IV antibiotics at home, although a test dose is usually given in hospital first. Colomycin 1–2 MU twice daily can cause bronchoconstriction, so a test dose should always be given.

• Long-term management. Azithromycin 500 mg orally results in improved lung function and reduced exacerbations in patients colonized with P. aeruginosa. It has immunomodulatory and anti-inflammatory actions.

Bronchodilators

Airflow obstruction occurs in CF secondary to mucus plugs, bronchial wall thickening due to inflammation and airway destruction. In addition, bronchial hyper-reactivity is common. An improvement in FEV₁ can be seen in response to β₂ agonists such as salbutamol 2–4 puffs 2–4 times daily. Beta₂ agonists are also helpful prior to physiotherapy to facilitate clearance of airway secretions. Long-acting β₂ agonists should be reserved for patients who show clear benefit. Antimuscarinics, such as inhaled ipratropium bromide 2–4 puffs 2–4 times daily, can also be used.

Anti-inflammatory agents

• Corticosteroids. Corticosteroids, e.g. prednisolone 20 mg daily, can be helpful in patients with recurrent wheeze. Alternate-day prednisolone at a dose of 1 mg/kg or 2 mg/kg improves lung function over 24 months. Side-effects (p. 585) are many, so oral corticosteroids are not recommended for routine use. They are useful in patients with allergic bronchopulmonary aspergillosis (a common complication of CF) or resistant bronchospasm and in patients who are profoundly ill and not responding to maximal therapy. Osteopenia (p. 324) prophylaxis is given.

Airway clearance

• Recombinant DNase. DNase can be used to decrease sputum viscosity by cleaving long strands of DNA into smaller ones. The usual dose is dornase alfa 2500 U (2.5 mg) once daily via a jet nebulizer. The most common side-effect is voice alteration; others include pharyngitis, laryngitis, conjunctivitis and chest pain.

• Hypertonic saline. Short-term studies have shown benefit from inhaled hypertonic saline in concentrations of up to 7%. Beta₂ agonists should be inhaled prior to administration to limit bronchospasm.

• N-acetylcysteine. Although this can reduce sputum viscosity, there are no RCTs that show benefit from its use.

• NIV. This may be used to improve symptoms in chronic respiratory failure or as a bridge to lung transplantation. There is no evidence of a survival benefit.

• Lung transplantation. In CF FEV₁ can be used as a predictor of mortality. Once FEV₁ is < 30% predicted, mean survival is about 2 years and patients should be referred to a specialized unit for assessment for lung transplantation.

Respiratory complications

• Haemoptysis, which is usually mild, is common during exacerbations but massive haemoptysis also occurs (see Box 13.1).

• Allergic bronchopulmonary aspergillosis does not seem to affect the clinical course of most patients without an allergic component. A four-fold rise in total serum IgE, associated with IgG precipitins to Aspergillus and large fleeting changes on the CXR, favour allergic bronchopulmonary aspergillosis. Treatment is with corticosteroids. The role of itraconazole remains controversial; however, some transplant centres recommend its use for the suppression of Aspergillus prior to transplantation.

• Pneumothorax should be treated in the conventional way (p. 529). Pleural stripping procedures to prevent recurrence may be a contraindication to subsequent lung transplantation.

Extrapulmonary disease

Gastrointestinal disease

• Pancreatic enzyme supplements. Pancreatic enzyme supplements (enteric-coated microspheres and mini-tablets) contain lipase, protease and amylase, and are taken with meals and snacks. Most adults take 4–8 tablets with main meals and 2–4 tablets with snacks; however, they learn to adjust the dosage to achieve normal stools. Pancreatin is available in a number of different strengths depending on the amount of lipase in the preparation (e.g. 10 000, 25 000 and 40 000 units). Large-bowel strictures have been associated with these high-strength preparations. Increasing the jejunal pH with a protein pump inhibitor or an H₂ antagonist can improve absorption.

• Nutrition. Patients should eat a normal healthy diet with a high calorie intake. If they are unable to maintain an adequate weight, overnight enteral feeding via a gastrostomy or naso-gastric tube can be used. Good nutritional status (multi-vitamin preparation daily) is associated with an improved prognosis and dietitians should be involved. Vitamin supplementation is given with fat-soluble vitamins A, D, E and K 10 mg daily. Iron-deficient patients should receive iron.

• Distal intestinal obstruction (DIOS). DIOS can be treated with a naso-gastric tube for decompression, IV fluids, correction of electrolytes, and a combination of enemas and laxatives. Mineral oil and fleet enemas may be used initially, as may oral laxatives such as senna and lactulose. In severe cases, gastrograffin or N-acetylcysteine is given orally or naso-gastrically and as an enema. Surgery is sometimes required. As DIOS is a recurring condition, the patient is given regular pancreatic supplements and regular laxatives once symptoms are relieved.

Liver disease

• Ursodeoxycholic acid leads to clinical and biochemical improvement but does not modify the course of chronic liver disease.

• Gallstones may require a laparoscopic cholecystectomy. However, anaesthesia is not without risk due to lung disease.

Endocrine disease

• Diabetes. Over 65% of patients have glucose intolerance by the age of 25. A blood glucose test should be performed 3-monthly. CF patients with diabetes are encouraged to eat a high-calorie diet to maintain growth and weight; insulin should be adjusted accordingly.

• Fertility

• Women. Fertility is usually normal and the oral contraceptive pill works in normal doses. For pregnancy, ideally the FEV₁ should be > 50% predicted and patients with an FEV₁ < 30% should be advised against pregnancy. Partners should undergo DNA analysis prior to conception. Teratogenic drugs should be avoided. Quinolones, aminoglycosides and DNase should also be avoided.

• Men. Male patients (98%) are infertile. They should receive seminal analysis and their partner should have DNA analysis. In vitro fertilization using aspiration of sperm and intracytoplasmic gamete injection can be successful.

Non-pharmacological therapies

• Physiotherapy and airway clearance techniques. Physiotherapy should be performed at least twice a day and increased during exacerbations. A number of techniques and devices are employed including postural drainage with percussion, active cycle of breathing techniques and ‘huffing’. Mechanical devices are also used, such as flutter valves, external oscillation thoracic jackets, and low-and high-pressure positive expiratory pressure devices. Exercise should be used in combination with physiotherapy, as it can help mobilize secretions and is part of patients’ pulmonary rehabilitation.

• Other therapies

• Sodium chloride tablets. These may be required in hot weather due to excess sodium chloride loss in sweat.

• Gene therapy. This is currently unavailable, mainly due to problems with vectors and delivery, but may be a treatment of the future.

• Vaccinations. Patients should receive pneumococcal polysaccharide vaccine 0.5 mL IM and a yearly influenza vaccination.

Prognosis

The current average age of death of patients with CF is about 30 years old. However, the life expectancy of a newborn baby with CF today is about 45–50 years old without gene therapy.

Asthma

Asthma is a chronic inflammatory disorder of the airways. It has three characteristics: airway hyper-responsiveness to a wide range of stimuli, reversible airflow limitation and inflammation of the bronchi. It is more common in developed countries and the prevalence is increasing, particularly in the second decade of life when the disease affects 10–15% of the population.

Pathophysiology

The development of asthma is likely to be due to a combination of genetic predisposition and environmental factors. Extrinsic asthma usually occurs in atopic individuals and is associated with a positive skin prick reaction to common inhalant allergens. Late-onset asthma in adults can be due to sensitization to chemicals or biological products at work, aspirin intolerance or stimulation following β-adrenoceptor blockers prescribed for hypertension or angina. Intrinsic asthma is often described as ‘late-onset’, as it usually starts in middle age. However, many patients developing late-onset asthma have a positive skin prick test and on close questioning actually had childhood symptoms compatible with asthma.

Clinical features

Cough, wheeze, shortness of breath and chest tightness occur. These symptoms are intermittent, variable, worse at night and provoked by triggers such as exercise. Cough variant asthma is cough without a wheeze. There is often a family history of asthma or other atopic disease, such as eczema or hay fever, and patients often know triggers that worsen symptoms.

Physical signs

There may be no signs of airflow obstruction present at the time of examination. If wheeze is not present, the patient is asked to do a forced expiratory manœuvre, which may provoke an audible wheeze. During an exacerbation there may be tachypnoea, use of accessory muscles, wheeze and pulsus paradoxus, but in a severe exacerbation the chest may be silent (i.e. no airflow). Eczema, hives or allergic rhinitis may be present, indicating other allergic disease. Nasal polyps may be found with or without an associated history of aspirin sensitivity.

Churg–Strauss syndrome is a triad of asthma (with rhinitis), eosinophilia and systemic vasculitis.

Investigations

• Respiratory function tests can be normal (if there is no airflow limitation) or show an obstructive airflow picture. There is a reduced FEV₁ and a proportionally smaller reduction in FVC, resulting in an FEV₁:FVC ratio of < 75%. The PEFR is also reduced, but variability of PEFR and/or FEV₁ over time is diagnostic of asthma.

• PEFR meters are inexpensive and easy to use, and patients can therefore be taught to use them at home. Measurements of PEFR on waking (prior to taking a bronchodilator) and before bed (after a bronchodilator) are useful in showing diurnal variation (see Fig. 13.2). An increase of 20% in PEFR after inhalation of a short-acting β-agonist, e.g. 400 mcg of salbutamol via a metered dose inhaler or after a trial or oral steroids (prednisolone 30 mg/day for 14 days), occurs in asthma. Patients with severe chronic asthma may have little reversibility.

• Patients should be encouraged to keep PEFR diaries. Those with possible occupational asthma should record PEFR for at least 2 weeks at work and 2 weeks off work.

• Exercise tests show a reduction in PEF or FEV₁ after 6 mins exercise.

• Histamine or methacholine bronchial provocation tests can be used to indicate the presence of bronchial hyper-responsiveness.

• Blood and sputum tests may reveal increased eosinophils (> 0.4 × 10⁹/L) and total IgE in the peripheral blood, indicating an allergic tendency. Eosinophils may also be elevated in the sputum. Radioallergosorbent tests (RAST) measure minute quantities of IgE antibody in the blood, which are specifically directed at particular antigens. However, they are expensive and less sensitive than skin prick tests.

• CXR shows no characteristic features. It is done at diagnosis and always in a severe exacerbation to exclude a pneumothorax.

• Skin prick tests should be performed in all cases to try to identify an allergic cause. Allergen provocation tests are useful if occupational asthma is suspected.

• Exhaled nitric oxide measurement indicates the degree of inflammation and is used as a test for the efficacy of corticosteroids.

Management

The aims of treatment are symptom control, reduction of exacerbations and restoration of normal or best possible lung function with minimal side-effects from medication, minimal absences from work or school, and no limitation on physical activity. In children treatment is to enable a normal growth pattern to occur.

Non-pharmacological therapies

Patient education

Patients and their families should be given information about the condition. Clinicians should regularly check their patients’ inhaler technique and should teach patients to use a PEFR metre. Patients should learn to recognize signs of poor control, such as increasing need for short-acting β-agonists, increasing breathlessness on exertion and waking at night with symptoms.

Primary prophylaxis

There are currently no recommendations on pre-natal or post-natal allergen avoidance. Breast feeding should be encouraged, as there is an association with reduced infant wheeze. Microbial exposure — the ‘hygiene hypothesis’ — suggests that early exposure to microbial products may prevent allergic disease such as asthma by switching off allergic responses. There is currently no good evidence for this. Smoking during pregnancy and after the child is born is associated with increased infant wheeze.

Secondary prophylaxis

• Allergen avoidance. Measures should be taken to avoid causative allergens, such as pets, mould and certain foods, as this may be helpful in reducing the severity of disease. Measures to avoid house dust mites have been shown to be ineffectual. In observational studies asthma symptoms have improved after removal of a pet from the house. Aspirin, other NSAIDs and β-blockers should not be used.

• Smoking. Active and passive smoking should be avoided.

• Weight reduction. This is recommended in overweight asthma patients to improve symptoms.

Drug treatment (Table 13.3)

• The mainstay of treatment for asthma involves the use of inhaled therapies that are delivered as aerosols or powders directly into the lung; thus first-pass metabolism is avoided and unwanted systemic effects are minimized.

• Asthma treatment involves a stepwise approach, enabling patients and doctors to increase or decrease medication according to symptoms (Table 13.4). This approach is based on the appreciation that asthma is an inflammatory disease and that anti-inflammatory drugs should be started, even in mild cases. Short-acting bronchodilator therapy should be used to relieve breakthrough symptoms only. Increasing use of short-acting therapy implies deteriorating uncontrolled disease and the need to step up therapy. Treatment is stepped down if control is good.

Table 13.3 Drugs used in asthma *

Drug	Regimen
Inhaled drugs
Inhaled short-acting β₂ agonists
Salbutamol (called albuterol in USA) Aerosol and powder preparations available	100 mcg per puff (metered dose) Take 2 puffs as required
Terbutaline Powder and nebulized solutions available	500 mcg per puff Up to 4 times daily as required
Inhaled long-acting β₂ agonist
Formoterol Powder and aerosol formulations available	12 mcg twice daily Up to 24 mcg twice daily
Salmeterol	50 mcg (2 puffs or 1 blister) twice daily Up to 100 mcg (4 puffs or 2 blisters) twice daily
Inhaled corticosteroids
Beclometasone dipropionate Dry (in blisters) and aerosol preparations	50, 100 or 200 mcg per metered dose 100–400 mcg twice daily, rising to 0.4–1 mg twice daily
Budesonide Powder or aerosol preparations	100, 200, 400 mcg per metered dose 100–800 mcg twice daily
Fluticasone propionate	50 mcg metered dose (powder) and 125 mcg (aerosol) 100–500 mcg twice daily
Mometasone furoate	200–400 mcg (powder) as a single dose in evening or in 2 divided doses
Compound inhaled long-acting β₂ agonist and inhaled corticosteroids
Budesonide and formoterol	100/6 combination 1–2 puffs, up to 4 puffs daily (combinations in higher concentrations available 200/6 and 400/12)
Fluticasone and salmeterol	100, 250 or 500 mcg 50 mcg 1–2 puffs twice daily
Other inhaled preventer therapy
Antimuscarinic bronchodilators Ipratropium bromide Tiotropium	(Aerosol 20–40 mcg 3–4 times daily) (Nebulized solutions 250–500 mcg 3–4 times daily) 18 mcg (powder) once daily 2.5 mcg (solution) 2 puffs once daily
Sodium cromoglicate	10 mg (2 puffs) 4–8 times daily
Nedocromil sodium	2 puffs (4 mg) 2–4 times daily
Oral agents
Leukotriene modifiers
Montelukast	10 mg once daily (evening)
Zafirlukast	20 mg twice daily
Theophylline
Theophylline modified release	200–400 mg every 12 hours (tablets) 250–500 every 12 hours (capsules)
Aminophylline	225 mg (tablets) twice daily, rising to 450 mg twice daily if necessary
Corticosteroids
Prednisolone	5 mg tablets 30–60 mg daily for acute asthma attack
β₂ agonists
Salbutamol	2–4 mg 3–4 times daily
Terbutaline	2.5 mg 3 times daily
Steroid-sparing agents, e.g. methotrexate, ciclosporin	Specialist centres only

* See Table 13.4.

Table 13.4 The stepwise management of asthma

Step	PEFR	Treatment
1 Occasional symptoms, less frequent than daily	100% predicted	As-required short-acting β₂ agonists If used more than once daily, move to step 2
2 Daily symptoms	≤ 80% predicted	Regular inhaled preventer therapy Anti-inflammatory drugs: inhaled low-dose corticosteroids up to 800 mcg daily. LTRAs, theophylline and sodium cromoglicate are less effective If not controlled, move to step 3
3 Severe symptoms	50–80% predicted	Inhaled corticosteroids and long-acting inhaled β₂ agonist Continue inhaled corticosteroid Add regular inhaled LABA If still not controlled, add either LTRA, modified-release oral theophylline or β₂ agonist If not controlled, move to step 4
4 Severe symptoms uncontrolled with high-dose inhaled corticosteroids	50–80% predicted	High-dose inhaled corticosteroid and regular bronchodilators Increase high-dose inhaled corticosteroids up to 2000 mcg daily Plus regular LABAs Plus either LTRA or modified-release theophylline or β₂ agonist
5 Severe symptoms deteriorating	≤ 50% predicted	Regular oral corticosteroids Add prednisolone 40 mg daily to step 4
6 Severe symptoms deteriorating in spite of prednisolone	≤ 30% predicted	Hospital admission

LABA, long-acting β₂ agonist; LTRA, leukotriene receptor agonist; PEFR, peak expiratory flow rate.

Step 1: Mild intermittent asthma

These patients have infrequent symptoms and should use a short-acting β₂ agonist, such as a salbutamol inhaler 100–200 mcg (1–2 puffs), as required. Beta₂ agonists should only be used for breakthrough symptoms and are a useful guide to changes in severity of asthma. If a patient is using two or more canisters of a β₂ agonist a month (> 10–12 puffs a day), this suggests poorly controlled disease. Beta₂ agonists are very effective for symptom relief but have no effect on underlying disease.

Ipratropium bromide, an antimuscarinic bronchodilator, is used for short-term relief in chronic asthma 20–40 mcg 3–4 times daily by inhaler.

Step 2: Regular preventer therapy

Patients should be moved to step 2 if they are using their short-acting β₂ agonist more than 3 times a week, if they have nocturnal symptoms more than once a week, or if they have had an exacerbation in the last 2 years requiring systemic corticosteroids or nebulized bronchodilators.

• Inhaled corticosteroids are the most effective preventers. The usual starting dose for beclometasone dipropionate is 100–400 mcg twice daily. The dose should be titrated to the lowest possible that controls symptoms. When changing between beclometasone dipropionate and budesonide, a 1 : 1 ratio should be assumed. Fluticasone 100–500 mcg twice daily, mometasone 200–400 mcg as a single dose and ciclesonide 80–320 mcg daily as a single dose are also available. Inhaled steroids are the first-line preventer therapy.

• Sodium cromoglicate and nedocromil sodium prevent activation of many inflammatory cells, especially mast cells, eosinophils and epithelial cells. It is difficult to predict who will benefit from them, but they are less effective ‘preventers’ than inhaled corticosteroids. Sodium cromoglicate is given by aerosol inhalation 10 mg (2 puffs) 4 times a day, increased to 6–8 times a day in severe cases. The dose of nedocromil sodium is 4 mg (2 puffs) daily.

• Leukotriene receptor antagonists inhibit the cysteinyl L1 receptor, one of the principal asthma mediators. They may be beneficial in aspirin-induced asthma, exercise-induced asthma or associated rhinitis, particularly if used in addition to an inhaled corticosteroid. Montelukast 10 mg daily in the evening and zafirlukast 20 mg twice daily are the most common leukotriene receptor antagonists used.

• Theophylline is a bronchodilator and sustained-release preparations are used in combination with inhaled corticosteroids in some cases of asthma. Modified release theophyllines include Slo-Phyllin 250–500 mg, Nuelin SA 250–500 mg and Uniphyllin Continus 200–400 mg, all 12-hourly. Brand names must be stated on prescription. Theophyllines have a narrow therapeutic window and interact with a number of other drugs. Plasma levels should be between 10 and 20 mg/L for optimal response.

Step 3: Add-on therapy

If 400–800 mcg a day of inhaled steroid fails to control symptoms with good compliance, a trial of add-on therapy is used, instead of increasing inhaled corticosteroid dose. The add-on therapy of choice is a long-acting β₂-agonist (LABA); when used in addition to inhaled corticosteroids, these agents have been shown to improve lung function and symptoms in symptomatic patients taking low- and moderate-dose inhaled corticosteroids. Choices include salmeterol 50 mcg (2 puffs) twice daily, increased up to 100 mcg (4 puffs) twice daily in severe disease, or formoterol 12 mcg 1–2 times daily, increased to 24 mcg daily in more severe disease. If there is an improvement but there are still symptoms, the LABA should be continued and the inhaled corticosteroid dose increased to 800 mcg a day. LABAs and inhaled corticosteroids can be given as combination therapy, which is more convenient for the patient. A combination of fluticasone and salmeterol and a combination of budesonide and formoterol are available. If there is no improvement in symptoms after addition of a LABA, it should be discontinued and the inhaled corticosteroid dose increased to 800 mcg daily. If control is still inadequate, one of the following is added: leukotriene receptor antagonists, modified-release oral theophylline or modified-release oral β₂ agonist.

Step 4: Persistent poor control

If there is persistent poor control despite the combination of a short-acting β₂ agonist as required, moderate-dose inhaled corticosteroid 800 mcg daily and add-on therapy (usually a LABA), one of the following can be used:

• Increase inhaled corticosteroids to 2000 mcg a day (monitor for side-effects).

• Do a 6-week sequential trial of one of the following: leukotriene receptor antagonist, modified-release oral theophylline or modified-release oral β₂ agonist.

• If the trial is ineffective, stop the medication; if inhaled corticosteroid is used, reduce to the original dose.

Step 5: Continuous or frequent use oral corticosteroids

Prednisolone is the oral corticosteroid of choice and should be used at the lowest dose that controls symptoms. Patients taking long-term steroids or 3–4 courses a year are at increased risk of side-effects (p. 324). Patients receiving steroids for more than 3 months should be prescribed a long-acting bisphosphonate to prevent osteoporosis. BP and blood glucose should be checked regularly. Methods of trying to decrease oral steroids include maximizing other therapy and using maximal doses of inhaled corticosteroids. Immunosuppressants (steroid-sparing agents), such as methotrexate, ciclosporin or oral gold, can be tried for 3 months.

Stepping down treatment

Patients who are well controlled for 2–3 months should start decreasing their therapy. This should be done slowly and, where possible, the patient should be maintained on the lowest dose of inhaled steroid that controls symptoms. Reduction should be considered every 3 months and the steroid dose should be reduced by 25–50% each time.

Recombinant humanized monoclonal antibodies

Recombinant humanized monoclonal antibodies (omalizumab) that form complexes with free IgE, blocking its interaction with mast cells and basophils, have been developed. However, although clinical trials have shown benefit in patients with severe asthma despite corticosteroids, omalizumab is not regularly prescribed. Omalizumab is given subcutaneously 2–4 times weekly.

Management of acute exacerbations of asthma

The best strategy for management of acute exacerbations of asthma is early recognition and prevention. Patients should have an action plan and know how to identify the onset of an exacerbation. The signs of an onset include worsening PEFR, increasing symptoms or greater use of inhaled short-acting β₂ agonists. Patients should, at this stage, avoid precipitating factors, use inhaled β₂ agonists for symptom relief and start on a course of oral corticosteroids. If there is no improvement or they are getting worse, they should immediately seek medical help.

History, examination and evaluation

Patients often present with increasing shortness of breath, wheeze, chest tightness or cough. Those at increased risk of severe acute exacerbations of asthma can be identified in the history. Previous near-fatal asthma attacks requiring ICU admission, previous hospital admissions within the last year, previous attacks requiring corticosteroids, a need for three or more classes of drug for asthma, increased use of β₂ agonists (more than 2 canisters a month), known brittle asthma and repeated A&E attendance within the last year indicate patients who are at risk. Patients who are non-compliant with treatment, fail to attend hospital appointments, usually self-discharge from hospital or have any psychological or behavioural illness are also at risk of developing severe exacerbations of asthma.

Investigations

• CXR should be performed to exclude a pneumothorax or consolidation.

• PEFR is used to stratify patients according to disease severity (see above), and to inform decisions as to intensity of treatment and whether patients should be treated in hospital or at home. Measurements should be repeated regularly to gauge response to therapy. Normal values vary according to size and age but a peak flow < 200 usually indicates severe airflow obstruction. Often patients with exacerbations are too breathless to perform a PEFR.

• ABGs should be measured in patients requiring hospital admission who have oxygen saturations < 92% or features of acute severe or life-threatening asthma. A normal PaCO₂ is a sign of life-threatening asthma and impending respiratory failure, possibly requiring endotracheal intubation and mechanical ventilation.

• Pulse oximetry should be used to monitor oxygen saturations throughout admission.

Treatment

• Assess the patient. Tachycardia, a high respiratory rate and an inability to speak in sentences indicate a severe attack.

• Apply high-flow oxygen (usually 40–60%), to maintain saturation > 92%.

• If PEFR is < 150 L/min (in adults), administer nebulized salbutamol 5 mg or terbutaline 10 mg — driven via oxygen. (Use a low-reading meter, as ordinary meters measure from 60 L/min upwards.)

• Give 200 mg IV hydrocortisone or prednisolone 40–50 mg orally.

In severe asthma not responding to the initial nebulizer:

• Repeat the salbutamol or terbutaline nebulizer at 15–30 min intervals or give continuous nebulization of salbutamol at 5–10 mg/hour (a special nebulizer is required).

• Add nebulized ipratropium bromide 0.5 mg 4–6-hourly to the nebulized salbutamol/terbutaline.

• Measure ABGs; if PaCO₂ is > 7 kPa, consider ventilation. If PaCO₂ is normal, monitor closely, as mechanical ventilation may be required.

• Take a CXR to exclude pneumothorax.

• If there is no improvement, magnesium sulphate IV 1.2–2 g over 20 mins, salbutamol IV 3–20 mcg/min, terbutaline IV 1.5–5 mcg/min or aminophylline loading dose (if not on maintenance oral therapy) 5 mg/kg over 20 mins, followed by a maintenance dose of 0.5 mg/kg/hour can be used.

• Corticosteroids. Steroid therapy is given to reverse the underlying airway inflammation. It is associated with an improved outcome in exacerbations of asthma and should be given as early as possible (Fig. 13.2). IV steroids (hydrocortisone 400 mg daily in 4 divided doses) are usually given. Oral steroids (prednisolone 40–50 mg daily) are as effective, provided the patient is able to swallow. Oral steroids should be continued until resolution of acute symptoms and a return to usual daily activities, and until a PEFR within 80% of the patient’s best or predicted has been obtained. They do not need to be tapered if the course is shorter than 3 weeks, provided patients are on an appropriate dose of inhaled corticosteroids.

• Antibiotics. There is no evidence that antibiotics are beneficial, as exacerbations are usually caused by viruses. Antibiotics should be reserved for cases where bacteria are cultured from the sputum or blood, or there is consolidation on CXR.

• IV fluids and correction of electrolytes. Many patients are dehydrated and require fluid replacement. They may develop hypokalaemia due to β₂ agonists and this should be corrected.

• Helium oxygen mixtures. These can be useful in exacerbations of asthma although evidence is lacking.

• Intensive care. Patients should be referred to ICU for possible endotracheal intubation and mechanical ventilation if they are not responding to treatment, i.e. there is persistent hypoxia, hypercapnia, confusion, drowsiness, deteriorating PEFR, increasing acidosis or respiratory arrest. NIV is not usually used in patients with severe exacerbations of asthma and should only be in an HDU/ICU setting.

Fig. 13.2 Diurnal variability in PEFR in asthma, showing the effect of steroids. M, morning; N, noon; E, evening.

Discharge

In moderate asthma, patients may quickly improve with nebulized therapy and may not require hospital admission. Their regular treatment should be increased and they should commence a 2-week course of oral prednisolone. If they are safe to discharge, follow-up must be arranged.

Hospitalized patients should be established on a drug regimen that they can safely take at home, and have a PEFR > 75% best or predicted and a diurnal variation of < 25% prior to discharge. Follow-up by a respiratory physician should be arranged.

Management of catastrophic sudden severe (brittle) asthma

This is a variant of asthma in which patients with well-controlled asthma suddenly develop severe asthma attacks and are at risk of sudden death. These patients require a detailed management plan for an exacerbation. On developing a wheeze they should go immediately to the nearest hospital and may require admission straight to ICU. Oxygen, resuscitation equipment, prednisolone 60 mg and nebulized β₂ agonists should be kept at home and at work. Patients should wear a MedicAlert bracelet and carry two self-injectable 0.3 mg adrenaline (epinephrine) syringes with them at all times.

Pneumonia

Pneumonia is an inflammation of the substance of the lungs. It can be classified by site (e.g. lobar, diffuse, bronchopneumonia) or by aetiological agent (e.g. bacterial, viral, fungal, aspiration, or due to radiotherapy or allergic mechanisms). Pneumonias can be community-acquired (CAP; commonest Strep. pneumoniae), hospital-acquired (often Gram-negative bacteria) or ventilator-associated (p. 548).

Causes

Strep pneumonia often follows a viral infection with influenza (p. 50) or parainfluenza viruses. Precipitating factors include cigarette smoking, alcohol excess, bronchiectasis, bronchial obstruction (e.g. carcinoma) or inhalation from oesophageal obstruction. IV drug users can contract a Staph. aureus infection and patients who are immunosuppressed (e.g. those having AIDS or receiving treatment with cytotoxic agents) develop pneumonia; the organisms include Pneumocystis jiroveci, Mycobacterium avium intracellulare and cytomegalovirus.

Community-acquired pneumonia (CAP)

The majority of patients with CAP are treated outside hospital with amoxicillin (see Fig. 13.4) but they should be reviewed at 48 hours. If the mild case has not improved or CAP is very severe, the patient should be admitted to hospital. There is a significant mortality, particularly in those over 65 years old. Overall mortality for those admitted to hospital is about 5%.

Fig. 13.4 Algorithm for management of community-acquired pneumonia.

Strep. pneumoniae accounts for the majority of cases and for two-thirds of the mortality.

Clinical features

This varies according to the infecting agent (Table 13.5) or the immune state of the patient.

Table 13.5 Clinical features of community-acquired pneumonia

Pneumonia	Clinical features
Streptococcus pneumoniae	Patient is ill with a high temperature (39.5°C). Dry cough becomes productive, with rusty-coloured sputum after 1–2 days. Labial herpes simplex. Breathlessness. Pleuritic pain. Crackle and wheezes with signs of consolidation and pleural rub. CXR is shown in Fig. 13.3
Mycoplasma pneumoniae	Common in young. Cycles of 3–4 years. Headaches and malaise often precede chest symptoms by 1–5 days. Rare extrapulmonary complications include myocarditis, pericarditis, erythema multiforme, haemolytic anaemia, meningoencephalitis. Recovery usually in 10–14 days. Can be protracted, with cough and X-ray changes lasting for weeks; relapses occur. Lung abscesses and pleural effusions rare
Legionella pneumophila	Sporadic or in outbreaks in e.g. hotels or foreign travel, or in immunocompromised. Middle to old age. Males > females 2 : 1. Incubation period 2–10 days. Malaise, myalgia, headache, fever (up to 40°C), rigors. Nausea, vomiting, diarrhoea, abdominal pain. Can be acutely ill with mental confusion and other neurological signs. Haematuria, occasional renal failure and deranged liver function tests. Breathlessness with initially dry cough, which can become productive and purulent. CXR slow to resolve
Viral pneumonias	Uncommon in adults — influenza A virus or adenovirus infection is commonest cause. May predispose patients to bacterial pneumonia Cytomegalovirus pneumonia is seen in immunocompromised patients (p. 3) Influenza A (H5N1) (p. 50) Management is as for ARDS (p. 549)
Other pneumonias
Haemophilus influenzae	Frequent cause of exacerbation of chronic bronchitis and can cause pneumonia in COPD patients. Pneumonia is diffuse or confined to one lobe. No special features to separate it from other bacterial pneumonias
Staphylococcus aureus	Rarely causes pneumonia, except after preceding influenzal viral illness. Patients are very ill. Patchy consolidation in one or more lobes, which break down to form abscesses. Pneumothorax, effusion and empyemas are frequent. Septicaemia develops with metastatic abscesses in other organs
Staphylococcal septicaemia	Areas of pneumonia (septic infarcts) frequently seen in IV drug users, and in patients with central catheters being used for parenteral nutrition. Infected puncture site is source of staphylococcus. Pulmonary symptoms often few but breathlessness and cough occur and CXR reveals areas of consolidation. Abscess formation is frequent

ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; SARS, severe acute respiratory syndrome.

Following a radiological (Fig. 13.3) and microbiological (if possible) diagnosis of the pneumonia, an early assessment of the severity of the pneumonia must be made in order to admit the patient to a medical ward or to ICU. The CURB-65 (Box 13.3) is a useful guide for doing this.

Fig. 13.3 Chest X-ray showing lobar pneumonia.

Referral to ICU will be necessary if there is a failure to respond with a CURB-65 score of over 3 or if there is progressive hypercapnia, persistent hypoxia, severe acidosis, shock and depression of consciousness.

Investigations

All hospitalized patients should have the following:

• CXR. Repeat the CXR 6 weeks after discharge unless complications occur.

• Strep. pneumoniae. Consolidation can lag behind clinical signs.

• Mycoplasma. Usually one lobe is involved but infection can be bilateral.

• Legionella. There is lobar and then multi-lobar shadowing, with the occasional small pleural effusion. Cavitation is rare.

• Blood tests. FBC, U&E, LFTs and CRP.

• Strep. pneumoniae. White cell count is > 15 × 10⁹/L (90% polymorphonuclear leucocytosis); ESR > 100 mm/hour; CRP > 100 mg/L.

• Mycoplasma. White cell count is usually normal.

• Legionella. There is lymphopenia without marked leucocytosis, hyponatraemia, hypoalbuminaemia and high serum levels of liver aminotransferases.

• Other tests

• Sputum culture.

• Blood culture.

• Pulse oximetry and ABG analysis.

Specific tests for individual organisms are as follows:

• Pneumococcal antigen

• Counter-immunoelectrophoresis (CIE) of sputum, urine and serum is 3–4 times more sensitive than sputum or blood cultures.

• Urinary antigen test detects C-polysaccharide. This is rapid and unaffected by antibiotics; sensitivity is 65–80% and specificity about 80%.

• Mycoplasma

• Measure serum antibodies (IgM and IgG) in acute and convalescent samples. Cold agglutinins are present in 50% of cases. Other methods of identification include complement-fixing antibodies and PCR.

• A kit for PCR is becoming available.

• NASBA tests are becoming available.

• Chlamydia antibodies are sought by immunofluorescent complement fixation.

Management

Management of CAP is shown in Fig. 13.4.

The patient in hospital should be re-evaluated regularly by the nursing staff, depending on the severity of the illness (see MEWS, p. 2).

• Antibiotic therapy. Antibiotics should be started as soon as possible, preferably in the A&E department. The choice of the antibiotic is inevitably empirical and directed towards Strep. pneumoniae, as this is the commonest organism. Acquired antibiotic resistance is a concern but is still rare in the UK.

• Mild uncomplicated CAP (CURB-65 0–1) is treated in the community with amoxicillin 500 mg 3 times daily (in the UK), or with clarithromycin 500 mg twice daily or doxycycline 200 mg followed by 100 mg daily (if penicillin-sensitive) for 5–7 days. The newer quinolones (e.g. levofloxacin 500 mg 1–2 times daily or moxifloxacin 400 mg once daily for 10 days) are used by some but increasing resistance is a concern and these agents are best reserved for patients with co-morbidities.

• More severe infections require amoxicillin 500 mg–1 g 3 times daily plus clarithromycin 500 mg twice daily. If oral therapy is contraindicated, IV amoxicillin 500 mg 3 times daily or benzyl penicillin 1.2 g 4 times daily plus IV clarithromycin 500 mg twice daily is used. In patients with high severity pneumonia (CURB 65 3–5), co-amoxiclav 1.2g 6–8-hourly is combined with IV clarithromycin 500 mg twice daily.

• If Staph. aureus infection is suspected or is proven on culture, IV flucloxacillin 1–2 g every 6 hours by slow IV injection or infusion ± sodium fusidate 500 mg 3 times daily if over 50 kg by IV infusion should be added. Quinolones are recommended for those intolerant of penicillins or macrolides. Community-acquired meticillin-resistant Staph. aureus (CA-MRSA) can be treated with vancomycin or linezolid.

• Parenteral antibiotics should be switched to oral once the temperature has settled for a period of 24 hours and provided there is no contraindication to oral therapy.

• Mycoplasma pneumonia is treated with a macrolide, e.g. clarithromycin 500 mg twice daily (or azithromycin) for 7–10 days, or a tetracycline, e.g. doxycycline 100 mg twice daily.

• H. influenzae pneumonia is treated with oral amoxicillin 500 mg 3 times daily.

• Legionella pneumophila pneumonia is usually treated with one of the macrolides, azithromycin being the drug of choice. Quinolones are also effective and rifampicin can be added in very ill patients. Mortality can be up to 30% in elderly patients but most patients recover fully.

• Oxygen. All patients with hypoxaemia, acidosis and hypotension should receive oxygen. The aim is to keep the saturation (SaO₂) > 92% and a PaO₂ > 8 kPa (60 mmHg). If there is no history of COPD with hypercapnia, 35% humidified O₂ can be given. NIV (p. 485) may be useful. Criteria for referral to ICU are given above and referral should not be delayed.

• Fluid balance/nutritional support. Oral intake should encouraged but, if this is not possible, then IV fluids need to be given. Nutrition may be a problem for a longer illness and will need to be addressed (p. 542).

Hospital-acquired pneumonia

• It is commonly treated with co–amoxiclav 1.2 g 3 times daily but meropenem 1 g 3 times daily is also used.

• Co-morbidities require more aggressive antibiotic therapy. Management is the same as for severe CAP, once appropriate samples for culture and sensitivities have been taken.

• Gram-negative bacteria are common and aminoglycosides (e.g. gentamicin 5 mg/kg) are often added.

• Patients with chronic chest infection and others in whom Pseudomonas infection is suspected should receive an anti-pseudomonal penicillin (e.g. piperacillin plus tazobactam) or ciprofloxacin 200–400 mg IV over 30–60 mins or ceftazidime 2 g bolus IV 8-hourly.

• Immunosuppressed patients may require very high-dose broad-spectrum antibiotics, as well as antifungal and antiviral agents.

• Aspiration pneumonia is relatively common in hospital and usually involves infection with multiple bacteria, including anaerobes. The oral route is usually inappropriate in these patients. A combination of metronidazole (IV or rectal) and co-amoxiclav is recommended.

Tuberculosis

Tuberculosis (TB) is a systemic granulomatous disease caused by Mycobacterium tuberculosis. It is more common in developing countries, in particular sub-Saharan Africa and South-East Asia. However, in the developed countries, following many years of steady decline, the incidence of TB is rising due to AIDS, the growing use of immunosuppressive drugs and increased immigration of people from areas of high endemicity. TB is transmitted between people by aerosol and therefore the most common site of infection is the lung.

• Primary TB is the first infection with TB and occurs in those without immunity. It is usually subpleural and a small lung lesion known as the Ghon focus may be seen in the mid- or upper zones within 4 weeks of infection. Hilar lymphadenopathy may be present as the tubercle bacilli drain into the lymphatics. Primary TB is often asymptomatic; there may be a mild cough, wheeze or erythema nodosum, and a transient pleural effusion. The bacilli will continue to proliferate and spread until an effective cell-mediated immune response is mounted (3–8 weeks), the spread of infection is arrested and the tuberculin skin test is positive. Tubercle bacilli remain dormant within calcified lesions but are capable of reactivation.

• Post-primary TB refers to all forms of TB that occur after the first few weeks of primary infection when immunity to Mycobacterium has developed. It occurs as a result of reactivation of a previously dormant focus in patients who have infection with HIV, diabetes mellitus, kidney disease, malnutrition, silicosis, malignancy and other forms of immunosuppression. Common symptoms include cough (often productive), fever, night sweats and weight loss.

• Disseminated TB occurs if there is unchecked proliferation and spread of bacteria due to a failure of the host to mount an effective cell-mediated immune response. Miliary TB is a form of disseminated TB in which the lesions on CXR resemble millet seeds.

TB is an AIDS-defining illness. It may arise in a patient with HIV from rapid progression of primary infection, reactivation of disease or re-infection (p. 115).

Diagnosis

• Sputum staining. Acid-fast bacilli in the sputum can be seen by staining with Ziehl–Neelsen (ZN) stain; alternatively, an auramine-phenol fluorescent test is performed. For patients who are unable to expectorate, a bronchoscopy can be performed and a bronchoalveolar lavage (BAL) or bronchial washing taken from the affected lobe.

• Transbronchial biopsies. These can be obtained for histological and microbiological assessment. Specimens for microbiology should be placed in 0.9% saline and not formalin. The presence of granulomas is virtually diagnostic of TB.

• Culture. Sputum is cultured on Ogawa or Lowenstein–Jensen medium for 4–8 weeks. Liquid cultures are often used, as they have shorter culture times. Antibiotic sensitivity should be performed on all cultures.

• Pleural fluid and biopsy. Pleural fluid culture is positive for M. tuberculosis in about 40% of patients, whereas pleural biopsy culture is positive in about 60% of patients with pleural TB. Pleural fluid adenosine deaminase is elevated in tuberculous pleural effusions and may aid diagnosis.

• Imaging. The typical CXR findings are upper lobe infiltrates with or without cavitations (Fig. 13.5). The infiltrates are often fibronodular and irregular. CT scans are sensitive at identifying earlier disease and may show clusters of nodules or a ‘tree in bud’ appearance.

Fig. 13.5 Chest X-ray showing TB of the left upper lobe with cavitation (arrowed).

Treatment (p. 86)

Treatment must include more than one drug to which the organism is susceptible; drugs must be taken at the appropriate doses and must be taken regularly; and therapy must be continued for a sufficient period of time.

Treatment can be taken at home. However, patients who are ill, smear-positive, highly infectious (especially with multi-drug resistant TB), non-compliant or those in whom the diagnosis is uncertain may require a short period of hospitalization.

• The initial phase should consist of four drugs — rifampicin, isoniazid and pyrazinamide plus ethambutol or rarely streptomycin for 2 months. Ethambutol can be omitted in patients who are thought to be at low risk for isoniazid resistance. This regimen is for patients with previously untreated TB, who are HIV-negative, are not immunosuppressed and have not been in contact with anyone with drug-resistant TB. Neither should they have come from an area with a high prevalence of drug-resistant TB. The drugs are best given as a combination preparation to aid compliance.

• The continuation phase starts after drug sensitivities are known (6–8 weeks) and should consist of two drugs to which the organism is susceptible, given for a further 4 months. Rifampicin and isoniazid are usually standard treatment for adults with pulmonary TB (for doses see p. 87). Pyridoxine 10 mg daily is not routinely required but should be given as prophylaxis against isoniazid neuropathy in patients at increased risk, such as diabetics, alcoholics and those with dietary deficiencies.

• Directly observed therapy (DOT) is used for patients who are unlikely to be compliant with treatment, such as the homeless, those dependent on alcohol and IV drug users. Special clinics are used and patients are observed taking their tablets. Some clinics use incentives such as free meals and cash payments to improve attendance. DOT can be given daily but intermittent regimens such as 3 times weekly are often more convenient. However, the effectiveness of DOT therapy is variable and compliance is still an issue. For doses, see p. 87.

Pregnant patients

These women should be given standard treatment. Pyrazinamide and streptomycin should be avoided. Patients can breast feed normally whilst taking anti-tuberculous chemotherapy. Those on anti-tuberculous therapy containing rifampicin should be informed of the reduced effectiveness of the oral contraceptive pill.

Treatment of extrapulmonary TB (see specific chapters)

In patients with infected peripheral nodes, bones and joints or pericarditis, the treatment is as for pulmonary TB for 6 months but is extended if the infection is more advanced or extensive. In tuberculous meningitis, isoniazid and rifampicin are given for 9 months, supplemented with pyrazinamide, streptomycin or ethambutol for the first 2 months. Adjuvant corticosteroids for 3 weeks are recommended.

Drug-resistant organisms

Primary drug resistance occurs in people exposed to others with drug-resistant organisms. Secondary drug resistance is the development of resistance after initial drug sensitivity and usually occurs as a result of poor compliance.

WHO define two categories of drug resistance:

• multi-drug resistance (MDR) — isoniazid, rifampicin

• extensive drug resistance (XDR) — isoniazid, rifampicin, quinolones and at least one of the following second-line drugs: capreomycin and amikacin.

MDR and XDR are major therapeutic problems worldwide, having a high mortality and occurring mainly in HIV-infected patients. Transmission of MDR-TB to healthcare workers and to other patients poses a major public health problem. The drug treatment of suspected drug resistance in both HIV-positive and HIV-negative patients is as follows:

• With MDR use at least three drugs to which the organism is sensitive.

• With resistance to one of the four main drugs, use the other three.

Therapy should be continued for up to 2 years, or for at least 12 months after negative cultures in HIV-positive patients. Second-line drugs available for treatment of resistant M. tuberculosis infection are capreomycin, cycloserine, clarithromycin, azithromycin, ciprofloxacin, ofloxacin, kanamycin, amikacin, moxifloxacin and rifabutin.

Monitoring response to therapy

Patients with smear-positive TB should have regular (every 1–2 weeks) sputum examination for acid-fast bacilli with smear and culture. Once sputum becomes negative for acid-fast bacilli, patients should have a monthly sputum examination until culture is also negative. This is the most reliable indicator of a response to therapy. If, after 3 months of treatment, symptoms have not resolved or sputum smear or culture is still positive, either there is non-compliance with medication or drug resistance has immerged. Specialist TB nurses and health visitors should monitor patients’ compliance with treatment. If drug resistance occurs, the addition of a single drug is not recommended. If new drugs are added, at least two or preferably three should be commenced which the patient has not already received. Subsequent treatment should be fully supervised.

Follow-up

Patients should receive baseline blood tests, including renal and liver function, prior to commencing therapy. They should be informed of the possible side-effects of treatment and the indications for stopping medication and seeking advice. They should be seen in clinic regularly for the duration of chemotherapy to ensure symptoms are improving and that there are no adverse drug reactions. A CXR should be taken at the end of treatment.

Chemoprophylaxis

In tuberculous disease the skin test is usually positive and there is either radiological evidence and/or symptoms of TB. Latent tuberculous infection is when a patient is asymptomatic, with a normal CXR but a positive tuberculin skin test. The Mantoux test and whole-blood interferon (IFN)-γ assay are used to check for TB infection (current or past). The Mantoux test is an intradermal injection of tuberculin purified protein derivative (PPD). A second visit is required for the test to be read (induration > 10 mm is positive) at 72 hours. Whole-blood IFN-γ assay requires only a blood test and remains negative after bacille Calmette–Guérin (BCG).

Chemoprophylaxis consists of isoniazid 300 mg daily for 6 months or isoniazid 300 mg + rifampicin 600 mg daily for 3 months. Chemoprophylaxis should only be prescribed after active disease has been fully ruled out. In the USA there are annual screening tests for asymptomatic patients who are thought to be at high risk and who would benefit from treatment of latent TB. These include patients with HIV, residents of long-term care facilities, those with medical conditions that increase the risk of active TB and people with ongoing contact with patients who may have active TB, such as healthcare workers.

Chemoprophylaxis is used in the following groups of patients:

• those with CXR appearances compatible with previous TB who are due to start immunosuppressive agents, such as anti-tumour necrosis factor (TNF)α, or treatment that has an immunosuppressive effect, such as renal dialysis or corticosteroids

• tuberculin-positive children identified in the BCG schools programme who have a history of contact with infectious TB or have been resident in a country with a high prevalence of TB within the last 2 years

• adults between the ages of 16 and 34 found at new immigrant screening without BCG history

• adults with latent TB who have risk factors for progression to active TB disease including those with documented recent tuberculin conversion, those with a history of untreated TB, and those with chronic disease and immunosuppressive disease

• close contacts of patients with active disease and a positive tuberculin test

• patients with HIV who have been in close contact with a person who has active TB; this should be irrespective of the tuberculin test, as in HIV there may be a loss of response to tuberculin.

Contact tracing

Contact tracing helps to prevent the spread of disease and to identify new cases at an early stage. All close family members, other individuals who share a kitchen or bathroom, or close contacts at school or work are screened. Those with symptoms are thoroughly investigated for TB and asymptomatic individuals are sent for CXR and a tuberculin skin test.

Diffuse parenchymal lung disorders

Diffuse parenchymal lung disorders (DPLD; also known as interstitial lung disease) are a heterogeneous group of disorders consisting of over 200 entities and accounting for about 15% of respiratory clinical practice. They are characterized by chronic inflammation and progressive fibrosis of the pulmonary interstitium.

Clinical features

Patients may be asymptomatic or present in one of the following ways:

• progressive onset of increasing shortness of breath or a persistent non-productive cough

• pulmonary symptoms associated with another disorder, such as an autoimmune rheumatic disease

• an abnormal CXR or abnormal lung function or spirometry, usually showing a restrictive defect

• rarely, haemoptysis, pleurisy or a pneumothorax.

• Signs. Clubbing suggests idiopathic pulmonary fibrosis, DPLD secondary to rheumatoid arthritis or asbestosis. Auscultation reveals fine end-inspiratory or more sporadic crackles and wheezes. There may be signs of pulmonary hypertension in patients with severe disease, or extrapulmonary signs, e.g. ocular features in sarcoidosis or vasculitis; skin disease may suggest a rheumatological disorder; erythema nodosum sarcoidosis or a mononeuritis multiplex may indicate a vasculitis.

Investigations

• Routine blood tests are rarely diagnostic but may aid the process.

• FBC, including differential, may show anaemia, e.g. chronic disease (e.g. rheumatoid arthritis), an iron deficiency secondary to alveolar haemorrhage, or peripheral blood eosinophilia (> 1.5 × 10⁹/L) secondary to pulmonary eosinophilia or drug reactions.

• IgE level is useful to discriminate between chronic forms of pulmonary eosinophilia in which IgE levels will be low and allergic forms.

• Hypercalcaemia might be present in patients with sarcoidosis.

• ACE concentrations are helpful in monitoring sarcoid treatment, although raised levels are not diagnostic of sarcoidosis.

• Serological tests. Antinuclear antibodies may be present in autoimmune rheumatic diseases. Antineutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement antibodies point towards a systemic vasculitis. Serum precipitins suggest a hypersensitivity pneumonitis secondary to farming or pigeon breeding.

• Raised ESR and hypergammaglobulinaemia may be present but are not diagnostic.

• Pulmonary function tests may be normal initially, but as disease progresses they show a restrictive pattern: reduction in total lung capacity (TLC), residual volume (RV), functional residual capacity (FRC) and flow rate (reduced FEV₁ and FVC with a normal or increased ratio).

• ABGs may be normal or show hypoxia with a respiratory acidosis. Carbon dioxide retention is unusual until end-stage disease. If ABGs are normal, exercise assessment must be performed, as arterial oxygenation frequently falls on exercise.

• Imaging with CXR and high-resolution computed tomography (HRCT) should be carried out. All radiology should be compared to previous films if available.

• Echocardiography assesses for pulmonary hypertension and the presence of cardiac failure that may be contributing to the diffuse shadowing on CXR.

• ECG to look for conduction defects, e.g. sarcoidosis.

Invasive diagnostic procedures

• Bronchoscopy and bronchoalveolar lavage (BAL) do not usually have a role in diagnosis or disease monitoring but are helpful if a surgical biopsy is not possible.

• Transbronchial biopsy taken during bronchoscopy. Biopsies are most useful in granulomatous diseases, such as sarcoidosis, and malignant disease, such as lymphangitis carcinomatosis.

• Lung biopsy is frequently required when the diagnosis remains uncertain.

• Surgical biopsy can be obtained from more than one site, guided by the HRCT results. Two approaches are commonly used: video-assisted thoracoscopic surgery (VATS) or a limited thoracotomy. VATS is preferred, as it is less invasive and is associated with lower morbidity and mortality.

Monitoring

Regular assessment of symptoms, spirometry, exercise tolerance, oxygenation and radiological changes is needed in order to follow progression of disease and response to therapy.

General treatment

This varies according to the underlying aetiology. Infection, malignancy and pulmonary oedema should be excluded. Histological confirmation is required in most cases prior to commencement of specific treatment. In general, drug regimens usually include corticosteroids, azathioprine, cyclophosphamide or mycophenolate.

Sarcoidosis

• This multi-system granulomatous disorder of unknown aetiology usually presents with bilateral hilar lymphadenopathy, pulmonary infiltrations, and skin and eye lesions.

• It commonly affects young adults, particularly women, with the peak incidence in the third and fourth decades.

• More than 90% of patients have involvement of the lungs and thoracic lymph nodes.

• The most common presentation is with respiratory symptoms, such as cough, dyspnoea and chest pain, or abnormalities found on the CXR (50%).

• Peripheral lymphadenopathy occurs in 5%, fatigue or weight loss in 5%, and fever in 4%.

• Extrapulmonary manifestations include:

• skin disorders: erythema nodosum, lupus pernio — 10%

• ocular lesions: anterior uveitis, posterior uveitis, conjunctivitis, retinal lesions, uveoparotid fever (bilateral uveitis, parotid enlargement with occasional development of facial nerve palsy) and keratoconjunctivitis sicca

• metabolic manifestations: hypercalcaemia (10% of cases) and hypercalciuria, which can result in the development of renal calculi and nephrocalcinosis

• CNS disorders: rare — 2%; can cause chronic meningoencephalitis, spinal cord lesions, cranial nerve palsies, polyneuropathy and myopathy

• bone and joint involvement: arthralgia and bone cysts

• hepatosplenomegaly

• cardiac involvement: rare (3%), including arrhythmias, conduction defects and cardiomyopathy with congestive cardiac failure.

Diagnosis

• CXR characteristically shows bilateral hilar lymphadenopathy (BHL). The differential diagnosis for BHL includes lymphoma, TB, enlarged pulmonary arteries, metastatic carcinoma and histoplasmosis. There are four stages of pulmonary involvement based on the radiological stage of the disease. The stage of disease provides prognostic information.

• Stage I: BHL alone

• Stage II: BHL with pulmonary infiltrates

• Stage III: pulmonary infiltrates without BHL

• Stage IV: fibrosis.

• HRCT chest shows enlarged hilar and mediastinal lymph nodes, and diffuse lung involvement with nodules along the bronchi and blood vessels and in sub-pleural regions. There is beading and irregular thickening of broncho-vascular bundles and bronchial wall thickening. Fibrosis and traction bronchiectasis occur late in the disease.

• Other investigations are as for DPLD. The tuberculin test is negative in 80% of cases but is of no diagnostic value. Serum ACE is raised in 75% of cases.

Treatment

• Patients with no symptoms, normal lung function and only hilar lymphadenopathy on CXR (stage I) require no treatment. Spontaneous resolution commonly occurs within a year or two of diagnosis.

• Corticosteroids are the mainstay of treatment for patients with infiltrates on CXR and abnormal lung function (stages II and III) and those with chronic progressive disease (stage IV). Systemic steroids should also be prescribed for ophthalmic symptoms not responding to topical steroids, cardiac or neurological symptoms, and hypercalcaemia.

• Prednisolone is usually started at 30 mg a day for 6 weeks and, in those who respond, treatment is gradually tapered down to 5 or 10 mg a day or alternate-day treatment. Treatment should be continued for a minimum of 1 year, keeping patients on the lowest possible dose that controls symptoms.

• Severe or persistent erythema nodosum and uveoparotid fever due to sarcoid will respond to a 2-week course of prednisolone 5–15 mg daily.

• Topical steroids can be beneficial for skin lesions, uveitis/iritis and nasal polyps. There is no clear evidence for the benefit of inhaled steroids.

• Ophthalmic reviews are carried out regularly for patients with eye signs, as uveitis can occasionally lead to blindness.

• Other forms of treatment clearly benefit some patients and drugs can be useful as steroid-sparing agents, although the evidence remains unclear. Methotrexate can be prescribed in chronic or refractory sarcoid at a dose of 10–25 mg once a week. Side-effects include gastrointestinal symptoms, hepatotoxicity, pulmonary oedema, interstitial pneumonitis and pulmonary fibrosis. Hydroxychloroquine can be used in acute and chronic disease at a dose of 200–400 mg/day. Side-effects include gastrointestinal disturbances, visual changes and retinal damage, headache and skin reactions. Azathioprine is used in chronic and refractory disease at a dose of 50–200 mg/day; for side-effects, see Table 6.3. Cyclophosphamide is given in chronic and refractory cases at a dose of 50–150 mg/ day orally; side-effects include gastrointestinal disturbances, haemorrhagic cystitis and haematological toxicity.

Mortality is usually < 5% in the UK but can be up to 10% in black Americans.

• Brain natriuretic peptide levels are raised in patients with pulmonary hypertension.

• Respiratory function tests show a restrictive pattern (p. 517).

• Invasive diagnostic procedures — see p. 517.

• Treatment. Treatment is with prednisolone, azathioprine and N-acetylcysteine unless there are contraindications. Domiciliary oxygen is given for disabling disease. If there is no response, other therapies such as cyclophosphamide may be tried.

• Prognosis. The median survival is about 5 years.

Hypersensitivity pneumonitis

Hypersensitivity pneumonitis (previously called extrinsic allergic alveolitis) is due to inhalation of organic dusts, e.g. microbial spores found in contaminated vegetable matter like straw or hay (farmer’s lung), or in the feathers or excreta of birds, e.g. pigeons (bird fancier’s lung). Fever, malaise, cough and shortness of breath occur after exposure.

• Diagnosis. Lung function tests show a restrictive pattern and precipitating antibodies to the antigen are found in the serum.

• Treatment. Treatment is by removal of the antigen, if possible, dust masks or, in acute cases, prednisolone.

Drugs and radiation-induced respiratory reactions

Drugs can produce a wide variety of respiratory problems. Mechanisms include direct toxicity (e.g. bleomycin), immune complex formation with arteritis, hypersensitivity and autoimmunity. TB reactivation is seen with immunosuppressive drugs, e.g. monoclonal antibodies. Table 13.6 gives some drugs and their respiratory reactions. For further interactions see www.pneumotox.com.

Table 13.6 Some drug-induced respiratory reactions

Disease	Drugs
Bronchospasm	Penicillins, cephalosporins
	Sulphonamides
	Aspirin/NSAIDs
	Monoclonal antibodies, e.g. infliximab
	Iodine-containing contrast media
	β-Adrenoceptor-blocking drugs (e.g. propranolol)
	Non-depolarizing muscle relaxants
	IV thiamine
	Adenosine
Diffuse parenchymal lung disease and/or fibrosis	Amiodarone
	Anakinra (interleukin-1 receptor antagonist)
	Nitrofurantoin
	Paraquat
	Continuous oxygen
	Cytotoxic agents (many, particularly busulfan, CCNU, bleomycin, methotrexate)
Pulmonary eosinophilia	Antibiotics (penicillin, tetracycline)
	Sulphonamides, e.g. sulfasalazine
	NSAIDs
	Cytotoxic agents
Acute lung injury	Paraquat
Pulmonary hypertension	Fenfluramine, dexfenfluramine, phentermine
SLE-like syndrome including pulmonary infiltrates, effusions and fibrosis	Hydralazine
	Procainamide
	Isoniazid
	Phenytoin
	ACE inhibitors
	Monoclonal antibodies
Reactivation of TB	Immunosuppressant drugs, e.g. steroids
Reactivation of TB	Biological agents, e.g. tumour necrosis factor blockers

CCNU, chloroethyl-cyclohexyl-nitrosourea (lomustine); NSAIDs, non-steroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus.

Irradiation damage following radiotherapy can cause a radiation pneumonitis. Patients present with breathlessness and a dry cough. They have a restrictive lung defect and corticosteroids can be used in the acute stage.

Pulmonary hypertension

Definition

Pulmonary hypertension is defined as a mean pulmonary arterial pressure of > 25 mmHg at rest. It may present spontaneously with no apparent underlying disease (idiopathic pulmonary hypertension) or it can occur in association with other diseases, e.g. COPD, pulmonary thromboembolism or left-sided heart disease (mitral stenosis).

Classification WHO

Group I is characterized by increased pulmonary artery pressure, i.e. pulmonary artery hypertension (PAH), followed by right ventricular failure. Groups II–V are classified as having pulmonary hypertension (PH).

• Group I: PAH. This consists of idiopathic, familial and pulmonary artery hypertension due to disease of the small muscular arterioles. The latter include autoimmune rheumatic diseases, congenital systemic to pulmonary shunts (e.g. congenital heart disease), portal hypertension, HIV infection and drug toxicity (e.g. dexfenfluramine). This group also includes diseases associated with significant venous or capillary involvement, e.g. pulmonary veno-occlusive disease.

• Group II: PH owing to left-sided heart disease. This describes increased pulmonary venous pressure due to left ventricular dysfunction or mitral valve disease.

• Group III: PH owing to lung diseases and/or hypoxia. This includes COPD, interstitial lung disease of sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude and developmental abnormalities.

• Group IV: Chronic thromboembolic pulmonary hypertension (CTEPH). This includes thrombosis of the proximal or distal pulmonary vasculature and also non-thrombotic pulmonary embolism (tumour, parasites, foreign material).

• Group V: PH with unclear multi-factorial mechanisms. This includes sarcoidosis, Langerhans’ cell histiocytosis, lymphangioleiomyomatosis and compression of pulmonary vessels (adenopathy, tumour or fibrosing mediastinitis).

Pathophysiology of cor pulmonale

There is increased pulmonary vascular resistance due to changes in the pulmonary vessels caused by remodelling, vasoconstriction, hypoxia and acidosis with thrombosis. This eventually leads to PH and an increase in right ventricular afterload, with right ventricular hypertrophy and heart failure.

Clinical features and diagnosis of PH

These are mainly breathlessness, fatigue, chest pain and syncope. A similar classification to the New York scheme for heart failure (p. 417) is used for assessment.

• CXR, ECG and transthoracic echocardiography are used to assess severity of PH; appropriate investigations to exclude causal problems is essential.

• HRCT is used to assess lung fields and size of the pulmonary artery.

• Cardiac MR with contrast provides high-quality images of the pulmonary circulation.

Treatment

This involves addressing any underlying disease, with diuretics for fluid overload and anticoagulation with warfarin for pulmonary thromboembolism. O₂ therapy is necessary for patients with hypoxia at rest or after exercise.

Vasodilatation therapy is being used in PAH; bosentan, sildenafil and inhaled iloprost have all shown some benefit. Atrial septostomy and lung transplantation is used for patients unresponsive to therapy.

N.B. There is no evidence for the use of angiotensin receptor blockers, ACE inhibitors or α-blockers.

Pulmonary embolism (PE) (pulmonary thromboembolism)

Thrombi from systemic veins, e.g. pelvic, abdominal or deep femoral veins, or rarely from the right heart can dislodge and embolize into the pulmonary arterial system. Thrombi can form due to sluggish blood flow, local injury, compression of the vein or a hypercoaguable state. Tumour or fat can also embolize.

Embolism results in the lung tissue being unperfused but ventilated, producing an intrapulmonary dead space and resulting in impaired gas exchange.

Clinical features

• Small to medium PEs cause a sudden onset of breathlessness, with pleuritic chest pain and haemoptysis.

• Multiple recurrent PEs can lead to breathlessness over weeks or months. They can cause fatigue, syncope on exertion and occasionally angina. The signs are those of PH.

• Massive PE is rare but a medical emergency. The patient may suddenly collapse with severe central chest pain, shock (pale and sweaty), tachypnoea and tachycardia. There may be cyanosis and syncope, and death can occur rapidly. On examination the patient is hypotensive, with signs of right ventricular overload (a right ventricular heave and a loud pulmonary second sound).

The revised Geneva score (Table 13.7) gives the clinical probability of a PE.

Table 13.7 Revised Geneva score for the clinical prediction of a pulmonary embolism

Criterion	Score
Risk factors
Age > 65 years	+1
Previous deep venous thrombosis or pulmonary embolism	+3
Surgery or fracture within 1 month	+2
Active malignancy	+2
Symptoms
Unilateral leg pain	+3
Haemoptysis	+2
Clinical signs
Heart rate (bpm)
75–94	+3
≥ 95	+5
Pain on leg deep vein palpation and unilateral oedema	+4
Clinical probability
Low	0–3
Intermediate	4–10
High	≥ 11